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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Page xiii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Lisa Bain, Chanel Matney, and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by contracts between the National Academy of Sci- ences and the Alzheimer’s Association; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (1R13FD005362-06) and National Institutes of Health (NIH) (75N98019F00769 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Inte- grative Health, National Eye Institute, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, NIH Blueprint for Neu- roscience Research, and NIH BRAIN Initiative; Department of Veterans Affairs (36C24E20C0009); Eisai, Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Develop- ment, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Sanofi; Simons Founda- tion Autism Research Initiative; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; and the Wellcome Trust. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/26218 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2021 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and M ­ edicine. 2021. Novel molecular targets for mood disorders and psychosis: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/26218. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the char- ter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was estab- lished in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

PLANNING COMMITTEE ON NOVEL MOLECULAR TARGETS IN MOOD DISORDERS AND PSYCHOSIS1 LINDA BRADY (Chair), National Institute of Mental Health TIFFANY FARCHIONE, Food and Drug Administration DAVID GRAY, Cerevel Therapeutics MAGALI HAAS, Cohen Veterans Bioscience STUART HOFFMAN, Department of Veterans Affairs JOHN KRYSTAL, Yale University School of Medicine CARLOS LARRAURI, National Alliance on Mental Illness HUSSEINI MANJI, Johnson & Johnson SHARON MATES, Intracellular Therapies STEVE PAUL, Karuna Therapeutics Inc. MORGAN SHENG, Broad Institute of the Massachusetts Institute of Technology and Harvard GREG SIMON, Kaiser Permanente Washington Health Research Institute ILINA SINGH, University of Oxford Health and Medicine Division Staff CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders CHANEL MATNEY, Program Officer (from October 2020) SHEENA M. POSEY NORRIS, Program Officer KIMBERLY SUTTON, Senior Program Assistant (until March 2021) ANDREW M. POPE, Senior Director, Board on Health Sciences Policy 1  The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing s­ peakers. The responsibility for the published Proceedings of a Workshop rests with the workshop ­rapporteurs and the institution. v PREPUBLICATION COPY—Uncorrected Proofs

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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 FRANCES JENSEN (Co-Chair), University of Pennsylvania JOHN KRYSTAL (Co-Chair), Yale University SUSAN AMARA, National Institute of Mental Health ELINE APPELMANS, Foundation for the National Institutes of Health RITA BALICE-GORDON, Muna Therapeutics KATJA BROSE, Chan Zuckerberg Initiative EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai SARAH CADDICK, Gatsby Charitable Foundation MARIA CARRILLO, Alzheimer’s Association EDWARD CHANG, University of California, San Francisco TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University ROBERT CONLEY, Eli Lilly and Company (until May 2021) BILLY DUNN, Food and Drug Administration MICHAEL EGAN, Merck Research Laboratories MICHELLE ELEKONICH, National Science Foundation NITA FARAHANY, Duke University JOSHUA GORDON, National Institute of Mental Health MAGALI HAAS, Cohen Veterans Bioscience RAMONA HICKS, One Mind (until May 2021) RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs JONATHAN HORSFORD, National Institute of Dental and Craniofacial Research YASMIN HURD, Icahn School of Medicine at Mount Sinai STEVEN HYMAN, Broad Institute of the Massachusetts Institute of Technology and Harvard University MICHAEL IRIZARRY, Eisai, Inc. PUSHKAR JOSHI, One Mind (from June 2021) GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke STORY LANDIS, National Institute of Neurological Disorders and Stroke (Emeritus) 1  The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

ALAN LESHNER, American Association for the Advancement of Science (Emeritus) HUSSEINI MANJI, Johnson and Johnson JOHN NGAI, BRAIN Initiative STEVEN PAUL, Karuna Therapeutics, Inc. SARAH SHEIKH, Takeda Pharmaceuticals International DAVID SHURTLEFF, National Center for Complementary and Integrative Health JOHN SIMS, Eli Lilly and Company (from June 2021) JOHN SPIRO, Simons Foundation Autism Research Initiative (from May 2021) SANTA TUMMINIA, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse ANDREW WELCHMAN, Wellcome Trust DOUG WILLIAMSON, Lundbeck RICHARD WOYCHIK, National Institute of Environmental Health Sciences STEVIN ZORN, MindImmune Therapeutics, Inc. Health and Medicine Division Staff CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders CHANEL MATNEY, Program Officer (from October 2020) SHEENA M. POSEY NORRIS, Program Officer EDEN NELEMAN, Senior Program Assistant (from July 2021) KIMBERLY SUTTON, Senior Program Assistant (until March 2021) PHOENIX WILSON, Senior Program Assistant (until October 2020) CHRISTIE BELL, Finance Business Partner (from October 2020) ANDREW M. POPE, Senior Director, Board on Health Sciences Policy viii PREPUBLICATION COPY—Uncorrected Proofs

Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: STEPHEN GODWIN, National Academies of Sciences, Engineering, and Medicine JAMIE MAGUIRE, Tufts University School of Medicine BRYAN L. ROTH, University of North Carolina School of Medicine CARLOS A. ZARATE, JR., National Institute of Mental Health Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by LESLIE Z. BENET, University of California, San Francisco. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. ix PREPUBLICATION COPY—Uncorrected Proofs

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Contents ACRONYMS AND ABBREVIATIONS xiii 1 INTRODUCTION AND BACKGROUND 1 Workshop Objectives, 2 Organization of the Proceedings, 2 2 CURRENT DRUG DEVELOPMENT LANDSCAPE AND LIMITATIONS OF MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS 5 The Lived Experience of Schizophrenia, 6 Living with Depression, 7 Serendipity in Psychiatric Drug Discovery, 10 Unmet Needs in Treating Psychiatric Disorders, 12 3 TARGETING GLUTAMATE RECEPTORS FOR TREATMENT-RESISTANT DEPRESSION 13 A Brief History of Ketamine and Esketamine, 14 Clinical and Patient Experiences with Intranasal Esketamine, 15 Ketamine’s Mechanism of Action on Synapses, Circuits, and Systems, 17 Strategies to Improve the Antidepressant Effects of Ketamine, 20 Identifying a Biomarker to Help Predict Responses to Ketamine, 23 xi PREPUBLICATION COPY—Uncorrected Proofs

xii CONTENTS 4 TARGETING GABA RECEPTORS TO TREAT POSTPARTUM DEPRESSION 25 Clinical and Patient Experiences with Brexanolone, 26 Brexanolone’s Mechanism of Action, 28 Convergence of Mechanisms: Ketamine and Brexanolone, 29 5 EMERGING DRUG TARGETS 31 mTOR Signaling—A Target for Depression and Psychosis, 32 Serotonin 5-HT2 Receptor Agonists for Mental Disorders, 33 TAAR1/5-HT1AR Agonists in Schizophrenia Treatment, 35 M1/M4 Acetylcholine Muscarinic Receptor Targeting for Psychosis, 37 NMDA Modulation to Improve Negative and Cognitive Symptoms in Schizophrenia, 38 The Added Complexity of Polypharmacy, 38 6 REGULATORY CONSIDERATIONS FOR THE NEXT GENERATION OF PSYCHIATRIC DRUGS 41 The Approval of Esketamine, 43 The Approval of Brexanolone, 44 7 ETHICAL AND LEGAL PRINCIPLES RELATED TO THE CLINICAL USE OF PSYCHOACTIVE DRUGS 47 Translating Ethical Principles to the Clinical Use of Psychoactive Drugs, 48 Psilocybin Therapy: Clinical Use and Legal Challenges, 54 8 POTENTIAL NEXT STEPS AND FUTURE OPPORTUNITIES 55 Novel Approaches Needed to Address Unanswered Questions, 57 Final Thoughts on the Future of Therapy for Psychiatric Disorders, 59 APPENDIXES A REFERENCES 61 B WORKSHOP AGENDA 67 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations 5-HT serotonin ABC-CT Autism Biomarkers Consortium for Clinical Trials AMP-Schizophrenia Accelerating Medical Partnerships–Schizophrenia AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid BNSS Brief Negative Symptom Scale CDC Centers for Disease Control and Prevention CGI Clinical Global Impressions Scale D dopamine receptor ECT electroconvulsive therapy FDA Food and Drug Administration FNIH Foundation for the National Institutes of Health GABA gamma aminobutyric acid HAM-D Hamilton Depression Rating Scale LSD lysergic acid diethylamide xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv ACRONYMS AND ABBREVIATIONS M muscarinic receptor mAChR muscarinic acetylcholine receptors MAO monoamine oxidase inhibitors MIT Massachusetts Institute of Technology mTOR mechanistic target of rapamycin NAMI National Alliance on Mental Illness NIDA National Institute on Drug Abuse NIMH National Institute of Mental Health NMDA N-methyl-D-aspartate PAM positive allosteric modulator PANSS Positive and Negative Syndrome Scale PET positron emission topography PPD postpartum depression PTSD posttraumatic stress disorder REMS risk evaluation and mitigation strategy SSRI selective serotonin reuptake inhibitor TAAR1 trace amine-associated receptor PREPUBLICATION COPY—Uncorrected Proofs

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Mood disorders - including depression and bipolar disorder - are common, disabling, and potentially lethal disorders, characterized by a shortened lifespan from comorbid medical illness and rising suicide rates. Medications for these conditions have been shown to be insufficiently effective in the majority of people who take them, and there remains a tremendous unmet medical need. Recent advances towards understanding the mechanisms of action for psychiatric medicines have led to the identification of potential novel molecular targets and agents for treating mood disorders. While these promising avenues for further investigation have re-energized scientific research in this area, many open questions remain. In response to this interest, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders convened a workshop in March 2021, Novel Molecular Targets for Mood Disorders and Psychosis.

The goal of this workshop was to explore the landscape of novel pharmacologic treatments for psychiatric disorders, review the challenges and opportunities that have been highlighted by the development of recently approved drugs, and reflect on how to apply those lessons learned towards current and future efforts to identify and validate additional novel molecular targets. With a grounding in the personal experiences of patients living with depression and schizophrenia, workshop participants discussed the scientific, clinical, technological, regulatory, and ethical considerations of this topic. Examples of drug classes discussed in the workshop include antagonists for NMDA (N-methyl-D-aspartate) receptors and GABA (gamma-aminobutyric acid) receptors, as well as modulators for muscarinic and serotonergic receptors. This publication summarizes the presentations and discussions from the workshop.

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