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Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals

Abstract

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

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Acknowledgements

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers U01MH092221 (MT) and U01MH092250 (PJM, RP, and MW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the EMBARC National Coordinating Center at UT Southwestern Medical Center and the Data Center at Columbia University and Stony Brook University.

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Correspondence to Tsafrir Greenberg.

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Financial disclosures are included below: JCF receives royalties from Guilford Press. TD has received research funding from the Depressive and Bipolar Disorder Alternative Treatment study, the International OCD Foundation, NARSAD, NIMH, TSA, and Tufts University; he has received honoraria, consultation fees, and/or royalties from Boston University, BrainCells, Catalan Agency for Health Technology Assessment and Research, Clintara, LLC, the Massachusetts General Hospital Psychiatry Academy, the Massachusetts Medical Society, the National Association of Social Workers-Massachusetts, the National Institute on Drug Abuse, NIMH, Oxford University Press, Systems Research and Applications Corporation, and Tufts University; and he has participated in research funded by the Agency for Healthcare Research and Quality, Cyberonics, Forest Research Institute, Janssen Pharmaceuticals, Medtronic, NIA, NIH, Northstar, Shire Development, and Takeda. MST received research funding from NIMH, Brain and Behavior Research Foundation, and fees from Otsuka for service on a study DSMB. BK has received research funding/grants from Evotec, Forest Pharmaceuticals, Johnson and Johnson, Naurex, NIMH, Pfizer, Rexahn, and Targacept. MGM received funding from the NIMH and consulting fees from Janssen and Otsuka Pharmaceuticals. MAO receives royalties from Research Foundation of Mental Hygiene for the commercial use of the Columbia-Suicide Severity Rating Scale. Her family owns stock in Bristol-Myers Squibb. MF reports lifetime disclosures of research support from Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; 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.; 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 Complemen tary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); 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; 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; has been on the advisory board and/or consultant for Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmace uticals; 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; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; Clexio Biosciences; 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; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labophar m 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.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; 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.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals, LLC; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; 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; has received compensation for speaking or publishing 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; has equity holdings in Compellis and PsyBrain Inc and hold patents 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). MW received funding from the NIMH, NARSAD, the Sackler Foundation, and the Templeton Foundation, and royalties from the Oxford University Press, Perseus Press, the American Psychiatric Association Press, and MultiHealth Systems. MT has consulted for or served on the advisory board of AcademyHealth, Alkeremes Inc., Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, ACI Clinical, Alto Neuroscience Inc, Axsome Therapeutics, American Society of Clinical Psychopharmacology (speaking fees & reimbursement), American Psychiatric Association (Deputy Editor for American Journal of Psychiatry), Avanir Pharmaceuticals, Boegringer Ingelheim, Janssen Pharmaceutical, Jazz Pharmaceutical, Johnson & Johnson Pharmaceutical Research & Development, Lundbeck Research USA, Medscape, Navitor, Otsuka America Pharmaceutical Inc., Perception Neuroscience Holdings, Pharmerit International, SAGE Therapeutics, Takeda Global Research; has received grants from Cancer Prevention and Research Institute of Texas, National Institute of Mental Health, National Institute of Drug Abuse, Johnson & Johnson, Janssen Research and Development LLC, and Patient-Centered Outcomes Research Institute; and has received editorial compensation from Healthcare Global Village, Engage Health Media, and Oxford University Press. MLP received an honorarium from Sunovion Pharmaceuticals. All other authors report no financial relationships with commercial interests.

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Greenberg, T., Fournier, J.C., Stiffler, R. et al. Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals. Mol Psychiatry 25, 1526–1536 (2020). https://doi.org/10.1038/s41380-019-0490-5

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