Novel Molecular Targets for
Mood Disorders and Psychosis
PROCEEDINGS OF A WORKSHOP
Lisa Bain, Chanel Matney, and Clare Stroud, Rapporteurs
Forum on Neuroscience and Nervous System Disorders
Board on Health Sciences Policy
Health and Medicine Division
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by contracts between the National Academy of Sciences and 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 Integrative 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 Neuroscience 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 & Development, 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 Foundation Autism Research Initiative; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; and 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: 978-0-309-68590-0
International Standard Book Number-10: 0-309-68590-7
Digital Object Identifier: https://doi.org/10.17226/26218
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Suggested citation: 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. https://doi.org/10.17226/26218.
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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
MORGAN SHENG, Broad Institute of the Massachusetts Institute of Technology and Harvard University
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 speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
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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.
ALAN LESHNER, American Association for the Advancement of Science (Emeritus)
HUSSEINI MANJI, Johnson & Johnson
JOHN NGAI, BRAIN Initiative
STEVEN PAUL, Karuna Therapeutics
SARAH SHEIKH, Takeda Pharmaceuticals International, Inc.
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
Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments 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:
Although the reviewers listed above provided many constructive comments 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.
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Contents
Organization of the Proceedings
The Lived Experience of Schizophrenia
Serendipity in Psychiatric Drug Discovery
Unmet Needs in Treating Psychiatric Disorders
3 TARGETING GLUTAMATE RECEPTORS FOR TREATMENT-RESISTANT DEPRESSION
A Brief History of Ketamine and Esketamine
Clinical and Patient Experiences with Intranasal Esketamine
Ketamine’s Mechanism of Action on Synapses, Circuits, and Systems
Strategies to Improve the Antidepressant Effects of Ketamine
Identifying a Biomarker to Help Predict Responses to Ketamine
4 TARGETING GABA RECEPTORS TO TREAT POSTPARTUM DEPRESSION
Clinical and Patient Experiences with Brexanolone
Brexanolone’s Mechanism of Action
Convergence of Mechanisms: Ketamine and Brexanolone
mTOR Signaling—A Target for Depression and Psychosis
Serotonin 5-HT2 Receptor Agonists for Mental Disorders
TAAR1/5-HT1AR Agonists in Schizophrenia Treatment
M1/M4 Acetylcholine Muscarinic Receptor Targeting for Psychosis
NMDA Modulation to Improve Negative and Cognitive Symptoms in Schizophrenia
The Added Complexity of Polypharmacy
6 REGULATORY CONSIDERATIONS FOR THE NEXT GENERATION OF PSYCHIATRIC DRUGS
7 ETHICAL AND LEGAL PRINCIPLES RELATED TO THE CLINICAL USE OF PSYCHOACTIVE DRUGS
Translating Ethical Principles to the Clinical Use of Psychoactive Drugs
Psilocybin Therapy: Clinical Use and Legal Challenges
8 POTENTIAL NEXT STEPS AND FUTURE OPPORTUNITIES
Novel Approaches Needed to Address Unanswered Questions
Final Thoughts on the Future of Therapy for Psychiatric Disorders
Acronyms and Abbreviations
| 5-HT | 5-hydroxytryptamine (also known as serotonin) |
| ABC-CT | Autism Biomarkers Consortium for Clinical Trials |
| AD | antidepressant |
| AMP-Schizophrenia | Accelerating Medical Partnerships–Schizophrenia |
| AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
| BDNF | brain-derived trophic factor |
| BNSS | Brief Negative Symptom Scale |
| BRAIN | Brain Research Through Advancing Innovative Neurotechnologies |
| CDC | Centers for Disease Control and Prevention |
| CGI-S | Clinical Global Impressions Severity |
| D | dopamine receptor |
| DEA | Drug Enforcement Administration |
| ECT | electroconvulsive therapy |
| FDA | Food and Drug Administration |
| FNIH | Foundation for the National Institutes of Health |
| GABA | gamma-aminobutyric acid |
| GABR | gamma-aminobutyric acid receptor |
| HDRS | Hamilton Depression Rating Scale |
| LSD | lysergic acid diethylamide |
| M | muscarinic receptor |
| mAChR | muscarinic acetylcholine receptor |
| MADRS | Montgomery-Asberg Depression Rating Scale |
| MAO | monoamine oxidase |
| MIT | Massachusetts Institute of Technology |
| mPFC | medial prefrontal corex |
| mTOR | mechanistic target of rapamycin |
| NAMI | National Alliance on Mental Illness |
| NHS | National Health Service |
| 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 tomography |
| PPD | postpartum depression |
| PTSD | posttraumatic stress disorder |
| PV | parvalbumin |
| REMS | risk evaluation and mitigation strategy |
| SNRI | serotonin and norepinephrine reuptake inhibitor |
| SSRI | selective serotonin reuptake inhibitor |
| TAAR1 | trace amine-associated receptor 1 |
| TBI | traumatic brain injury |
