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PREPUBLICATION COPY: UNCORRECTED PROOFS 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.

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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.

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.

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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 speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.

v PREPUBLICATION COPY—Uncorrected Proofs PREPUBLICATION COPY—Uncorrected Proofs 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 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:

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 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.

ix PREPUBLICATION COPY—Uncorrected Proofs PREPUBLICATION COPY—Uncorrected Proofs 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

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Introduction and Background1

Mental and substance use disorders are the third leading cause of disability in the United States, said Linda Brady, director of the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health (NIMH) (IHME, 2021). Of particular concern, she said, is that anxiety, mood, impulse control, and substance abuse disorders start at younger ages than most other disorders and often persist throughout the life span, resulting in a lifetime of suffering for many individuals. Onset during childhood and adolescence also highlights the importance of early intervention, said Brady (Casey et al., 2014). Mental illness has worsened during the 2020–2021 COVID-19 pandemic, said Samantha Meltzer-Brody, the Assad Meymandi Distinguished Professor and chair of the Department of Psychiatry at the University of North Carolina. The prevalence of anxiety and depression, as defined by the Centers for Disease Control and Prevention (CDC), increased 3- to 4-fold, she said (Czeisler et al., 2020). Yet, despite this high burden, new drug approvals for psychiatric disorders in recent years have been scant, said Brady. Of 245 new drugs approved between 2015 and June 2020, only 6 were for the treatment of psychiatric diseases (Drug Bank Online, 2021; FDA Approved Drugs, 2021). These six

1 The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.

1 PREPUBLICATION COPY—Uncorrected Proofs 2 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS included three approved in 2019: esketamine for treatment-resistant depression, brexanolone for postpartum depression (PPD), and lumateperone for schizophrenia. “There is a dire need for novel targets and novel mechanisms,” said Brady. To help address this need, the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous System Disorders (Neuroscience Forum) convened a workshop in March 2021 titled Novel Molecular Targets for Mood Disorders and Psychosis.

WORKSHOP OBJECTIVES The goal of the workshop was to catalyze the development of new pharmacologic treatments for psychiatric disorders by reviewing the challenges and opportunities encountered during the development of recently approved drugs and applying the lessons learned to the exploration of novel molecular targets, said Brady (see Box 1-1). With a grounding in the personal experiences of patients living with these disorders, workshop participants considered scientific, clinical, technological, regulatory, and ethical challenges.2 The scope of the workshop prioritized discussions on ketamine and other NMDA (N-methyl-D-aspartate) receptor antagonists, neurosteroids, muscarinic antagonists, and serotonergic receptor modulators. Given this focus, the workshop touched briefly on psychedelics and some other therapeutics currently under investigation, and did not cover the use of novel therapeutics in adolescents and young adults.

ORGANIZATION OF THE PROCEEDINGS To illustrate the importance of keeping lived experiences at the center of work in this domain, Chapter 2 opens with two personal narratives from individuals living with these disorders. Chapters 3 and 4 discuss the two recently approved therapeutics of esketamine and brexanolone, examine the mechanisms of action underlying their therapeutic effects, and consider strategies to identify additional targets and pathways with therapeutic potential. Chapter 5 provides an overview of other novel molecular targets being developed for treatment of psychiatric disorders. The regulatory approvals of esketamine and brexanolone and how lessons learned may be applied to future drug development are discussed in Chapter 6. Chapter 7 explores ethical and legal issues that play an especially important role in the development and use of psychoactive drugs. Final thoughts on the future of drug development for psychiatric disorders are presented in Chapter 8.

2 Biosketches of the planning committee members and the workshop speakers are available at https://www.nationalacademies.org/event/03-08-2021/novel-molecular-targets-for-mood- disorders-and-psychosis-a-workshop (accessed July 21, 2021).

PREPUBLICATION COPY—Uncorrected Proofs INTRODUCTION AND BACKGROUND 3

BOX 1-1 Statement of Task

A planning committee of the National Academies of Sciences, Engineering, and Medicine will organize and conduct a 1.5-day public workshop that brings together experts and key stakeholders from academia, government, industry, and nonprofit organizations to explore novel molecular targets for mood disorders and psychosis, including ketamine, other NMDA [N-methyl-D-aspartate] receptor antagonists, neurosteroids, muscarinic antagonists, and hallucinogens, as well as over-the-horizon opportunities such as epigenetic- and inflammation-related targets. Invited presentations and discussions will be designed to:

• Review the current landscape of novel therapeutic targets and agents in development for mood disorders. • Discuss commonalities among mechanisms of action and lessons learned in translation and clinical development that could be applied across programs to develop novel therapeutics for mood disorders. • Explore the development of predictive biomarkers and prioritization of potential intervention points along the signaling pathways. • Examine key clinical questions—such as those related to dosing, safety, treatment aims, duration, diagnosis, place in the sequence of treatments, strategies to prolong efficacy and minimize risk, and the treatment set- ting--and regulatory challenges and opportunities. • Explore what is known about use of these agents across the lifespan, including in adolescents and young adults. • Consider emerging molecular targets for treating psychosis and cognitive impairment in schizophrenia, and how therapeutic development could be informed by lessons learned in developing novel therapeutics for mood disorders. • Discuss open research questions and opportunities to move the field forward.

The planning committee will develop the agenda for the workshop, select and invite speakers and discussants, and moderate the discussions. A proceedings of the presentations and discussions at the workshop will be prepared by a designated rapporteur in accordance with institutional guidelines.

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Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis

Highlights • Recently approved antipsychotics and antidepressants have dramatically benefited patients, but are only modestly effective and are associated with substantial side effects (Paul). • Early intervention, community-based treatment, and access to health care can be critical factors for recovery in the treatment of schizophrenia (Larrauri). • Currently available antipsychotic treatments reduce positive symptoms of schizophrenia, such as delusions and hallu cinations. However, they often do little to improve negative symptoms, such as loss of motivation and the inability to feel happiness, or cognitive symptoms, such as impaired concentration and memory (Larrauri). • Intravenous ketamine can rapidly and dramatically reverse symptoms of treatment-refractory depression in some patients, but without consistent access to the drug, the debilitating symptoms may return within weeks (Clayton). • Most drugs used to treat psychiatric disorders were discovered by serendipity, and their mechanisms understood much later. Eventually, rational drug discovery led to the development of fluoxetine (Prozac) and other selective serotonin reuptake compounds (Paul).

5 PREPUBLICATION COPY—Uncorrected Proofs 6 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS

• The limited efficacy of antidepressants and high patient burden of mood disorders points to the need for additional therapeutic targets (Manji, Paul).

NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants.

Steven Paul, president and chief executive officer at Karuna Thera- peutics, Inc., said that while the current generation of antipsychotics and antidepressants have been godsends, “the drugs that we have now to treat schizophrenia and depression, [and] serious mood disorders are just simply inadequate.” Currently available second-generation antipsychotic drugs are only modestly effective in treating positive symptoms of psychosis (e.g., hallucinations, delusions, and disordered speech and behavior) and are associated with substantial side effects, he noted. Paul added that about 20 to 30 percent of patients taking medication for schizophrenia do not see reductions in positive symptoms of the disorder, and a very high percentage of patients discontinue treatment within a few months. The current generation of drugs does provide modest benefits over earlier formulations when they do work, Paul acknowledged, but many patients show no responses at all. In addition, most antidepressants have a delayed onset of action and troubling side effects, leading to reduced adherence; these drugs also carry black box warnings for suicidal ideation in adolescents, he said. Although the field of psychiatry has an improved understanding of the fundamental pathophysiology of disorders such as schizophrenia and depression, this understanding has not yet yielded many new therapeutics, said Paul.

THE LIVED EXPERIENCE OF SCHIZOPHRENIA1 Carlos Larrauri, a psychiatric mental health nurse practitioner and a member of the board of directors for the National Alliance on Mental Illness (NAMI), was diagnosed with schizophrenia at the age of 23. His symptoms began during high school, but he managed to function well. At age 18, he was accepted at The Ohio State University medical school through an early admissions placement program. As his cognitive and mood symptoms worsened, he became depressed, missed classes, and gained

1 This section is based on the presentation of Carlos Larrauri, National Alliance on Mental Illness.

PREPUBLICATION COPY—Uncorrected Proofs CURRENT DRUG DEVELOPMENT LANDSCAPE AND LIMITATIONS 7 weight, ultimately returning home to his supportive family. He got better and left home again to continue his undergraduate studies. However, his symptoms resurfaced, and he began experiencing florid psychosis with delusions. Fortunately, a family friend alerted his mother, and together, they began to address his mental health challenges, leading to his schizophrenia diagnosis and treatment. Today, he teaches and performs psychiatric mental health care as a nurse practitioner and serves on the board of directors for NAMI. Larrauri also described how he has recently decided to attend law school at the University of Michigan to pursue his goal of mental health care policy reform and advocacy. Larrauri attributes his recovery to three key factors: early intervention, community-based treatment, and access to health care. After about 1 year from the onset of florid psychosis, he received what he called “lifesaving, necessary medication” and realized that he had a serious brain condition that would require lifelong management. He began receiving multidisciplinary treatment, mostly in community settings. “I never had to see the back of a cop car or crisis stabilization unit,” he said. Finally, the Patient Protection and Affordable Care Act’s provision that expanded coverage to adult-dependent children until the age of 26 ensured that he had access to the medical care he needed. Although the medication has allowed him to lead a full life and pursue his goals, Larrauri noted the limitations of current treatments. They reduce the intensity, frequency, and duration of positive symptoms (see Box 2-1), such as delusions and hallucinations, he said, but come with serious side effects. Furthermore, the drugs do little to reduce negative symptoms or cognitive symptoms (see Box 2-1). “We still do not have adequate treatments for cognitive symptoms, which are often the most disabling and the most associated with negative or poor functional outcomes,” he said. Cur- rent medications are also ineffective in treating other negative symptoms, such as anhedonia (reduced capacity to experience pleasure) and lack of motivational drive, said Larrauri.

LIVING WITH DEPRESSION2 Symptoms of mental illness appeared at about age 10 for Ashley Clayton, a research associate at the Family Violence Research Program at Yale University. She described herself as a “bright kid who happened to be particularly sensitive,” who was liked by friends and loved by family. Her challenges with severe depression began at a very early age. Clayton experienced sexual abuse between the ages of 6 and 13, started showing signs of mental illness when she was about 10, began practicing self-harming

2 This section is based on the presentation of Ashley Clayton, Yale University.

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BOX 2-1 Positive, Negative, and Cognitive Symptoms in Schizophrenia

Positive symptoms describe altered perceptions (e.g., changes in vision, hear- ing, smell, touch, and taste), abnormal thinking, and odd behaviors. These may manifest as: • Visual, auditory, and sensory hallucinations • Delusions (e.g., irrational thinking and paranoia) • Disorganized speech

Negative symptoms include loss of motivation, disinterest or lack of enjoyment in daily activities, social withdrawal, difficulty showing emotions, and difficulty functioning normally. These may manifest as: • Difficulty planning, beginning, and sustaining activities • Diminished feelings of happiness in everyday life • Reduced emotional expressiveness • Reduced speaking

Cognitive symptoms include problems in attention, concentration, and memory. This may manifest as: • Difficulty processing information to make decisions • Problems using information immediately after learning it • Trouble focusing or paying attention

SOURCE: Adapted from NIMH, 2021.

behaviors at age 11, and attempted suicide for the first time at age 13. Her psychiatric symptoms became more severe in high school, landing her in the hospital twice, including once for a nearly lethal suicide attempt. She described receiving her college acceptance letters while in the hospital, and recalled needing to get permission from the hospital to leave the site to attend her high school graduation. In time, her health care team identified effective medications to treat the depression and enable her to attend college. Despite a diagnosis of treatment-resistant depression, extensive therapy and effective management of her illness helped Clayton thrive in college. She tapered off her antidepressant medications, graduated from college with honors, and headed to Yale University in New Haven, Connecticut, for graduate school. During this period of remission, she found a therapist who helped her work through her trauma, accepted a research position at Yale, and fell in love with the man she would later marry. Four years later, her depression returned. “I was fatigued, self-critical, and felt hollowed and empty or overwhelmed with sadness,” she said. Most

PREPUBLICATION COPY—Uncorrected Proofs CURRENT DRUG DEVELOPMENT LANDSCAPE AND LIMITATIONS 9 concerning was the accompanying suicidal ideation. Not long after that, the symptoms of her treatment-resistant depression became so severe that she was chronically suicidal. “I admitted myself to the hospital at the end of the year because I was not sure I could keep surviving,” said Clayton. “It is exhausting to have to fight every day not to die.” Despite multiple medications, other forms of therapy, a loving hus- band, meaningful work, and friendships, Clayton’s mental health steadily deteriorated over the next 2 years. “I had a life that I desperately wanted to live, but I also had an illness that made living excruciatingly painful,” she said. With her memory and concentration declining, she took a medical leave from work. A colleague and friend referred her to Gerard Sanacora, professor and director of the Yale Research Depression Program and an expert on ketamine and mood disorders. Through Sanacora, she was able to enroll in a Phase 2 clinical trial testing the antidepressant efficacy of different doses of ketamine administered as a single intravenous infusion. After her first infusion treatment, “I had energy and excitement and felt a strange and unfamiliar sense of self-worth,” she said. “It felt like magic.” The exhila- rating effects lasted for 2 weeks, followed by a dramatic decline into what Clayton described as a “labyrinth of suffering.” She recollected that she was, “consumed once again by suicidal thoughts” and “devastated to have lost that sense of self that ketamine had seemingly miraculously restored.” At the conclusion of the clinical trial, Clayton and Sanacora tried to find a way for her to continue receiving ketamine treatment through an interven- tional psychiatry service offered at Yale, but her insurance provider declined to cover the cost. “Months went by with no progress,” she said, “and I was all but certain I would die by suicide and soon.” Following the advice of another colleague, she tried electroconvulsive therapy (ECT). More than a dozen ECT treatments provided little help and came with significant side effects. Ultimately, her doctors convinced the hospital administrators to allow her to receive 4 weeks of ketamine treatments free of charge. This regimen provided substantial relief from her treatment-resistant depression. However, the doctors did not know how they could cover the expense. As a result, the program administrators were approving each subsequent appointment beyond those initial 4 weeks on a treatment-by-treatment basis. As the intervals between ketamine treatments increased, she began to crash more frequently and described her state as “exceptionally fragile.” “I was left to face the devastating fact that without better access to treatment, ketamine would not save me,” said Clayton. Eventually, she was able to gain access to the drug on a more consistent basis. Now, 4 years and 116 treatments later, Clayton said she “is alive and mostly well.” While ketamine is not a magic bullet or a cure, “it has kept me out of the abyss and most notably resolved almost completely my

PREPUBLICATION COPY—Uncorrected Proofs 10 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS suicidal ideation,” she said. “It has restored to me all the good stuff like experiencing joy and awe and the feeling of love deep down in my bones.”

SERENDIPITY IN PSYCHIATRIC DRUG DISCOVERY Most drugs currently used to treat psychiatric disorders were discovered by serendipity, with the mechanisms of action typically not discovered until 10 or 20 years after their introduction, said Paul. For example, the first antipsychotic drug introduced—chlorpromazine —was discovered by the French Navy Surgeon Henry Laborit, who theorized that antihistamines could have a calming effect during surgery by lowering body temperature, said Paul. Laborit went on to show that Thorazine (chlorpromazine), a derivative of the phenothiazine antihistamine promethazine, did indeed reduce stress during surgery without producing marked sedation. Psychiatrists Jean Delay and Pierre Deniker subsequently showed that in manic patients, Thorazine also displayed antipsychotic effects, separate from its sedative properties and unrelated to histamine. “The rest was history,” said Paul. The introduction of chlorpromazine sparked the development of many other antipsychotic drugs with different efficacy, tolerability, and side effect profiles, but which all fundamentally worked the same way, he said. Not until nearly 30 years later was the mechanism of action identified, said Paul. “The therapeutic effects of chlorpromazine and virtually all marketed antipsychotics are linked to direct blocking of postsynaptic dopamine receptor D2,” he said (Seeman, 2011). Yet, while D2 receptor antagonists reduce positive symptoms, they provide little relief from negative and cognitive symptoms, he noted. Additionally, they cause a cluster of side effects known as extrapyramidal symptoms— including acute dystonia (involuntary muscle contractions) and tardive dys- kinesia (stiff, jerky, repetitive, and involuntary movements [e.g., grimacing and eye blinking]), said Paul. Even newer agents that are partial D2 receptor agonists instead of D2 receptor blockers essentially function as antagonists, he said, which supports the idea that positive symptoms of schizophrenia, such as hallucinations and delusions, result from the hyperactivity of meso- limbic dopamine neurotransmission in the brain. In the search for additional compounds with antipsychotic properties, the drug clozapine was discovered as the first antipsychotic compound to produce efficacy without extrapyramidal symptoms, said Paul. This “quint- essential atypical antipsychotic” is thought to act by reducing D2 receptor occupancy and increasing antagonism at the 5HT2A (serotonin) receptor, he said. Several follow-on atypical antipsychotics have been developed, including olanzapine, risperidone, quetiapine, and aripiprazole, but none has an effect size as large as clozapine, especially in patients with treatment- resistant depression and suicidal ideation, said Paul (Leucht et al., 2013).

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“We do not really know what the secret sauce of clozapine is,” he said. However, he added that the drug has five black box warnings associated with substantial weight gain and other associated comorbidities. Today, it is primarily used in a limited manner in treatment-resistant patients who have not responded to other therapies, said Paul. Another example of serendipity in psychiatric drug development involves the tuberculosis drug isoniazid, said Paul. After researchers observed that tuberculosis patients treated with isoniazid showed improved mood, sleep, and appetite, the psychiatrist Nathan Kline began a trial in patients with depression and demonstrated similar mood-enhancing effects. Isoniazid, a derivative of hydrazine, was found to inhibit monoamine oxidase (MAO), which resulted in increased serotonin levels (Ramachandraih et al., 2011). Although isoniazid and some other hydrazine derivatives had the potential to cause liver toxicity, their discovery led to the development of a new class of antidepressants, the MAO inhibitors. The first tricyclic antidepressant was also discovered through serendipity when psychiatrist Roland Kuhn tested imipramine, a structural analog of chlorpromazine, in psychotic patients, only to demonstrate that although it did not improve psychosis, it had mood-elevating properties in patients with comorbid depression (Cahn, 2006). According to Paul, this led directly to the work of Julius Axelrod and colleagues at NIMH who demonstrated that tricyclic antidepressants block the presynaptic uptake of biogenic amines, including the neurotransmitters norepinephrine and serotonin. These serendipitous discoveries of treatments for depression eventually gave way to rational drug discovery efforts, according to Paul. Focusing on the monoamine hypothesis3 and using the tools of medicinal chemistry, investigators went on to identify compounds that selectively blocked the reuptake of serotonin and norepinephrine. These included Prozac (fluoxetine), a selective serotonin reuptake inhibitor (SSRI), said Paul. By 1993, he said, Prozac was prescribed to nearly five million patients in the United States and gave rise to the development of many other selective serotonin reuptake therapies that are now the standard of care for depression and other mood disorders. However, Paul said that while these drugs have better side effect profiles, they still have only modest efficacy. Another somewhat serendipitous discovery came in the late 1960s. At that time, the chemist Leo Sternbach was tasked with developing a tranquilizer to compete with meprobamate, which was the first minor tranquilizer to be approved by the Food and Drug Administration (FDA). His unsuccessful attempts to develop a competitor to meprobamate led to the

3 The monoamine hypothesis predicts that the underlying pathophysiological basis of depression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the central nervous system (Delgado, 2000).

PREPUBLICATION COPY—Uncorrected Proofs 12 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS discovery of Librium, Valium, and the introduction of benzodiazepines as a new class of anxiolytics, said Paul (Calcaterra and Barrow, 2014). Today, benzodiazepines remain one of the most commonly used treatments for anxiety disorders, said Paul. Yet, more than 15 years passed before investigators discovered that benzodiazepines work by binding to a subset of gamma-aminobutyric acid (GABA) receptors, said Paul (Mohler and Okada, 1977). GABA is the major inhibitory neurotransmitter in the brain and is synthesized from glutamate, which is the major excitatory synaptic neurotransmitter in the brain. It is hypothesized that most cortical pathology reflects an imbalance in glutamatergic excitation and GABAergic inhibition (Krystal et al., 2017). Both GABA and glutamate neurons thus represent potentially druggable targets for psychiatric disorders that involve synaptic transmission.

UNMET NEEDS IN TREATING PSYCHIATRIC DISORDERS Although many antidepressant formulations have been available since the 1950s, depression continues to be a leading cause of disability, with a full 30 percent of people with major depressive disorder receiving little or no benefit despite treatment with multiple drugs, said Husseini Manji, global head at Johnson & Johnson Science for Minds. Even when currently available antidepressants work, they often have a slow onset of action, said Manji. One reason for the disappointing history of antidepressant treatment, he said, is that until recently, nearly all of the available treatments worked by the same monoamine-based mechanisms. Only in the past 2 years have treatments emerged with completely novel mechanisms, he said. Paul added that there is still much to learn about the known therapeutic targets in depression. For example, there are 14 molecularly distinct serotonin receptors, but it is not exactly clear which ones are involved in the antidepressant effects of SSRIs and whether efficacy or safety could be increased by targeting specific subtypes or by using combination approaches. Thus, while it often takes 2–6 weeks to observe a clinical response with SSRIs, it is unclear if this results from different receptors being activated or from some other downstream consequence of receptor activation, said Paul. Noting that the attrition rate of conventional small molecule psychiatric drug candidates remains high, he suggested the consideration of other therapeutic modalities.

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Targeting Glutamate Receptors for Treatment-Resistant Depression

Highlights • Antidepressants targeting glutamate receptors regulate plasticity, are rapidly acting, and provide persistent therapeutic effects (Manji). • Ketamine delivered intravenously and esketamine delivered intranasally provide rapid, robust antidepressant effects (Canuso). • Weekly or every-other-week dosing of esketamine can prevent relapse of depression in about 70 percent of patients (Canuso). • Ketamine blocks synaptic transmission at the NMDA receptor, with antidepressant effects observed at doses that do not produce anesthesia or other side effects (Krystal). • It may be possible to extend the antidepressant effects of ketamine with a low dose of rapamycin given before dosing with ketamine (Krystal). • Behavioral interventions used in conjunction with ketamine treatment may increase the magnitude of the therapeutic effect (Krystal). • Developing strategies to improve the antidepressant effects of ketamine will require a better understanding of the mechanism, and the development of new tools for studying circuits, systems, and biomarkers (Krystal, Sheng, Zarate).

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• To go beyond ketamine, drugs with a different mechanisms of action that mediate similar upstream or downstream neurobiological effects could prove to be effective antidepressants (Sheng).

NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants.

Tremendous progress in understanding the key role glutamate receptors play in regulating synaptic plasticity has fueled the development of novel, rapidly acting antidepressants—ketamine and esketamine—that have shown effectiveness against treatment-resistant depression, said Husseini Manji. Moreover, he said, the therapeutic effects of these medications appear to persist even when the drug has cleared from the body, allowing for intermittent administration.

A BRIEF HISTORY OF KETAMINE AND ESKETAMINE Ketamine has been used as an dissociative anesthetic since the mid- 1960s. The use of ketamine as a treatment for depression began in the early 2000s when investigators at Yale conducted a small study of intravenous ketamine in seven patients with depression (Berman et al., 2000), said workshop speaker Carla Canuso, vice president of clinical development at Janssen Research and Development. Ketamine was known to be a potent antagonist of the NMDA glutamate receptor. and there was a growing understanding of the role of glutamate and the NMDA receptors in the pathophysiology of depression, she said. In this initial proof of concept study, researchers demonstrated that a single subanesthetic dose of ketamine produced a rapid, robust antidepressant effect, said Canuso (see Figure 3-1). A few years later, a randomized controlled trial in 18 subjects with treatment-resistant depression showed a similar rapid, robust response after a single dose that waned over the course of 1 week (Zarate et al., 2006), she said. Following these initial studies, many clinical trials have confirmed the efficacy of ketamine and esketamine1 administered orally, intravenously, or intranasally (McIntyre et al., 2020). Importantly, Canuso added, a moderate to very large effect size was seen in all of these trials. Rates of remission achieved with ketamine and esketamine have been shown to be similar,

1 Esketamine is one of two racemic (mirror-image) structural chemical forms of ketamine.

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FIGURE 3-1 The antidepressant effects of ketamine in depressed patients. Mean changes from baseline in the Hamilton Depression Rating Scale (HDRS) are reduced after ketamine infusion (solid circles), but not saline infusion (open circles), in seven subjects. SOURCES: Presented by Carla Canuso, March 8, 2021; adapted from Berman et al., 2000. about 25–30 percent, which is much higher than what had been seen in previous studies of standard antidepressants in treatment-resistant depression (Correia-Melo et al., 2020). The extent to which ketamine caused feelings of dissociation, a well-described side effect broadly defined as altered consciousness and awareness of the self, environment, and reality (Ballard and Zarate, 2020), were also similar across clinical trials, said Canuso.

CLINICAL AND PATIENT EXPERIENCES WITH INTRANASAL ESKETAMINE Canuso leads the team at Janssen Research and Development that developed intranasal esketamine (Spravato®) for TRD in adults. Spravato® was granted FDA approval with Fast Track and Breakthrough Therapy designations in March 2019 for use in TRD and for patients with major depressive disorder accompanied by acute suicidal ideation and behavior.

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Canuso added that intranasal esketamine has also shown promise for other conditions such as bipolar depression, posttraumatic stress disorder (PTSD), and substance use disorder. Canuso reviewed the evidence that led to the approval of intranasal esketamine, including data from two Phase 3 studies and other Phase 2 and 3 studies demonstrating safety and efficacy (Singh et al., 2020). Sub- group analyses confirmed a favorable treatment response across all patient subgroups whether based on gender, baseline depression scores, history of previous treatment, background antidepressants, or functional status, said Canuso. A key question of interest concerned whether ketamine’s dissociative effects are necessary for its antidepressant effects (Ballard and Zarate, 2020). To address this issue, the Janssen team’s clinical trials demonstrated that neither esketamine- nor ketamine-induced dissociation was required to achieve an antidepressant response, said Canuso. Preventing relapse was another important issue explored in the drug development process, said Canuso. In previous studies of antidepressant treatments, relapse rates were very high when drugs were withdrawn after achieving remission (Rush et al., 2006). Similarly, high relapse rates were also seen when esketamine was removed from the treatment regimen, said Canuso. However, relapse was avoided in about 70 percent of patients who transitioned to every-other-week dosing instead of weekly dosing (Daly et al., 2019). Because ketamine is a controlled substance, the long-term safety and abuse potential of esketamine in the therapeutic context of treatment- resistant depression treatment remains a concern. Canuso noted that FDA approval was contingent on a risk evaluation and mitigation strategy (REMS), which requires the continued long-term study of patients. So far, she said, no changes in cognition have been seen, other than slightly slowed reaction times in patients older than 65. There have been no observations of abuse, dependence, withdrawal, or problems related to bladder, kidney, liver, or blood pressure health. She added that no signs of tolerance to the antidepressant effects of intranasal esketamine were observed. Because of ketamine’s rapid antidepressant effects (Grunebaum et al., 2018; Wilkinson et al., 2018), Canuso’s team was particularly interested in studying intranasal esketamine in patients with acute suicidal ideation, when quickly bringing symptoms under control is essential. She noted that patients who are acutely suicidal are typically excluded from clinical treatment trials of antidepressants, in part because these patients often receive extensive clinical care that can confound study outcomes. In addition, because of methodological issues—including the difficulty of measuring suicidality and its rapidly fluctuating nature—studies of esketamine’s effect on suicidality have produced mixed results, said Canuso. Nevertheless, she said much has been learned by including patients who meet the criteria

PREPUBLICATION COPY—Uncorrected Proofs GLUTAMATE RECEPTORS FOR TREATMENT-RESISTANT DEPRESSION 17 for acute suicidality in esketamine’s clinical trials. Ninety percent of the patients studied in Janssen’s pivotal trials had moderate to severe suicidality, and 60 percent reported a prior suicide attempt, said Canuso. She called for more research in diverse groups of patients, including adolescents, as well as comparative research across different drug formulations.

KETAMINE’S MECHANISM OF ACTION ON SYNAPSES, CIRCUITS, AND SYSTEMS Precisely how ketamine alleviates depression remains unclear, said John Krystal, the Robert L. McNeil, Jr. Professor of Translational Research and professor of psychiatry and neuroscience at the Yale School of Medicine. One relevant observation, he said, is that ketamine exerts its antidepressant effects across a very narrow range of doses. Dose increases above the plasma concentration of 0.5 micromolar, which is the level produced by the standard antidepressant dose of ketamine (0.5 mg/kg administered intravenously over 40 minutes) increase the intensity of dissociative and psychotic side effects, he said, without improving antidepressant efficacy. At anesthetic doses, beginning about 4-fold higher than the antidepressant dose, ketamine does not appear to be an effective antidepressant. Therefore, he said, the underlying mechanisms relevant to ketamine’s antidepressant effects are most likely molecular targets that are engaged within a 2- to 4-fold range from the target antidepressant plasma level. The molecular targets engaged at higher doses are probably not relevant to the anti depressant effects of ketamine, although they may play a role in mediating its anesthetic effects. As mentioned earlier, ketamine primarily NMDA glutamate receptors, said Krystal. Figure 3-2 illustrates the many types of glutamate receptors present in glutamate synapses. In NMDA glutamate receptors, the binding of glutamate and its co-agonists glycine and D-serine opens an ion channel within the receptor, allowing calcium to enter neurons. However, when ketamine binds to the NMDA glutamate receptor, the ion channel within the receptor remains closed. Ketamine is most potent at blocking NMDA receptors containing the GluN2A-GluN2C subunits. Besides NMDA receptors, ketamine binds to many other targets in the brain, albeit at concentra- tions that are in excess of a typical anesthetic dose in humans. Ketamine’s blockage of NMDA receptors could affect microcircuits through different mechanisms depending on whether the receptors are on inhibitory or excitatory neurons, for example, said Krystal. Studies suggest that ketamine increases glutamate release, he continued, and the signatures associated with the increased glutamate are related to the antidepressant response in depressed patients (Abdallah et al., 2018; Esterlis et al., 2018; Gilbert and Zarate, 2020; Stone et al., 2012).

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FIGURE 3-2 Ketamine blocks synaptic transmission by inhibiting glutamate binding at the NMDA glutamate receptor. Glutamate released at presynaptic terminals (boutons) binds to multiple receptors at the postsynaptic dendritic spine, including the AMPA and NMDA receptors. The NMDA receptors have a tetrameric structure containing four subunits: two GluN1 subunits and two GluN2 subunits. There are four subtypes of GluN2 classes, designated A, B, C, and D. Ketamine is most potent at GluN2C and GluN2D receptors. SOURCE: Presented by John Krystal, March 8, 2021.

In animal models, he said, the early phase of ketamine administration causes the cortical expression of genes associated with neural activation, such as Arc, phosphor-ERK, and Akt/mTORC. Later, beginning at about 6 hours after ketamine administration, there is an increased expression of genes associated with new synapses, including genes expressed by axon terminals, such as synapsin 1 and SV2A, and genes that are expressed by the postsynaptic dendritic spine, such as PSD95 and GluR1, said Krystal. Yale scientists Ronald Duman and George Aghajanian demonstrated that ketamine triggers the rapid regrowth of dendritic spines that had previously undergone pruning, he continued. One model that has emerged to explain this phenomenon posits that when ketamine blocks NMDA receptors on GABA neurons, there is a reduction in GABA release and an increase in glutamate release, said

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Krystal. Increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation by glutamate induces brain-derived trophic factor (BDNF) gene expression, local BDNF release, and its binding to TrkB receptors. This triggers a shuttling of intracellular AMPA receptors to the cell surface, thus increasing the efficacy of synaptic communication and increasing neuroplasticity. Meanwhile, the stimulation of TrkB receptors activates the Akt/mTOR pathway, resulting in increased protein synthesis and the recre- ation of pruned dendritic spines, he said. This conceptual framework could be viewed as a presynaptic model for ketamine efficacy (see Figure 3-3). A different approach to understanding ketamine’s mechanism of action emerged from the work of Vanderbilt University scientists Lisa Monteggia and Ege Kavalali. Their model proposes that the spontaneous glutamate release from glutamate nerve terminals stimulates synaptic NMDA receptors. Under normal circumstances, BDNF levels are suppressed and AMPA trafficking is curtailed in response to the stimulation of synaptic NMDA receptors, he said. Monteggia and Kavalali proposed that ketamine antagonism at NMDA receptors relieves the brake on BDNF levels while upregulat ing AMPA receptor trafficking to the nerve terminal.

FIGURE 3-3 The presynaptic model of ketamine action. This proposal posits that ketamine reduces inhibition, enhances glutamate release, and increases BDNF. In this model, BDNF is hypothesized to drive the trafficking of AMPA receptors to the synapse, and to trigger spine synthesis via the mTORC1 pathway. SOURCE: Presented by John Krystal, March 8, 2021.

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Together, this leads to a rapid increase in synaptic efficacy, stimulation of Trk B receptors, mTORC1 activation, and the reformation of pruned dendritic spines. This is known as the postsynaptic model (see Figure 3-4). There is also the possibility, Krystal added, that ketamine may stimulate TrKB receptors directly. The work of Weill Cornell Medicine scientist Conor Liston highlighted that there might be different mechanisms underlying the initiation and maintenance of ketamine’s antidepressant effects, with initiation caused by enhanced AMPA receptor function and trafficking to the cell surface and maintenance caused by newly regrown dendritic spines, said Krystal. If interfering with the maintenance of recreated dendritic spines shortens the therapeutic effect of ketamine, he said it raises the question of whether it is possible to increase the duration of the antidepressant effects by increasing the duration of the newly restored dendritic spines.

STRATEGIES TO IMPROVE THE ANTIDEPRESSANT EFFECTS OF KETAMINE As noted earlier, ketamine or esketamine treatment for depression can cause a remittance in symptoms that lasts for about 1 week after a single dose. As Krystal said, a deeper understanding of the mechanism of action raises the possibility that different pharmacological strategies could be

FIGURE 3-4 The postsynaptic model of ketamine action. This proposal posits ketamine blocks the spontaneous glutamate release at the GluN2B receptor, thus increasing BDNF signaling and AMPA receptor trafficking to the receptor and stimulating spine generation via the mTORC1 pathway. SOURCE: Presented by John Krystal, March 8, 2021.

PREPUBLICATION COPY—Uncorrected Proofs GLUTAMATE RECEPTORS FOR TREATMENT-RESISTANT DEPRESSION 21 developed to increase the duration of the antidepressant effects of ketamine. Clinicians and researchers have explored different strategies for extend- ing the antidepressant effect of ketamine, said Carlos Zarate, chief of the Section on Neurobiology and Treatment of Mood Disorders and Section of Experimental Therapeutics and Pathophysiology Branch at NIMH and clinical professor of psychiatry at The George Washington University. These include adjunctive drugs such as glutamatergic modulators; psychotherapies such as cognitive-behavioral therapy or motivation enhancement therapy; non-invasive neurostimulation; repeated racemic ketamine 2 infusions; and continued use of intranasal esketamine, said Zarate. Of these approaches, only continued intranasal esketamine treatment demonstrated the ability to maintain ongoing antidepressant effects, he said. A study conducted by Krystal and colleagues demonstrated that a low dose of the powerful anti-inflammatory drug rapamycin given before dosing with ketamine extended the duration of ketamine’s antidepressant effects (Abdallah et al., 2020). However, the mechanism underlying this remains unclear, said Krystal. Different molecular mechanisms may also underlie the variable symp- tomatology and responses to therapy in different patients, said Krystal. For example, he noted that by using positron emission tomography (PET) to detect the presence of synaptic vesicles at presynaptic terminals, investigators demonstrated that reduced synaptic density correlated with reduced functional connectivity between the dorsolateral prefrontal cortex and the posterior cingulate cortex and also correlated with increased severity of depression (Holmes et al., 2019). Ketamine’s ability to increase synaptic density may thus explain its rapid antidepressant effects, said Krystal. He added that another aspect of ketamine treatment that is not well understood at a neurobiological level is the effect of repeated exposure to ketamine over time and why some patients can eventually taper down to less frequent dosing while maintaining clinical benefits. Krystal added that because ketamine interferes with learning and other forms of neuroplasticity, it might be possible to increase the magnitude of the therapeutic effect by combining ketamine treatment with behavioral interventions designed to “rewrite” maladaptive memories that may be contributing to mental unwellness (Das et al., 2019). In addition, because ketamine appears to be implicated in a cascade of intracellular events that contribute to its antidepressant properties and that enhance neuroplasticity, it is possible that behavioral interventions might have enhanced efficacy during this period, said Krystal. Lastly, Krystal discussed how different aspects of the signaling mechanisms implicated in the antidepressant effects of ketamine might be directly targeted with

2 Racemic ketamine contains both mirror-image structures (isomers) of ketamine.

PREPUBLICATION COPY—Uncorrected Proofs 22 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS novel treatments. These targeted interventions might have the possibility of recapitulating aspects of the antidepressant efficacy of ketamine while increasing safety and tolerability. Morgan Sheng, co-director of the Stanley Center for Psychiatric Research at the Broad Institute of the Massachusetts Institute of Technol- ogy (MIT) and Harvard and professor of brain and cognitive science at MIT, agreed that developing a “better ketamine” will require more research to understand how ketamine works. Rather than modifying ketamine, he suggested pursuing drugs with different molecular mechanisms of action that mimic the neurobiological effects of ketamine upstream at the circuit or brain system level or that modulate a downstream pathway. Zarate added, however, that it will likely be difficult to develop a drug that has ketamine’s broad therapeutic effects across multiple mental health conditions (e.g., PTSD, obsessive-compulsive disorder, anhedonia, suicidality). Krystal suggested that ketamine may, at least in part, rely on interneuron-dependent effects. Pathology in interneuron populations could explain why patients respond differentially to ketamine, he said. Drugs such as 5-HT2A agonists and psychedelics, which directly stimulate excitatory pyramidal neurons rather than interneurons, might prove more effective in these patients, he said. Moving upstream of the synapse to the circuit or systems level will also require a better understanding of the circuits and brain regions that are affected by ketamine, noted Manji. Technologies such as structural and functional imaging, magnetoencephalography, electroencephalography, proteomics, and metabolomics may be useful to interrogate these systems, said Zarate. For example, Abdallah and colleagues used functional magnetic resonance imaging to show that ketamine treatment normalizes prefrontal global brain connectivity in patients with treatment-resistant depression (Abdallah et al., 2017), explained Zarate. He added that investigators are also studying how ketamine and other treatments affect three networks implicated in depression: the default mode network, which is involved in rumination and self-referential thoughts (Zhou et al., 2020); the salience network, which identifies emotionally salient stimuli (Seeley et al., 2007); and the central executive network, which is involved in the regulation of emotions, behaviors, and thoughts (Miller et al., 2018). In addition to studying these networks, scientists are using animal models to study which cell types (e.g., inhibitory interneurons, excitatory pyramidal neurons, etc.) are involved. To do this, researchers leverage in vivo single-cell recordings of many cells simultaneously during treatment with ketamine, said Sheng. He suggested further studies using single-cell RNA-Seq to identify the transcriptomic responses of different cell types. Sheng also suggested the use of spatial transcriptomics to study how antidepressants exert cell-specific and region-specific effects on gene expression.

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In the search for more effective treatments, Zarate supported continued exploration of preclinical targets that overlap with ketamine’s targets, while still trying to harness ketamine’s therapeutic effect. This approach will help elucidate which of ketamine’s molecular targets exert broad versus selective effects, he said. Treatments that target synaptic plasticity and synapse growth make intuitive sense as a broader spectrum strategy not only for treating depression, but for other disorders as well, added Sheng. Krystal added that there are a number of molecular mechanisms that are engaged in the presynaptic and postsynaptic models of ketamine efficacy discussed earlier, and some of these may be targets to potentiate the antidepressant effect of ketamine. These include muscarinic antagonists, psychedelic agents, 5-HT2A agonists, GABA-A receptor partial inverse agonists, AMPAkines, metabotropic glutamate receptor-2 antagonists, and ketamine metabolites.

IDENTIFYING A BIOMARKER TO HELP PREDICT RESPONSES TO KETAMINE While ketamine’s efficacy and rapid onset of effectiveness have provided dramatic benefits for patients like Ashley Clayton, not all patients with depression experience these strong effects, as Krystal mentioned earlier. Why some patients respond to ketamine while others do not is unclear. Researchers are hoping to find a reliable biomarker that would help predict how likely it is for a particular patient to benefit from treatment before that patient enrolls in clinical trials. This patient stratification biomarker could enable more productive clinical studies as well as more individualized treatment, yet no such biomarkers have been identified in the depression field, said Zarate. Krystal and colleagues have been exploring the use of PET to assess levels of SV2A, a protein that can be used to measure synaptic density; the hypothesis is that patients with low synaptic density in certain brain regions may be good candidates for ketamine. However, the high cost of PET scans limits the feasibility of using this tool for patient stratification. In addition, said Sheng, SV2A PET measures have limited predictive value. He suggested that brain oscillations assessed using EEG might prove to be a more useful predictive or diagnostic stratification biomarker.

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Targeting GABA Receptors to Treat Postpartum Depression

Highlights • Brexanolone, which targets GABA receptors, is the first treatment approved PPD and the first neuroactive steroid approved for a psychiatric condition (Meltzer-Brody, Zorumski). • Brexanolone is administered via a 60-hour intravenous infusion and produces rapid relief from symptoms of PPD (Meltzer-Brody). • Brexanolone is a formulation of the neurosteroid allopregna- lone, which modulates synaptic and extrasynaptic GABAA receptors (Zorumski). • Preclinical studies showed that allopregnanolone analogs improved maternal behavior and pup survival by modulating neural network activity in the basal lateral amygdala (Maguire). • The fact that ketamine, brexanolone, and electroconvulsive therapy all trigger long-lasting antidepressant effects suggest a possible convergence of mechanisms at the cellular or circuit level, which could be explored with new tools such as single- neuron RNA seq (Koroshetz, Maguire, Monteggia, Murray).

NOTE: These points were made by the speakers identified above; they are not intended to reflect a consensus among workshop participants.

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March 2019 was a good month for psychiatry, said Charles (Chuck) Zorumski, the Samuel B. Guze Professor, head of the Department of Psychiatry, and professor of neuroscience at the Washington University School of Medicine. The second drug that received FDA approval that month, after intranasal esketamine for treatment-resistant depression, was brexanolone (Zulresso™) for women with PPD. Brexanolone, a modulator of GABA, represents the first neuroactive steroid to be approved for a psychiatric indication, said Zorumski.

CLINICAL AND PATIENT EXPERIENCES WITH BREXANOLONE Brexanolone is a novel formulation of the endogenous neuroactive steroid allopregnanolone, and has been approved by FDA as a breakthrough therapy for the treatment of PPD. Between 10 to 20 percent of women worldwide experience PPD after childbirth (Gerbasi et al., 2021). The condition is commonly characterized by depression, unstable mood, sadness, fear, and difficulty forming an emotional attachment with the baby (Vliegen et al., 2014). PPD is a major cause of maternal mortality and morbidity (Azhar and Din, 2021). Untreated, the condition can last for months or longer. Without intervention, there may be lasting negative effects not only on mothers, but on their children as well, explained Samantha Meltzer- Brody. SSRI antidepressants have been considered the gold standard for treating PPD, but they are slow acting and ineffective for many women, she continued. Although the underlying cause of PPD is not fully understood, it is likely multifactorial—involving inflammatory signaling, fluctuations in perinatal hormones, dysregulation of stress pathways, and GABA signaling dysfunction, she continued. Brexanolone was already known to be a positive allosteric modulator1

(PAM) of GABAA receptors, said Meltzer-Brody (see Figure 4-1). There had been a longstanding theory that PPD was associated with GABAergic hypo- function, providing an underlying theory that made a strong case for why it was important to investigate the impact of brexanolone in PPD patients. In the initial open-label study of brexanolone (then called SAGE-547), in which both health care providers and patients were aware that the drug was being administered, Meltzer-Brody recalled the excitement of seeing the first patient exhibit a rapid and dramatic improvement in their PPD symptoms. Promising results with three more patients prompted SAGE to move forward with two double-blind Phase 3 studies, she said. These studies showed that a 60-hour intravenous infusion of the drug produced a

1 Positive allosteric modulators are drugs that bind to a secondary binding site on a receptor, causing a conformational change to the primary binding site, leading to enhanced binding affinity for ligands at the primary binding site (Abdel-Magid, 2015).

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FIGURE 4-1 The action of positive allosteric modulators on GABAA receptors. Positive allosteric modulators (PAMs) bind at secondary binding sites on GABAA receptors, causing a conformational change at the primary binding site such that tonic GABAergic current is increased through the channel. SOURCES: Presented by Jamie Maguire and Samantha Meltzer-Brody, March 8, 2021. © Sage Therapeutics, Inc., All Rights Reserved.

dramatic antidepressant effect at the 24-hour mark that was sustained for several weeks (Meltzer-Brody et al., 2018). Now using brexanolone clinically, Meltzer-Brody said, “it remains a very dramatic experience to watch people with this acute affective state change within a day. Women who were severely depressed suddenly have affective brightening and relief of horrible symptoms of depression and comorbid anxiety.” An oral formulation called zuranolone is also in clinical development for both PPD and major depressive disorder, said Meltzer-Brody. This once-daily tablet does not work as fast as brexanolone, but still produces dramatic results, she said, with an onset of action observed after around 2 days and the full effect seen after about 1 week. Meltzer-Brody and others are optimistic that brexanolone may provide relief for patients experiencing symptoms from other psychiatric illnesses as well. Moreover, she called brexanolone a “great example of using underlying hypotheses of pathophysiology to develop novel treatments.” Although

PREPUBLICATION COPY—Uncorrected Proofs 28 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS brexanolone has not been studied for mood disorders outside of PPD yet, she suggested that it provides an important opportunity to probe circuits and get a better understanding of what is happening. “I think there’s a tremendous amount we have yet to learn about this really dramatically powerful drug,” she said. “It’s untapped right now.”

BREXANOLONE’S MECHANISM OF ACTION Brexanolone is a novel formulation of the endogenous neuroactive steroid allopregnanolone, and is the first neuroactive steroid to be approved for a psychiatric indication, said Zorumski. Neurosteroids describe a class of steroids that are synthesized in the brain and nervous system from cholesterol or steroid precursors and act on the brain, he said. Neuroactive steroids like brexanolone are potent, highly effective, and broad-spectrum positive allosteric modulators of GABAA receptors, and can modulate both phasic inhibition and tonic inhibition, said Zorumski. Working at low con- centrations in the nanomolar range to modulate GABAA receptor function, these agents are among the most effective positive allosteric modulators that exist for GABAA receptors. He added that these agents also engage intracellular molecular targets that may be important considerations for understanding the mechanism of action, including effects on inflammation and receptor trafficking. Working with Istvan Mody at the University of California, Los Angeles, in 2008, Jamie Maguire, the Kenneth and JoAnn G. Wellner Professor of Neuroscience at the Tufts University School of Medicine, discovered that mice lacking neurosteroid-sensitive GABA receptors exhibit abnormal maternal behaviors as well as behavioral deficits in the postpartum period, with pups suffering increased mortality due to cannibalism or neglect (Maguire and Mody, 2008). Maguire’s research further showed that a selective agonist of the delta subunit of GABAA receptors improved maternal behaviors and increased pup survival. Therefore, Maguire proposed that high levels of neurosteroids during pregnancy are associated with a homeostatic downregulation of GABAA receptors to maintain an ideal level of inhibition during the pregnancy. When these neurosteroids begin to dramatically decrease at the time of delivery, the GABAA receptors need to be recovered to maintain an ideal level of inhibition in the postpartum period, she said. Deficits in the ability to recover these receptors at the time of delivery may increase the mother’s vulnerability to PPD, she explained. She also proposed that potentiating

GABAA receptors may be therapeutic for the treatment of PPD. More recently, Maguire and colleagues showed that treatment of the GABA receptor knock-out mice with a compound from SAGE Therapeutics called SAGE-516 improved postpartum behavior and decreased pup mortality.

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Taken together, Maguire said, these preclinical studies laid the foundation for the idea that GABA PAMs would be beneficial for the treatment of PPD in humans. Harder to explain, said Maguire, is how the action of PAMs on GABA receptors results in the persistent antidepressant effect of brexanolone seen in women with PPD. University of North Carolina School of Medicine Scientist David Rubinow proposed that allopregnanolone may mediate effective switching between neural network states, Maguire continued. Inspired by this idea, Maguire and colleagues proposed that these neuro steroids may help potentiate a high level of tonic inhibition that synchro- nizes the neural network and mediates a transition to a more stable and a healthier network state (Pavlov et al., 2014). Shifting their focus to the basal lateral amygdala, an area of the brain involved in emotional processing, Maguire’s team demonstrated a critical role for parvalbumin (PV) interneurons2 in mediating shifts between behavioral states related to fear; they showed that these interneurons express a high level of neurosteroid-sensitive GABA receptors (Antonoudiou et al., 2021). Further studies of the action of neurosteroids on PV interneurons confirmed that allopregnanolone and its synthetic analogs, such as SAGE-516, modulate behavioral states and neural network activity in the basal lateral amygdala via the delta subunit of the GABAA receptor on PV interneurons, said Maguire. In animals exposed to chronic stress, SAGE-516 had a profound effect on reversing anhedonia and other behaviors indicative of learned helplessness, she said. Her lab is now trying to harness the capability of endogenous neurosteroid synthesis to ensure the production and delivery of allopregnanolone at the intended site of action as a possible strategy to prevent some of the adverse side effects associated with exogenous neuroactive steroid treatment. Maguire added that there are likely multiple ways to disrupt this network, which may underlie the heterogeneity of symptoms observed in major depression or PPD.

CONVERGENCE OF MECHANISMS: KETAMINE AND BREXANOLONE Different agents, including ketamine and brexanolone, may mediate their antidepressant effects by converging on the same molecular targets, Lisa Monteggia, the Barlow Family Director of the Vanderbilt Brain Institute and professor of pharmacology, psychiatry, and psychology at Vanderbilt University. One indicator of convergence, she said, is that both drugs can trigger antidepressant effects for up to 1 week. Because this time course

2 PV interneurons are a subset of GABAergic interneurons that help regulate excitation and inhibition in brain circuits to drive behaviors (Ferguson and Gao, 2018).

PREPUBLICATION COPY—Uncorrected Proofs 30 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS supersedes the time it takes the drugs to clear the central nervous system and is not due to persistent blocking of NMDA or neurosteroid receptors, Monteggia suggested that some type of plasticity is engaged. Similar molecular mechanisms may also underlie the downstream effects of blocking

NMDA and GABAA receptors, said Monteggia. To understand this possible convergence, she suggested mapping out the neurocircuitry of antidepressant effects at a molecular level, adding that this could also help to identify new targets for pharmacological intervention. For example, if brexanolone and ketamine trigger antidepressant effects by engaging different receptors, but with convergence occurring downstream either molecularly or synaptically, a more nuanced but systematic approach may be needed to probe these pathways further, she said. Maguire said she has also been intrigued by the potential convergence between the mechanisms of ketamine and GABA PAMs and how changes in neural network states relate to the therapeutic effects of these compounds and their impact on behavior. She noted that modulation of both NMDA and GABA receptors may influence neural network function and could have similar effects on plasticity, adding that just as there are numerous ways to disrupt the neural network, there may also be multiple ways to restore a healthy neural network state. Indeed, György Buzsáki, the Biggs Professor of Neuroscience at New York University, said nearly every psychiatric condition can be characterized by a change in the constellation of neural network effects, and virtually every drug used in psychiatry affects the balance of inhibition and excitation. He added that tonic suppression of spiking may not equally affect neurodynamics in every brain state and that finding brain region-specific effects could be very useful for therapy. John Murray, assistant professor of psychiatry, neuroscience, and physics at Yale, added that by looking at cell-specific gene expression using single-neuron RNA seq data, it may be possible to identify the pathways involved at the cellular and microcircuit levels, which could help illuminate the paradoxical effects of central nervous system drugs on inhibitory neurons in certain brain structures. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, noted that electroconvulsive therapy (ECT) produces a sustained reduction in depressive symptoms similar to what is seen with brexanolone and ketamine, suggesting there are circuit changes that respond to the types of short-term neural circuit manipulations that ECT causes. Maguire agreed that this represents another point of convergence. If ECT is resetting the network in a similar way to ketamine and GABA PAMS, investigating these commonalities might lead researchers in the direction of more targeted treatments, she said.

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Emerging Drug Targets

Highlights • The search for novel antidepressants appears to be converging on the glutamate, NMDA, and mTOR pathways in the pre frontal cortex (Davis). • The protein complex mTORC1 regulates synaptogenesis; this pathway is suppressed in patients with major depressive disorder and chronically stressed animals, suggesting that mTORC1 activators may have antidepressant effects without the abuse potential of ketamine (Saiah). • Preclinical and Phase 1 clinical studies suggest that the first- in-class mTORC1 activator NV-5138 activates key synaptic proteins in brain regions implicated in depression and may relieve symptoms of depression (Saiah). • Classic serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and mescaline target 5-HT2A receptors with dramatic psychological effects (Gobbi). • In animal models, low doses of LSD increased social interaction and reversed symptoms of anxiety (Gobbi). • Using an in vivo screening approach in mice, scientists discovered an antipsychotic with a novel mechanism. It is an agonist of the TAAR1 and t-HT1A receptors with antidepressant properties at low doses and antipsychotic properties at high doses (Koblan).

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• A Phase 2 clinical trial of xanomeline, an M4/M1 muscarinic acetylcholine receptor agonist, showed improvements in psychotic symptoms and in an exploratory analyses also improved behavioral and cognitive scores (Breier). • Most drugs interact with or target multiple pathways, but the effects of polypharmacy are complex and difficult todeconvolute and study clinically (Davis, Gobbi, Koblan, Paul, Roth). • Drugs that target more than one molecular pathway may be required for efficacy (Brier).

NOTE: These points were made by the speakers identified above; they are not intended to reflect a consensus among workshop participants.

The lived experiences of people with psychiatric disorders vary significantly in terms of symptoms, frequency, and impact on their lives, challenging both clinicians and researchers to match effective treatments with patients who can benefit most, said David Gray, vice president of chemistry at Cerevel Therapeutics. Targeting the glutamatergic mechanisms (see Chapters 3 and 4) has made a substantial difference for some individuals, he said, but other mechanisms and treatment options are also emerging, supported by preclinical and clinical data. Moreover, even for the mechanisms discussed earlier, many unknowns exist with respect to the subtle modes of action, different modes of target modulation, and different downstream effects that may be keys to efficacy, said Gray. The search for novel antidepressants appears to be converging on a final common pathway—the glutamate receptor (NMDA/AMPA) to mTOR pathway—which modulates cellular activity in the prefrontal cortex, said Robert Davis, senior vice president and chief scientific officer atIntracellular Therapeutics. Multiple entry points into this pathway provide potential new targets for antidepressants, he said. Moreover, it is a very tightly controlled system with many checks and balances, he added. Several novel approaches to evaluating the role of this pathway in psychiatric illnesses are discussed in this chapter although this is not a comprehensive review.

mTOR SIGNALING—A TARGET FOR DEPRESSION AND PSYCHOSIS Rapamycin, a naturally occurring antifungal and immunosuppressive compound product discovered in 1975 (Vézina et al., 1975) opens the door

PREPUBLICATION COPY—Uncorrected Proofs EMERGING DRUG TARGETS 33 to the mechanistic target of rapamycin (mTOR) pathway. The mTOR pathway regulates cellular growth and the cellular response to nutrients through the activity of two protein complexes called mTORC1 and mTORC2, said Eddine Saiah, chief scientific officer at Navitor Pharmaceuticals. mTORC1 plays an especially important role in brain and mood disorders by regulating synaptogenesis via protein synthesis, axon elongation, and dendritic branching, said Saiah. For example, several studies have shown that the mTOR pathway is suppressed in patients with major depressive disorder and in animals that are chronically stressed, said Saiah. In addition, the efficacy of ketamine requires the activation of the mTORC1 signaling pathway and is blocked by rapamycin (Duman et al., 2016), he said (see Figure 5-1). These discoveries suggested the potential to identify direct mTORC1 activators that might have antidepressant effects similar to ketamine, but without the psychotomimetic effects and abuse potential, said Saiah. Research by several groups, including David Sabatini and colleagues at the Whitehead Institute and MIT, also led to the discovery of amino acid sensors that are required for the activation of mTORC1 and the development of small molecule modulators of these sensors that can also activate mTORC1. At Navitor Pharmaceuticals, Saiah and colleagues discovered a compound called NV-5138 that activates mTORC1 by disrupting the interaction between the amino acid sensor Sestrin2 and a protein called Gator2 (Sengupta et al., 2019). In animal models, they demonstrated that orally administered NV-5138 has favorable pharmacokinetics, activates key synaptic proteins in brain regions implicated in depression, shows efficacy comparable to ketamine, and is dependent on BDNF signaling (Kato et al., 2019). Saiah said that subsequent Phase 1 studies with NV-5138 have shown similar pharmacokinetics and efficacy even after a single dose. These studies established NV-5138 as a first-in-class direct mTORC1 activator, said Saiah. It gets into the brain, is rapidly absorbed, shows rapid and persistent molecular target engagement, provides rapid relief of core symptoms of depression, and has a favorable safety and tolerability profile. Saiah added that preclinical models demonstrate the efficacy of NV-5138 for up to 7 days, even though the compound has a half-life of only 2–4 hours. One possible explanation, he said, is that once the compound triggers mTORC1 to initiate protein synthesis, the drug can be cleared from the system in 2–4 hours while still mediating its effects over the course of 1 week.

SEROTONIN 5-HT2 RECEPTOR AGONISTS FOR MENTAL DISORDERS In Chapter 2, Steven Paul described how drugs that target serotonin receptors have been used for decades to treat depression and psychosis.

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FIGURE 5-1 Working model for the role of mTORC1 in the antidepressant response. This simplified model shows how ketamine inhibits or antagonizes NMDA receptors, leading to glutamate release, and activation of AMPA receptors and mTORC1, which results in synaptic protein translation and synthesis of factors that lead to release of BDNF. SOURCE: Presented by Eddine Saiah, March 9, 2021.

5-HT2A agonists also include a class of drugs called psychedelics or classic serotonergic hallucinogens, such as LSD, psilocybin, and mescaline, said Gabriella Gobbi, professor of psychiatry at McGill University. Although LSD was synthesized in the 1930s and shown to have dramatic psychological effects, abuse of the drug in the 1960s stifled clinical research for decades (Passie et al., 2008). Interest in using LSD therapeutically reemerged in the 1990s (Carhart-Harris and Goodwin, 2017). Earlier, Paul described how drugs that target serotonin receptors have been used for decades to treat depression and psychosis. 5-HT2A agonists also include

PREPUBLICATION COPY—Uncorrected Proofs EMERGING DRUG TARGETS 35 a class of drugs called psychedelics or classic serotonergic hallucinogens, such as LSD, psilocybin, and mescaline, said Gobbi. Although LSD was synthesized in the 1930s and shown to have dramatic psychological effects, abuse of the drug in the 1960s stifled clinical research for decades (Passie et al., 2008). Interest in using LSD therapeutically reemerged in the 1990s (Carhart-Harris and Goodwin, 2017). In 2016, Gobbi and colleagues demonstrated the electrophysiological effects of increasing doses of LSD on serotonin and dopamine neurons in different brain regions (De Gregorio et al., 2016). What they found was that low doses of LSD decreased serotonin firing activity, but with con tinued treatment over 7 days, activity increased. This observation led them to investigate long-term treatment with microdoses of LSD, said Gobbi. Using several different behavioral tests in mice, they showed no effect on depression or anhedonia, but increases in social interaction (De Gregorio et al., 2021). To determine the neurological basis of these behavioral changes, Gobbi and colleagues used electrophysiological methods to show that LSD increased activity at 5-HT2A and AMPA receptors in the medial prefrontal cortex (mPFC), but not 5-HT1A or NMDA receptors, she said. Using optogenetics in mouse models, they went on to show that inhibiting excitatory neurons in the mPFC nullified the prosocial effects of LSD. Gobbi said they also showed that LSD exerts its effects through the mTORC pathway. Still puzzled by the observation that LSD had prosocial effects but did not reduce depressive behaviors, Gobbi said they used a stress model in which animals were stressed for 15 days, and showed that low doses of LSD for 7 days reversed the symptoms of anxiety. The next question, said Gobbi, is whether low doses of LSD can be effective clinically for patients with depression, social anxiety, and/or autism spectrum.

TAAR1/5-HT1AR AGONISTS IN SCHIZOPHRENIA TREATMENT Kenneth Koblan, chief scientific officer at Sunovion Pharmaceuticals, described a recently developed antipsychotic drug that, unlike many conventional medications for psychosis, does not antagonize monoamine receptors. This agent, SEP-856, was granted breakthrough therapy designation by FDA, said Koblan. SEP-856 is an agonist at the TAAR1 receptor (Trace amine receptor 1) as well as at the 5-HT1A receptor, he said. SEP-856 was discovered with an in vivo screening approach using the SmartCube® system developed by PsychoGenics, said Koblan. SmartCube® uses reference compounds and pattern recognition software to build databases that link compounds to the types of behavioral phenotypes those compounds cause in rodents (Alexandrov et al., 2015). SmartCube® then compares this database against novel compounds to predict the potential

PREPUBLICATION COPY—Uncorrected Proofs 36 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS antipsychotic signatures of those compounds. Using this approach to opti- mize for antipsychotic compounds that do not interact at the D2 receptor or at 5-HT2A receptors, Koblan’s team discovered SEP-856, a small compound that has an antipsychotic-like profile in a number of different animal assays. They found that SEP-856 at low doses has antidepressant effects, while at higher doses it has antipsychotic effects (Dedic et al., 2019) (see Figure 5-2).

In vitro screening confirmed that the agent does not interact at the 2D or 5-HT2A receptor. “We believe that it modulates presynaptic dopamine synthesis capacity,” Koblan said regarding its hypothesized mechanism of action. A global, 4-week Phase 2 clinical study in acutely psychotic patients showed that across all geographies and subgroups, participants randomized to SEP-856 rather than placebo improved significantly on the Positive and Negative Syndrome Scale (PANSS), a scale used to measure the severity of symptoms in patients with schizophrenia. Participants were then able to roll over into an open-label safety study for 6 months, where they showed continued improvement. These robust effects were seen not only in PANSS

FIGURE 5-2 The behavioral drug signature of SEP-856 in behaving mice includes anxiolytic (yellow) and antipsychotic (purple) components in SmartCube®. NOTE: * antipsychotic (purple) and high-dose antipsychotic (dark purple); ** anti depressant (green) and high-dose antidepressant (dark green). SOURCES: Presented by Kenneth Koblan, March 9, 2012; adapted from Dedic et al., 2019.

PREPUBLICATION COPY—Uncorrected Proofs EMERGING DRUG TARGETS 37 scores, but in all other key secondary endpoints, including the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS); there was no evidence of treatment-emergent adverse effects, said Koblan (Koblan et al., 2020).

M1/M4 ACETYLCHOLINE MUSCARINIC RECEPTOR TARGETING FOR PSYCHOSIS Multiple lines of evidence suggest that muscarinic acetylcholine receptors (mAChRs) are involved in the pathogenesis of schizophrenia, said Alan Breier, the Indiana University Mental Health Research and Education Senior Professor of Psychiatry. Therefore, they represent excellent therapeutic targets, he explained. Five types of mAChRs are expressed in the brain; two of them, M1 and M4, have been implicated in neuropsychiatric disorders, said Breier. M4 serves as a gatekeeper for acetylcholine release. One hypothesis is that activation of M4 receptors may exert antipsychotic effects by decreasing acetylcholine release, which leads to decreased firing of dopamine neurons, he said. Several agents that target M4 and M1 receptors are in development for schizophrenia. Breier focused his attention on xanomeline, a muscarinic agonist that engages all five mAChRs, but preferentially engages M1 and M4. A Phase 2 placebo-controlled clinical trial of xanomeline in patients with Alzheimer’s disease unexpectedly showed dose-dependent significant improvement in psychotic symptoms, said Breier (Bodick et al., 1997). This was followed by a small exploratory study in patients with refractory schizophrenia, which demonstrated significant improvements in psychotic symptoms according to multiple clinical measures, including PANSS (Shekhar et al., 2008). Although the results of both xanomeline studies looked promising, Breier said there were high rates of side effects that commonly result from activating the peripheral cholinergic system, including nausea, vomiting, diarrhea, and excessive sweating. As a result, he said, the drug was licensed by Eli Lilly and Company to Karuna Therapeutics. Scientists at Karuna Therapeutics hypothesized that combining xanomeline with an older generic drug called trospium chloride, which reduces peripheral cholinergic side effects, might mitigate those unwanted outcomes while leaving the antipsychotic effects intact. A recently published Phase 2 study demonstrated that this combined therapy improved the patients’ PANSS total score, with similar improvements observed in clinical subscales that assessed the drug’s impact on positive and negative psychosis symptoms (Brannan et al., 2021). Breier noted that while there were no significant improvements in cognition relative to placebo, a post-hoc subgroup analysis suggested that participants with high baseline impairment did improve significantly.

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Importantly, he said, the combination of xanomeline and trospium demonstrated an improved safety profile with much lower rates of adverse events than were seen in studies of xanomeline alone. Meanwhile, he continued, two Phase 3 studies are under way.

NMDA MODULATION TO IMPROVE NEGATIVE AND COGNITIVE SYMPTOMS IN SCHIZOPHRENIA Venkatesha Murthy, global head of psychiatry in the Takeda Neuro science Therapeutic Area Unit, commented on the role of NMDA receptor modulation in the treatment of negative symptoms and cognitive impairment associated with schizophrenia. Clinical trials with bitopertin, a GlyT-1 inhibitor that modulates NMDA receptors failed to demonstrate the successful treatment of schizophrenia’s negative symptoms (Bugarski- Kirola, 2017). Similarly, a recent Phase 2 study of luvadaxistat, a D-amino acid oxidase inhibitor, did not meet its primary endpoint for reducing the severity of negative symptoms in stabilized schizophrenic patients (Neurocrine Biosciences Inc., 2021). With neither of these two different and well-characterized proof-of-concept clinical trials achieving their target endpoints for alleviating negative symptoms, Murthy suggested that, “we should exercise extreme caution in pursuing NMDA modulators for these effects, and also potentially consider a different regimen.” Although luvadaxistat was not found to improve negative symptoms, the drug developer for this compound reported that signals of improved cognitive performance were observed in some schizophrenia patients (Neurocrine Biosciences Inc., 2021). Similarly, a recent Phase 2 study of the glycine transporter-1 inhibitor, BI 425809, also demonstrated improved cognition in schizophrenia patients. (Fleischhacker et al., 2021). Given these indicators, the effects of NMDA modulators on cognitive performance need to be deeply characterized and replicated, said Murthy.

THE ADDED COMPLEXITY OF POLYPHARMACY Only rarely does a drug to interact with just one target or one pathway, said Davis. New targets and opportunities, as well as new challenges, may be identified by focusing attention on drug actions beyond receptors. Look- ing beyond receptors will add complexity to studies as well as the potential generation of large amounts of data that must be deconvoluted. Moreover, he noted, new tools are needed to facilitate the translation of novel compounds from nonclinical to clinical settings. Among the drugs discussed at this workshop, several also have pro- nounced polypharmacologic activity, said Bryan Roth, the Michael Hooker Distinguished Professor of Pharmacology at the University of North

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Carolina at Chapel Hill School of Medicine. For example, LSD could be called either one of the “dirtiest” drugs or the one with the most robust pharmacology, hitting probably 50 targets in the brain with very high potency. Which target is responsible for its effects remains unclear. Roth continued by noting that it is similarly unclear whether the effects of xanomeline result from actions on the M1 receptor, the M4 receptor, both, or lower affinity action at other receptors. Paul suggested that both M1 and M4 receptor targeting may be important—M1 more for treating the precognitive effects and negative symptoms and M4 more for treating psychosis. In Roth’s lab and others, researchers are leveraging computational approaches to construct roadmaps for developing drugs that interact with multiple molecular targets. Brier emphasized that hitting more than one target may be required for efficacy in complex diseases such as schizophrenia and depression. The extraordinary heterogeneity of these disorders adds further complexity, added Roth. Hundreds or maybe even thousands of loci may contribute to the genetic risk of these disorders, so it is not surprising that more than one molecular target would need to be engaged to affect the broad patient population. Whether targeted therapies for individual patients may ultimately prove beneficial remains an unanswered question, said Roth. Roth continued by remarking that unbiased proteomic and single- cell transcriptomic technologies are interrogating “a whole universe of intracellular pathways” and are studying those pathways longitudinally. Thanks to the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and other initiatives, he said, it is now possible to delve into the detailed chemical and molecular biology of drug actions for existing drugs and use that knowledge to identify even safer and more effective medications. He added that tools are also now available to examine whether these various drugs work similarly on a network level by altering excitatory and inhibitory neurotransmission pre- or postsynaptically. Other clinical endpoints could be useful in evaluating novel compounds, including those with polypharmacological properties, for their antipsychotic effects. For example, Koblan cited technological innovation around the use of electroencephalography, while Gobbi added that the measures of sleep duration and sleep quality have also been recently used as outcome measures in the development of drugs for neurological disorders.

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Regulatory Considerations for the Next Generation of Psychiatric Drugs

Highlights • FDA has provided regulatory guidance on the development of novel antidepressants with regimens and delivery methods different from those traditionally used, including agents given as a single dose with long-lasting effects, drugs given at fixed intervals, and those given to jumpstart treatment before dosing with traditional antidepressants (Farchione). • Study designs for rapidly acting antidepressants will require early endpoints as well as late endpoints to characterize the durability of the effect (Farchione). • Both esketamine and brexanolone received breakthrough therapy designation, were granted priority reviews, convened public advisory committee meetings, and used risk evaluation and mitigation strategies included as part of their approvals (Farchione). • Because the term “rapidly acting” is non-specific, the FDA labels for both brexanolone and esketamine show time-to- onset curves that demonstrate the treatment effect over time (Farchione). • In the esketamine trials, to ensure that participants with treatment-resistant depression did not receive placebo, all participants were treated with an oral antidepressant in addition to intranasal esketamine (Farchione).

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• Because sedation or loss of consciousness may occur when a patient is treated with brexanolone, continuous monitoring is essential and the sponsor agreed to postmarketing evaluation of alternative dosing regimens (Farchione).

NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants.

In 2018, FDA published draft guidance on drug development for major depressive disorder, which included advice for evaluating novel anti depressants (FDA, 2018), said Tiffany Farchione, director of the Division of Psychiatry in the Office of Neuroscience at FDA. Although the draft guidance was published before the approvals of esketamine and brexanolone, it was informed by the agency’s regulatory considerations from these drugs and other products under development at the time, she said. Traditional antidepressants include all antidepressants approved prior to 2019—SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and other drugs that are taken orally on a daily basis, said Farchione. By contrast, novel antidepressants could include drugs given as a single dose with long-lasting effects, drugs given at fixed intervals, drugs given on an as-needed basis, and drugs given to jumpstart treatment for an initial period before the effects of traditional antidepressants are noticeable, she said. To approve such drugs, Farchione said, FDA needs to see data that enable the agency to write a label that tells prescribers how to use the product. She added that the study design will vary depending on the intended use of the drug. For example, to assess the efficacy of a rapidly acting antidepressant, an early endpoint is useful. In addition to that, later endpoints are also needed to characterize the durability of the effect. The population for whom the drug is intended also must be clearly defined, she said. For example, a drug may be developed for the treatment of TRD, PPD, or other types of depression. Farchione noted that for traditional antidepressants, FDA has allowed maintenance studies to be conducted after market approval through randomized withdrawal studies because experience has demonstrated that these treatments continue to work. However, for novel antidepressants, data are needed to demonstrate appropriate dosing regimens over the long term for this chronic cyclical illness.

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THE APPROVAL OF ESKETAMINE As noted earlier, both esketamine and brexanolone received breakthrough therapy designation and priority reviews, and both had public advisory committee meetings prior to approval, said Farchione. Both of these drug approvals also include REMS, she said. For example, esketamine must be administered under supervision because it can induce feelings of dissociation. The initial treatment strategy for esketamine, which prescribes two doses per week, was based on preliminary data from previous ketamine studies. Because the drug is indicated for TRD, eligible trial participants must have failed at least two antidepressants of the same or different class, given at an adequate dose and of adequate duration. Farchione said inclusion in the trials was assessed retrospectively so that physicians could determine suitability for the trial based on the patient’s medication history. This approach enabled the trial to align with clinical practice, said Farchione. There were concerns that patients who had not responded to many treatments, and thus were in need of effective care, might be given a placebo rather than an active drug, Farchione said. To address these concerns, trial participants were started on a new oral antidepressant at the same time that the double-blind intranasal esketamine treatment was initiated. This “in conjunction with” treatment, where an oral antidepressant and intranasal ketamine were in simultaneous use, was another aspect of clinical trials that differed from trials of other conventional drugs in review. It also resulted in esketamine’s FDA labeling including the words “in conjunction with” rather than calling it an adjunctive treatment. Furthermore, FDA obtained commitments that the submitting drug development company would study whether esketamine can be given as a monotherapy, said Farchione. Because prior experience with traditional antidepressants is not appli- cable to drugs approved under a novel paradigm, Farchione said, FDA informed the submitting drug development company that it would not be sufficient to demonstrate an acute treatment effect to gain approval, but that they would also need to provide long-term data. In this case, the drug development company opted to conduct a trial supporting its unique dosing approach in which dosing changes over the course of treatment, starting with twice per week in the induction phase followed by once weekly or once every 2 weeks in the maintenance phase, she added. The agency also addressed the issue of time to onset in a unique way, Farchione continued. Because the definition of “rapidly acting” is not specific, the FDA label includes a figure showing the time course of efficacy (see Figure 6-1). The figure shows that while the two treatment curves separate as early as 24 hours after initial dosing, symptoms continue to improve with time, resulting in a statistically significant treatment effect at the day 28 endpoint. Interestingly and unexpectedly, participants who

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FIGURE 6-1 Esketamine versus placebo efficacy-time measures. The curves for esketamine + oral antidepressant (AD) and placebo + oral AD diverge as early as 24 hours after dosing, but continue to improve over time, resulting in a solid treatment effect by day 28. NOTE: In this flexible dose study, dosing was individualized based on efficacy and tolerability. Few subjects (<10 percent) had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly. SOURCES: Presented by Tiffany Farchione, March 9, 2021; esketamine full prescribing information, initial approval, March 5, 2019.

received the intranasal placebo also improved when they switched their oral antidepressants; however, those in the esketamine group improved more, which led to the product approval, she said.

THE APPROVAL OF BREXANOLONE Prior to the introduction of brexanolone, postpartum depression was treated similarly to an episode of major depressive disorder, said Farchione. However, as noted by Samantha Meltzer-Brody, a more rapidly acting drug was needed to prevent the risk of lasting negative effects on both the mother and child. Administered as a one-time, 60-hour infusion in a targeted population, the trials for brexanolone were complex, said Farchione. Participants in these studies were no more than 6 months postpartum. To assess the durability of the antidepressant effect while limiting the number of participants who might otherwise drop out of the study, the primary endpoint was the

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Hamilton Depression Rating Scale (HAM-D), assessed at hour 60 (the end of the infusion) and the secondary endpoint at day 30. Farchione said the rationale for making the second assessment at day 30 was that most participants did not start the trial immediately after giving birth, and if depression recurred more than 30 days later, it was more likely to reflect a traditional depressive episode that could be treated with a traditional antidepressant. Administration of the drug required continuous monitoring, said Farchione, because in the development program some patients experienced excessive sedation or even loss of consciousness. When this occurred, patients were aroused without incident when the drug infusion was sus- pended, she said. Because investigators were unable to identify predictors of loss of consciousness, a more stringent monitoring plan was necessary. In addition, the company agreed to a post-marketing commitment to evaluate alternative dosing regimens, such as in an outpatient, non-24-hour facil- ity. As with esketamine, the time to onset efficacy curves were included in the FDA label (see Figure 6-2). Farchione noted that a second study (not shown here) showed no difference from placebo at day 30 because the placebo group continued to improve and eventually caught up with the brexanolone-treated group. Farchione noted that neither the Montgomery-Asberg Depression Rating Scale (MADRS), which was used in the esketamine trials, nor the HAM-D are particularly good for detecting early signals of efficacy because many of the items rated by these measures would not be expected to change quickly. She said FDA accepted letters of intent for two patient-reported clinical outcome measures in development that focus on recall of depression symptoms over hours rather than days. She added that if either esketamine or brexanolone is evaluated for other chronic conditions such as PTSD, maintenance studies will most likely be required.

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FIGURE 6-2 Brexanolone versus placebo efficacy-time measures. The curves for brexanolone at two doses versus placebo diverge. Statistical significance is observed at hour 60, with the effects persisting until day 30. NOTE: ZULRESSO was administered via a 6-hour intravenous infusion as fol- lows: 90 mcg/kg/hour-target dosage: 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 20 hours, 90 mcg/kg/hour for 28 hours, 60 mcg/kg/hour for 4 hours, 30 mcg/kg/hour for 4 hours; 60 mcg/kg/hour-target dosage: 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 52 hours, 30 mcg/kg/hour for 4 hours. SOURCES: Presented by Tiffany Farchione, March 9, 2021; brexanolone full prescribing information, initial approval, March 19, 2019.

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Ethical and Legal Principles Related to the Clinical Use of Psychoactive Drugs

Highlights • The potential for new antidepressants and antipsychotics to elicit dissociative experiences raises ethical concerns beyond those of traditional psychopharmacological treatments (Appelbaum, Mates). • Patients with a history of suicidality or drug abuse should be included in clinical trials of antidepressants because these patients are most likely to seek clinical care for depression (Appelbaum). • New approaches, including integration of information about the patient experience, are needed to obtain meaningful consent from patients and trial participants, particularly regarding the risk of dissociative experiences (Appelbaum, Clayton). • New approaches are needed for assessing capacity for consent in patients with severe and disabling depression (Appelbaum). • To monitor the abuse potential of psychoactive medications, post-marketing monitoring may be necessary (Appelbaum). • Oversight of commercial centers for delivery of psychoactive medications may be needed to prevent coercive and otherwise problematic practices (Appelbaum). • The high cost of lifesaving treatments for depression creates unequal access to different population groups and must be addressed at the societal level (Appelbaum, Clayton, Singh).

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• Precautionary approaches designed to safeguard patients have the potential to limit patient access to lifesaving treatments, but increasing access may contribute to more widespread abuse (Appelbaum, Marks, McShane, Singh, Volkow). • The classic hallucinogen psilocybin is classified as a Schedule I controlled substance by the Drug Enforcement Administra- tion (DEA), but has also received breakthrough therapy status for depression by FDA, raising complicated legal challenges (Marks).

NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants.

While new agents for the treatment of depression and schizophrenia have helped some patients who have not had success with other agents, the dissociative side effects and other events have raised concerns about appropriate patient selection, patient consent, and the risk of abuse, said Sharon Mates, co-founder, chair, and CEO of Intracellular Therapies. Paul Appelbaum, the Elizabeth K. Dollard Professor of Psychiatry, Med- icine, and Law and director of the Center for Law, Ethics, and Psychiatry at the Vagelos College of Physicians and Surgeons at Columbia University, agreed. He added that the use of psychoactive drugs1 like ketamine and brexanolone raises ethical concerns that differ in extent and sometimes in nature from those used in conventional psychopharmacologic treatment. However, given the potential for greater effectiveness for intractable and treatment-refractory conditions, he suggested that rather than abandoning the use of these treatments, systematic and proactive approaches should be developed and implemented to ensure their appropriate use.

TRANSLATING ETHICAL PRINCIPLES TO THE CLINICAL USE OF PSYCHOACTIVE DRUGS Translating the general ethical principles that apply to all aspects of medical practice—beneficence, non-maleficence, respect for persons, and

1 NIDA defines psychoactive drugs as drugs that act on the central nervous system and alter its normal, everyday activity, causing changes in mood, awareness, and behavior. These include depressants like alcohol and sleeping pills; stimulants like nicotine and ecstasy; opioids like heroin and pain medications; and hallucinogens like LSD (Bellum, 2010).

PREPUBLICATION COPY—Uncorrected Proofs ETHICAL AND LEGAL PRINCIPLES 49 distributive justice—to the clinical use of psychoactive drugs presents many challenges, said Appelbaum. These ethical challenges, he said, should be seen not as roadblocks but as speed bumps, signaling the need to slow down and develop thoughtful approaches and policies. He summarized six of these challenges and offered suggestions for how they might be addressed.

Ensuring Likely Benefits Outweigh Risks for Individual Patients As mentioned earlier, clinical trials frequently exclude the very categories of patients commonly seen in clinical practice, said Appelbaum. For example, the esketamine trials had an exclusion criterion of suicidal behavior in the past year or suicidal ideation with some intent to act in the previous 6 months. Patients with a history of substance abuse are also typically excluded from clinical studies, especially for drugs with the potential for abuse. While these exclusion criteria are used in trials of nearly all new medications, Appelbaum suggested that they are particularly salient for psychoactive drugs because issues like intractable suicidality are exactly why patients seek clinical care and are what motivates clinicians to look beyond standard treatments to something such as ketamine. Moreover, he said, the differential impact of a drug on people with substance abuse histories may be more important for drugs with abuse potential. Thus, excluding patients in either of these two subgroups makes it less likely that the trial will be able to accurately ascertain either the benefits or the risks associated with the drug among these typical patients. To ensure that benefits outweigh the risks for high-risk groups, Appelbaum suggested that clinical trials be required to include patients with conditions likely to be found in the target population. This does not mean that acutely suicidal people or those with histories of abuse should be included in the first trials of a new medication, he added, but only after some evidence of efficacy has been demonstrated.

Obtaining Meaningful Informed Consent To obtain truly informed consent, the risks and benefits of treatment must be conveyed to patients in terms that are understood and meaningful. However, this may be particularly difficult for psychoactive medications, said Appelbaum. For example, dissociative experiences were the most commonly seen severe side effects in the esketamine trials, yet are difficult to describe to someone who has never experienced dissociation, he said. It also may be difficult to explain to a patient that although treatment may provide relief from the severe psychic pain associated with treatment-resistant depression, adjusting to a life without depression presents other significant challenges that may need further treatment and therapy, said Appelbaum.

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He suggested further research to better understand how to convey inherently alien experiences like dissociation or recovery from chronic depression. Whether dissociative experiences are integral to obtaining efficacy or a side effect of the drug, people need to understand the risk even if it is a low-incidence risk, he said. Paper-based consent forms may not be sufficient, he said, suggesting that creativity and new technologies such as virtual reality may be needed. Lessons may also be learned from the adver- tising industry, which knows how to communicate concepts concisely and in engaging ways, he said. Ashley Clayton, whose personal experiences with ketamine treatment for treatment-resistant depression were described in Chapter 2, suggested leveraging the patient experience to improve the process of informed consent for experiences that may be difficult to articulate. When considering ECT, for example, she noted that reading the scientific literature and talking to her physician failed to give her the insight she obtained from reading patient narratives.

Ensuring Competent Consent Patients with severe or intractable conditions such as treatment-resistant or postpartum depression may also have diminished competence to consent to treatment, said Appelbaum. Moreover, their desperation to receive treatment may lead them to underestimate the risks and overestimate the likelihood of benefits. He suggested that new approaches may be needed to systematically assess patients’ capacity for consent to treatment for severe and disabling conditions.

Dealing with Abuse Potential Appelbaum cited three possible ways that treatment with psychoactive medications may lead to abuse: (1) the psychoactive effect is experienced as pleasurable; (2) an incomplete treatment response may lead patients to seek drugs on the black market, believing that more frequent or higher doses would lead to a better outcome even though escalating doses could also increase the risk of adverse effects; and (3) incentives may exist to divert medication to the unregulated market, as has been seen with stimulants prescribed for attention deficit hyperactivity disorder that are widely spread on college campuses, for example. Research suggests that, at least for esketamine, abuse has been rare. Nonetheless, concerns remain, especially as the drug transitions to general clinical use with less strict regulatory oversight. Appelbaum added that while FDA required a REMS for esketamine, more regular post-marketing monitoring of abuse of approved drugs may

PREPUBLICATION COPY—Uncorrected Proofs ETHICAL AND LEGAL PRINCIPLES 51 also be needed. “This is probably the primary lesson that comes out of the opioid epidemic because of how long it took us to awaken to the reality of widespread abuse in the community,” he said.

Mitigating Risks Associated with Commercialization When for-profit centers provide prescriptions for psychoactive medications, Appelbaum worried that there might be incentives for clinicians “to behave in a less than completely cautious way” by prescribing for less severely ill patients, those with less clearly defined diagnoses, or those who might respond to standard medication. He added that ketamine infusion centers are largely unregulated and can be easily accessed. These centers can offer inducements to patients, such as rebates for continued treatments that may not be needed, he said (Sisti et al., 2014). Appelbaum suggested that intensive oversight may be needed to identify and restrict problematic practices. He added that it might be necessary to restrict direct-to-consumer marketing of drugs like ketamine.

Ensuring Fair Access to Medications In Chapter 2, Ashley Clayton described her struggle to receive lifesaving ketamine treatments for TRD. She said that while she continues to rely on free access to ketamine, this could end if hospital administrators decide they can no longer absorb the cost of her care. Doctors can prescribe ketamine off-label, but reimbursement for treatment remains a huge barrier, she said. FDA’s approval of esketamine for TRD may help, but according to Clayton, “like most of mental health care, unequal access is a significant problem.” A session of treatment with esketamine can cost more than $700, and a 60-hour infusion of brexanolone $34,000, said Appelbaum. Yet, whether insurers will cover these medications is not clear, and many patients lack health coverage. Fair access can only be achieved on a societal level, he said, by instituting policies such as those that regulate predatory pricing or encourage companies to create patient assistance programs. Global access to these medications represents an additional ethical dilemma, added Ilina Singh, professor of neuroscience in society at the University of Oxford. Underlying this access issue are two challenges: (1) the lack of trial data from these populations, and (2) insufficient infra- structure for the delivery of care using these drugs. Singh advocated for further exploration of how to tackle these dual challenges in contexts where there is a significant lack of clinical services and personnel.

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Safeguarding Patients While Expanding Access Singh raised additional ethical issues that have implications for clinicians treating patients with antidepressants and antipsychotics. First, she said, is the philosophical question of how these treatments may affect a patient’s sense of authenticity or identity, and what the appropriate role is for the clinician in relation to this concept. For example, she recalled how Ashley Clayton described a dual kind of suffering she experienced from the depression itself, followed by the loss of the person who was briefly released from that suffering (see Chapter 2). Singh suggested that the rapid onset of the therapeutic effects can have the potential for harm when the medications cause revelatory highs followed by abrupt drops. These swings could disrupt the patient’s sense of authenticity, and more discussion is needed to understand and address this phenomenon, she said. The second issue Singh raised relates to building an ethical framework around the regulation of these potentially lifesaving drugs that balances the need for good drug stewardship and the need to maximize access. She, along with research and clinical colleagues in the United Kingdom, published an article in 2017 that proposed an ethical framework around the regulation of ketamine (Singh et al., 2017). This framework argued that despite limited evidence, patient needs could outweigh uncertainty if certain precautionary conditions were put in place, such as restricted access to those with severe TRD and close monitoring by the clinician. They also suggested creating international registries to share trial information and data on safety and efficacy. However, she also questioned whether this precautionary approach is inadvertently fueling the problem of lack of access to these medications. For example, she noted that more trial evidence is now available on the use of intranasal ketamine, which is regulated under a REMS, while at the same time, information in the lay literature is leading people to seek out ketamine in oral or intranasal form for depression. In cases like these, a shift may be needed in balancing patient access and suggested precautions, she said. She also noted the potential value of real-world data from black and grey market sources. There is no question that REMS is needed, she said, but parallel processes are needed that take into account what is happening outside the clinic and on the street, she said. Although the European Medicines Agency approved intranasal esketamine for adults with treatment-resistant major depressive disorder in 2019, the United Kingdom’s National Institute of Clinical Excellence rejected it for use within the National Health Service (NHS), saying that it is not cost-effective, said Singh. Meanwhile, the Medicines and Healthcare Products Regulatory Agency has mandated a company registry that collects data on each treatment with intranasal esketamine, said Rupert McShane,

PREPUBLICATION COPY—Uncorrected Proofs ETHICAL AND LEGAL PRINCIPLES 53 associate professor in psychiatry at the University of Oxford. McShane runs an off-label ketamine infusion clinic within the NHS, where a few patients (usually Americans) come seeking “ketamine top-ups” because they do not think they are getting enough relief from esketamine alone. The problem, said McShane, is that clinicians prescribing ketamine are not able to look at the registry to see if a person has been getting esketamine somewhere else. He suggested that a publicly funded registry with prescribing information on multiple drugs could mitigate this problem and protect both patients and clinicians from the dangers of overprescribing. However, Mason Marks, assistant professor at the Gonzaga Univer- sity School of Law, argued that increasing access rather than increasing restrictions is the best way to get these drugs to the people who need them. Prescription monitoring databases raise significant concerns about privacy, can stigmatize people, and can perpetuate systemic racism and bias, particularly if they are using artificial intelligence to formulate risk prediction scores, he said. Appelbaum countered that easing access can contribute to more widespread abuse, as has been demonstrated with the opioid epidemic, where increasing the legitimate prescription of opioids failed to alleviate the oxycontin black market. In response, Marks raised the point that since opioid overdoses are predominately the result of illicit use, this is a good illustrative example of how restricting prescribing did not decrease overdoses, but instead had the unfortunate effect of limiting opiate medication access to patients with chronic pain and other conditions. He suggested that anonymous data collection is needed to estimate the extent of the problem with ketamine. Singh added that the therapeutic alliance, where patients and clinicians work cooperatively to manage the patient’s care, is key to solving the problem of potential abuse. Nora Volkow, director of NIDA, said that evidence supports both sides of the argument: that better regulation and oversight can be protec- tive, but can also have negative consequences. She added that the approval and increased use of ketamine for depression have increased awareness of the importance of research on substances that have addictive potential. Moreover, for drugs such as PCP and LSD, which do not have the addictive quality that dramatically destroys people’s lives, some people have very negative reactions to the drugs. Understanding how to use them in a way that will minimize these negative outcomes is crucial, she said, yet what she called “extremely draconian regulation” of Schedule I substances makes it difficult to conduct such research.

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PSILOCYBIN THERAPY: CLINICAL USE AND LEGAL CHALLENGES Psilocybin is a classic hallucinogen similar to LSD, which was discussed briefly in Chapter 5. It is a 5-HT2A receptor agonist that has been shown to produce sustained decreases in symptoms of depression and anxiety, said Marks. However, despite no clear evidence of physical or psychological dependence—unlike some other compounds such as ketamine and benzodiazepines, he continued—psilocybin is classified as a Schedule 1 controlled substance. Therefore, DEA holds the position that this compound has no currently accepted medical use, has a high potential for abuse, and has a lack of accepted safety for use under medical supervision (DEA, 2020). However, FDA has given psilocybin breakthrough therapy status for depression, and several clinical trials are underway in the United States and other countries. In this context, psilocybin may be administered orally under controlled, supervised conditions over an eight-hour period, he explained. Marks noted that agricultural products containing psilocybin can be purchased over the counter in the Netherlands. Canada allows people at the end of life to access psilocybin through a compassionate use program. In the United States, advocates are working at the state level to relax restrictions on the medical use of psilocybin. Oregon passed a measure in November 2020 to set up a statewide industry for psilocybin therapy and will begin issuing licenses for manufacturers and facilitators in 2023. Other states have proposed similar bills or have taken more conservative approaches such as limiting its use to end-of-life care, creating task forces to explore the issue further, or developing bills to decriminalize psilocybin, he remarked. Marks highlighted examples of issues and unresolved questions relat- ing to psilocybin. Firstly, U.S. states are grappling with how to regulate the compound. Although several issues remain unresolved, states are moving forward to formulate regulations, said Marks. For example, the governor of Oregon is about to appoint a psilocybin advisory board that will recom- mend regulations and training guidelines for psilocybin therapy facilitators, he remarked. Secondly, he continued, a major open question asks what are the best practices for psilocybin research, psilocybin-assisted therapy, and clinical screening.

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Potential Next Steps and Future Opportunities

Highlights • A more sophisticated understanding of chemical neuro transmission and synaptic biology, as well as new clinical paradigms, are needed to facilitate the development of new and better therapeutics for psychiatric disorders as well as predictive biomarkers for stratification of patients (Clayton, Farchione, Murthy, Paul). • Psychiatric disorders may represent dysrhythmias of brain neurocircuits and may require novel treatment approaches combining multiple drugs, procedures, and devices (Paul). • A systems perspective could help answer unresolved questions regarding treatment refractoriness to enable the identification of new targets and to help design polytherapeutic, precision medicine approaches (Haas, Meltzer-Brody). • Multidisciplinary approaches that look beyond neurons to consider systemic issues, such as inflammation, could help identify novel therapeutic targets (Hoffman). • Improving cognition and function in patients with schizophrenia is an important goal, which may be realized through cognitive training as well as pharmaceutical and psychosocial treatments (Staglin).

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• Better stewardship of valuable new medications is essential to prevent overuse, backlash, and stigma. This will require collaboration with patients to collect large datasets that demonstrate outcomes and safety of these drugs (McShane). • Computational methods that simulate what is known experimentally across different pathways, circuits, and systems could enable the creation of in silico models to predict complex biological effects and test those assumptions (Haas). • Comorbidity, unclear taxonomies, reduced specificity across diagnostic categories, and increased molecular complexity pose challenges to the development of precision medicine approaches for psychiatric disorders (Simon). • New research efforts and more companies entering the psychiatric treatment space offer hope for the future identification of novel targets, drugs, and treatment paradigms (Farchione).

NOTE: These points were made by the individual speakers identified above; they are not intended to reflect a consensus among workshop participants.

Despite recent successes in the development of new therapeutics for psychiatric disorders, many questions remain unanswered, said Steven Paul. He suggested that a more sophisticated knowledge of chemical neuro transmission and synaptic biology or an increased understanding of etiology and pathophysiology may lead to the identification of new and better drug targets. This increased understanding may also yield predictive biomarkers that will allow the stratification of patients for more precise treatments. Farchione noted that several research programs, including the Acceler- ating Medicines Partnership for Schizophrenia (AMP Schizophrenia)1 and the Foundation for the National Institutes of Health (FNIH) Autism Biomarkers Consortium for Clinical Trials2 (ABC-CT), are working to identify biomarkers and more accurately define the pathophysiology of disorders. She expressed optimism about the future of psychiatric treatments, not only because of the identification of new targets, drugs, and treatment paradigms, but also because new companies are entering this space.

1 To learn more about AMP Schizophrenia, see https://www.nih.gov/research-training/ accelerating-medicines-partnership-amp/schizophrenia (accessed August 7, 2021). 2 To learn more about the FNIH Autism Biomarkers Consortium for Clinical Trials, see https:// fnih.org/our-programs/biomarkers-consortium/autism-biomarkers (accessed August 7, 2021).

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Paul agreed that new clinical paradigms, such as small sample size proof- of-principle trials, are needed to test novel compounds as antidepressants and antipsychotics. Venkatesha Murthy noted that high placebo responses in clinical studies for mood disorders, schizophrenia, and other psychotic disorders had limited the ability to translate innovative mechanisms into promising treatments. He suggested that shared placebo data and/or com- parator trials against the standard of care rather than a placebo may help mitigate this problem.

NOVEL APPROACHES NEEDED TO ADDRESS UNANSWERED QUESTIONS In certain areas of medicine, unanticipated approaches have proven to be instrumental in changing the field, and these types of “black swan” approaches may be on the horizon in psychiatry, said Paul. He suggested that such strategies may involve boosting resiliency to pathogenic processes as well as the use of optogenetics and chemogenetics, invasive and non- invasive neuromodulation, and combinations of drugs and devices. Black swan approaches require an entirely different way of thinking, he said. For example, he posited that psychiatric disorders may represent dysrhythmias of brain neurocircuits and may require novel treatment approaches similar to the way cardiac arrhythmias are treated with multiple drugs, procedures, and devices.

Taking a Systems Perspective One poorly understood aspect of psychiatric disorders is treatment refractoriness, said Samantha Meltzer-Brody, who spoke about the clinical effects of brexanolone in PPD patients in Chapter 4. In the case of post partum depression, for example, she said, it is not uncommon for patients to report that they are suffering from PPD even many years after the birth of their child. Brexanolone can be given for up to one year postpartum, she said, but there has not been sufficient research to know how to treat these women appropriately with precise and targeted therapies. Meltzer-Brody suggested that a systems perspective is needed to design polytherapeutic and precision medicine approaches. In precision psychiatry, treatments are refined based on the underlying pathophysiology and the molecular genetic profile of an individual patient. She noted that the results of a very large genetic study are coming out soon. These may provide biomarkers that can help guide treatment. Magali Haas, chair, CEO, and president of Cohen Veterans Bioscience, also advocated for a systems perspective. In stark contrast to other fields where the classification of diseases is defined by disease mechanism, neuro

PREPUBLICATION COPY—Uncorrected Proofs 58 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS psychiatry continues to diagnose disorders based on emergent behavioral outcomes, she said. She argued that the field needs to come together as a community to craft an integrated view of the evidence. Using computational methods to simulate what is known experimentally across different pathways, circuits, and systems could enable the creation of in silico models to predict complex biological effects and test those assumptions, thus inform- ing and improving understanding of disease mechanisms, said Haas. The challenge, however, is that large, deep, and rich phenotypic datasets with biomarker data collected longitudinally across populations and mapped to a common data model are currently unavailable. A systems perspective such as the one Haas envisions could enable the identification of novel molecular targets, then use that information to inform rational approaches to polytherapies that could integrate drug treatments with device and digital solutions. Multidisciplinary approaches to therapeutic development for mental health conditions that go beyond a sole focus on neurons may also fuel progress, said Stuart Hoffman, senior health science officer for Traumatic Brain Injury (TBI) for the Office of Research and Development at the Department of Veterans Affairs. He noted that TBI often leaves people with neurobehavioral conditions such as depression, anxiety, PTSD, and impul- sivity. Given that TBI is also often associated with both acute and chronic inflammation, that neurons themselves express receptors for cytokines and other inflammatory mediators, and that lymphocytes have neurotransmitter receptors, Hoffman suggested that the mechanisms underlying the effects of some of the therapeutics discussed at this workshop may involve non- neuronal networks.

Cognitive Training to Improve Function in Schizophrenia Brandon Staglin, president of One Mind, spoke about his experience living with schizophrenia, in particular how a turning point in his recovery came about in 1998 when he took part in a clinical trial of cognitive training led by Sophia Vinogradov at the University of California, San Francisco. The trial used computer-based exercises designed to strengthen specific neural pathways in the brain and improve cognition and function. Staglin believes this approach helped not only by inducing neuroplasticity in his brain, but also because the training gave him a sense of purpose. Vinogradov and others went on to show that auditory training improves auditory cognition as well as executive function, working memory, and behavioral organization by strengthening specific circuits in the prefrontal cortex, said Staglin. By addressing the primary symptoms of schizophrenia that contribute to disorganized thinking, Staglin said the approach improved his occupational functioning and ability to work.

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A second turning point for Staglin came when he began taking aripiprazole, a partial D2 receptor agonist, which he believes also improved his cognition and motivation. He suggested that digital, pharmaceutical, and psychosocial treatments may work synergistically to help patients in a broad and deep way, helping them renew their sense of purpose and live fulfilling lives.

FINAL THOUGHTS ON THE FUTURE OF THERAPY FOR PSYCHIATRIC DISORDERS For decades there was no light at the end of the tunnel in terms of new drugs for schizophrenia and depression, said Bryan Roth. Data presented at this workshop, however, suggest that “we have almost an embarrass- ment of riches,” he said. These include xanomeline and NV5138, two new drugs that appear to lack the metabolic and motoric side effects of all known antipsychotic drugs, as well as several new antidepressants, including brexanolone, with robust and sustained effects. Rupert McShane, however, noted that the history of psychiatry is littered with potent interventions that have been overused, leading to backlash and stigma. Careful stewardship of these new valuable medicines will be necessary to avoid this fate again, he said. Specifically, he worried that the slow acceptance of ketamine as a treatment tool might lead to a societal response that is excessively restrictive regarding its therapeutic use. This may exacerbate poor access, increase costs, drive up instances of self-treatment, and foster stigma. Alternatively, he said, the vision that Paul Appelbaum espoused may be realized, where trials continue with fewer restrictions, broader inclusion criteria so that problems are identified early, and longer term follow-up. To achieve this, he said, will require collaboration with patients in the collection of large datasets that enable establishing outcomes and safety. Greg Simon, an investigator at Kaiser Permanente Washington Health Research Institute and psychiatrist in Kaiser Permanente’s Behavioral Health Service, argued that the push in psychiatry for greater precision and more refined therapeutic targets has been stymied by increasing diffu- sion across the taxonomies of disorders and therapeutics. Comorbidity has become the norm, he said, with people often receiving multiple diagnoses across the domains of anxiety, mood, and psychotic disorders, while at the same time polypharmacy is becoming more common. Reduced specificity across diagnostic categories and in the selection of pharmacological therapies, he said, has resulted in treatments with mediocre effectiveness across multiple categories. Moreover, he suggested that these unclear taxonomies and non-specific outcome measures may hinder the discovery of better therapeutics. To emerge from this “morass,” he suggested following the path taken in the cancer space, where new targets and new therapeutics

PREPUBLICATION COPY—Uncorrected Proofs 60 NOVEL MOLECULAR TARGETS FOR MOOD DISORDERS AND PSYCHOSIS remade the taxonomy, which led to the discovery of more new targets and new therapeutics in a self-reinforcing positive cycle. Simon acknowledged, however, that more complex scenarios are likely to pose unexpected challenges. Using the analogy of a door with multiple locks, Simon suggested that each lock may need to be engaged by a different key, with the relative importance of each key varying from door to door. Even more complexity could arise if efficacy requires each key to engage its lock in a particular order, he said. Meeting what she called the pandemic’s “mental health tsunami” has been a challenge, said Meltzer-Brody, but it is also an opportunity for the field to come together with a singularity of purpose to do the important work necessary to address the huge rates of anxiety, depression, PTSD, and other mental health consequences of the pandemic.

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Workshop Agenda

Novel Molecular Targets for Mood Disorders and Psychosis: A Workshop March 8–9, 2021 | Via Zoom

WORKSHOP OBJECTIVES This public workshop will bring together experts and key stakeholders from academia, government, industry, and nonprofit organizations to explore novel molecular targets for mood disorders and psychosis, including ketamine, other NMDA receptor antagonists, neurosteroids, muscarinic antagonists, and serotonergic receptor modulators. Invited presentations and discussions will be designed to:

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• Explore the different types of bioethical frameworks that will be needed to guide the regulation and administration of novel therapeutics that mediate profound effects on consciousness. • Consider emerging molecular targets for treating psychosis and cognitive impairment in schizophrenia and how therapeutic development could be informed by lessons learned in developing novel therapeutics for mood disorders. • Discuss open research questions and opportunities to move the field forward.

DAY 1, MARCH 8, 2021

Session 1: Introduction to Drugs and Drug Targets for Mood Disorders and Psychosis Objectives: • Provide a high-level overview of the current landscape of novel molecular targets for mood disorders and psychosis. • Discuss the scientific and clinical limitations of current pharmacological interventions to address mental illness. • Highlight the unmet needs of people living with schizophrenia and treatment-resistant depression via testimonials from individuals who can speak to the subjective experience of these disorders.

2:00pm EST Welcome and overview of workshop LINDA BRADY, National Institute of Mental Health (NIMH), Workshop Chair

2:10pm The lived experience and unmet needs of individuals with schizophrenia and depression CARLOS LARRAURI, National Alliance for Mental Illness ASHLEY CLAYTON, Yale University

2:30pm Introductory talk: Scientific perspective on the history of drug treatments for mood disorder and psychosis STEVE PAUL, Karuna Therapeutics

2:50pm Audience Q&A

3:00pm BREAK

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Session 2: Promising Developments with Glutamate Receptors Objectives: • Review clinical and preclinical data of ketamine as a case study of a novel, rapidly acting antidepressant that acts by blocking glutamate receptors. • Examine possible explanations for the underlying mechanism of action. • Explore the clinical and regulatory ramifications of rapidly acting antidepressants. • Identify lessons learned and how they can help advance drug development targeting novel pathways.

3:10pm Session overview HUSSEINI MANJI, Janssen Research & Development, LLC

3:15pm GluRs as a novel molecular target: Clinical data on the use of ketamine and esketamine CARLA CANUSO, Janssen Research & Development, LLC • Who are the best candidates for treatment and why? • Which specific major depressive disorder symptoms and behaviors show the most improvement? • Is there evidence demonstrating that ketamine can prevent relapses? • After a single treatment, how long does the antidepressive effect persist? • What are the implications of intermittent drug administration over the long term?

3:35pm GluRs: Investigating the mechanism of action for therapeutic ketamine JOHN KRYSTAL, Yale University • What are the relevant downstream cellular events? • How does ketamine alter cellular and circuit activity? • Are there biomarkers that could be predictive of clinical efficacy? • Why is NMDA-R antagonism via ketamine effective for depression, while NMDA-R antagonism via other drug compounds is not?

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3:55pm Panel discussion: Identifying lessons learned and key open questions The Session 2 speakers above will be joined by panelists: MORGAN SHENG, Broad Institute of the Massachusetts Institute of Technology and Harvard CARLOS ZARATE, NIMH

4:35pm Audience Q&A

4:50pm Day 1 synthesis and closeout LINDA BRADY, NIMH, Workshop Chair

5:00pm ADJOURN

DAY 2, MARCH 9, 2021

Session 3: Promising Developments with GABA Receptors Objectives: • Review clinical and preclinical data demonstrating that novel drugs targeting gamma-aminobutyric acid receptors (GABARs) can alleviate depressive symptoms. • Examine how drug development directed toward novel targets and pathways could be informed by a new understanding of GABA modulators in depression. • Discuss how emerging drug targets for GluRs and GABARs advance our understanding of excitation/inhibition balance in mood circuits.

10:00am Overview of session CHARLES ZORUMSKI, Washington University School of Medicine

10:05am GABARs as a novel molecular target: Promising clinical data SAMANTHA MELTZER-BRODY, University of North Carolina at Chapel Hill • How long does it take for a treatment effect to be observed? • What is the treatment effect size relative to the standard of care? • What is the impact of route of administration (oral versus intravenous)?

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• How is information like patient age, symptom severity, and disease onset used to design effective treatment plans? • Wh ich molecular pathways are presumed to be involved?

10:20am GABARs: Mechanisms of action for GABA-A modulators in depression JAMIE MAGUIRE, Tufts University • How have hormone withdrawal and neurosteroid signaling been implicated in the pathophysiology of postpartum depression? • How and why are phasic and tonic GABAR signaling differentially effected? • Why are some GABAergic modulators, but not others, effective antidepressants and what does that tell us about the etiological specificity of depressive disorders?

10:35am Panel discussion: Tuning the balance of excitation and inhibition The Session 3 speakers will be joined by: GYÖRGY BUZSÁKI, New York University LISA MONTEGGIA, Vanderbilt University JOHN MURRAY, Yale University

11:15am Lessons learned from a regulatory perspective TIFFANY FARCHIONE, Food and Drug Administration (FDA) • How do the regulatory approaches to esketamine and brexanalone inform considerations for similar incoming programs? • What framework do regulators use when considering rapidly acting antidepressants and drugs that are administered via an intermittent dosing?

11:45am Audience Q&A

12:00pm LUNCH

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Session 4: The Road Ahead for Emerging Drug Targets Objectives: • Consider emerging drug development pathways for mood disorders and psychosis. • Discuss lessons learned in translation and clinical development that could be applied across programs to develop novel therapeutics. • Explore how these emerging targets inform new scientific strategies for drug development.

1:00pm Overview of session DAVID GRAY, Cerevel Therapeutics

1:05pm mTOR signaling in depression treatment EDDINE SAIAH, Navitor Pharmaceuticals

1:15pm Serotonin 5-HT2 receptor agonists for mental disorders GABRIELLA GOBBI, McGill University

1:25pm TAAR1/5-HT1AR agonists in schizophrenia treatment KENNETH KOBLAN, Sunovian Pharmaceuticals

1:35pm M1/M4 acetylcholine muscarinic receptor targets ALAN BREIER, Indiana University–Purdue University, Indianapolis

1:45pm Panel Q&A: Emerging developmental pathways in mood disorder and psychosis The Session 4 speakers will be joined by: ROBERT DAVIS, Intracellular Therapies BRYAN ROTH, University of North Carolina at Chapel Hill • What are the challenges and opportunities of developing drug compounds that act on mechanisms downstream of the primary target? • How should we think about convergent modulation of multiple signaling mechanisms in the context of intracellular pathways and microcircuit networks? • What are useful frameworks for predicting clinical efficacy for drugs with multiple targets and multiple measures of target engagement?

2:30pm Audience Q&A

2:45pm BREAK

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Session 5: Bioethical Considerations Objective: • Explore the different types of bioethical and scientific frameworks that will be needed to guide drug development as additional emerging targets are identified.

2:50pm Overview of session SHARON MATES, Intracellular Therapies

2:55pm The bioethical considerations of using psychoactive drugs to treat mental illness PAUL APPELBAUM, Columbia University • How are the bioethical considerations even more pointed for agents where the dissociative experiences are a main effect, rather than a side effect? • How do we ensure informed consent when referring to ineffable subjective experiences that may be induced? • How do we help the patient adapt to significant changes in/improvements to mood state? • How do we ensure appropriate use, monitoring, and oversight? • How do we weigh the therapeutic benefit against the risk of adverse effects and abuse potential?

3:15pm Panel discussion Dr. Appelbaum will be joined in the discussion by: MASON MARKS, Gonzaga University ILINA SINGH, Oxford University • Is a precautionary approach appropriate here? Do these frameworks need updating as we know more about the science and as the public becomes more aware and interested? • What can be learned from the systems developed around ketamine clinics in the United Kingdom? • How are health inequities and unequal access to care exacerbated when in-need/vulnerable populations are not reached by these novel therapies?

3:50pm Audience Q&A

4:00pm BREAK

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Session 6: Synthesis and Next Steps Objectives: • Synthesize key themes. • Discuss critical research gaps, next steps, and promising areas for future action.

4:05pm Synthesis of workshop’s key themes LINDA BRADY, NIMH, Workshop Chair

4:10pm Next steps and opportunities TIFFANY FARCHIONE, FDA MAGALI HAAS, Cohen Veterans Bioscience STUART HOFFMAN, Department of Veterans Affairs RUPERT McSHANE, Oxford University VENKATESHA MURTHY, Takeda GREG SIMON, Kaiser Permanente BRANDON STAGLIN, One Mind JOSHUA GORDON, NIMH

4:55pm Acknowledgments and concluding remarks LINDA BRADY, NIMH, Workshop Chair

5:00pm END OF WORKSHOP

PREPUBLICATION COPY—Uncorrected Proofs