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Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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1

Introduction and Background
1

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 lifespan, 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

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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.

Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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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.

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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).

Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×

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Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Page 1
Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 2
Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
×
Page 3
Suggested Citation:"1 Introduction and Background." National Academies of Sciences, Engineering, and Medicine. 2021. Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26218.
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Mood disorders - including depression and bipolar disorder - are common, disabling, and potentially lethal disorders, characterized by a shortened lifespan from comorbid medical illness and rising suicide rates. Medications for these conditions have been shown to be insufficiently effective in the majority of people who take them, and there remains a tremendous unmet medical need. Recent advances towards understanding the mechanisms of action for psychiatric medicines have led to the identification of potential novel molecular targets and agents for treating mood disorders. While these promising avenues for further investigation have re-energized scientific research in this area, many open questions remain. In response to this interest, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders convened a workshop in March 2021, Novel Molecular Targets for Mood Disorders and Psychosis.

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

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