Novel multi-modal methodology to investigate placebo response in major depressive disorder.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest Dr. Cusin has received consulting fees from Clexio, Compass Pathways, Janssen, and research funding from Livanova, Atai, NIMH, AFSP. Over the past 3 years, Dr. Pizzagalli has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceutical, Sage Therapeutics, Sunovion Pharmaceuticals, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Bird Foundation, Brain and Behavior Research Foundation, Dana Foundation, Millennium Pharmaceuticals, NIMH, and Wellcome Leap; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the human version of the probabilistic reward task through Harvard University. Dr. Maurizio Fava Reports 3-year disclosures as below - Research Support: Abbvie; Acadia Pharmaceuticals; Aditum Bio Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceuticals LLC; Axsome; Benckiser Pharmaceuticals, Inc.; BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge ScienceCorporation; Centrexion Therapeutics Corporation; Cybin IRL Limited; Damona Pharmaceuticals; EmbarkNeuro; Eliem Therapeutics LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Gerbera Therapeutics, Inc.; GH Research Ireland Limited; Happify; Johnson & Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Medpace, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; NeuraWell Therapeutics, Inc.; Neurocrine Biosciences, Inc.; Novaremed; Otsuka; Pfizer; Premiere Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Relmada Therapeutics Inc.; Shenox Pharmaceuticals; Stanley Medical Research Institute (SMRI); Takeda; University of Michigan; University of Florida Board of Trustees; Vistagen; WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; XW Pharma Ltd.; National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); and PCORI. Dr. Fava has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital, except for Revival Therapeutics (no longer in existence) and Sensorium Therapeutics. Speaking/Publishing: Lecture given at Global Medical Education, Inc. Mood Disorders Summit, November 2020. Stock/Other Financial Options: Equity Holdings: Compellis (no longer in existence); Neuromity; Psy Therapeutics; Revival Therapeutics (no longer in existence); Sensorium Therapeutics. Royalty/patent, other income: 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); patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven; and patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691) licensed to Nestle and for Compound for improving l-arginine bioavailability (US_11,655,210) licensed to DimeRx. Copyright 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), Anxiety Symptoms Questionnaire (ASQ), and SAFER; Belvoir; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. Dr. Jacob Hooker reports as COI Massachusetts Institute of Technology; ACS Publications; Eikonizo Therapeutics Co-Founder, Advisor; Sensorium Therapeutics Co-Founder, Advisor; Psy Therapeutics Consultant; Delix Therapeutics Advisor; Fuzionaire Diagnostics Advisor; Proximity Therapeutics. Advisor; Rocket Science, Advisor; Human Health, Advisor; Entheos Labs, Advisor. None of the other authors report COI.