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.

Contents

• The National Academies of SCIENCES • ENGINEERING • MEDICINE
• PLANNING COMMITTEE ON NOVEL MOLECULAR TARGETS IN MOOD DISORDERS AND PSYCHOSIS
• FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS
• Reviewers
• Acronyms and Abbreviations
• 1. Introduction and Background
  • WORKSHOP OBJECTIVES
  • ORGANIZATION OF THE PROCEEDINGS
• 2. Current Drug Development Landscape and Limitations of Molecular Targets for Mood Disorders and Psychosis
  • THE LIVED EXPERIENCE OF SCHIZOPHRENIA
  • LIVING WITH DEPRESSION
  • SERENDIPITY IN PSYCHIATRIC DRUG DISCOVERY
  • UNMET NEEDS IN TREATING PSYCHIATRIC DISORDERS
• 3. Targeting Glutamate Receptors for Treatment-Resistant Depression
  • A BRIEF HISTORY OF KETAMINE AND ESKETAMINE
  • CLINICAL AND PATIENT EXPERIENCES WITH INTRANASAL ESKETAMINE
  • KETAMINE’S MECHANISM OF ACTION ON SYNAPSES, CIRCUITS, AND SYSTEMS
  • STRATEGIES TO IMPROVE THE ANTIDEPRESSANT EFFECTS OF KETAMINE
  • IDENTIFYING A BIOMARKER TO HELP PREDICT RESPONSES TO KETAMINE
• 4. Targeting GABA Receptors to Treat Postpartum Depression
  • CLINICAL AND PATIENT EXPERIENCES WITH BREXANOLONE
  • BREXANOLONE’S MECHANISM OF ACTION
  • CONVERGENCE OF MECHANISMS: KETAMINE AND BREXANOLONE
• 5. Emerging Drug Targets
  • mTOR SIGNALING—A TARGET FOR DEPRESSION AND PSYCHOSIS
  • SEROTONIN 5-HT2 RECEPTOR AGONISTS FOR MENTAL DISORDERS
  • TAAR1/5-HT1_AR AGONISTS IN SCHIZOPHRENIA TREATMENT
  • M1/M4 ACETYLCHOLINE MUSCARINIC RECEPTOR TARGETING FOR PSYCHOSIS
  • NMDA MODULATION TO IMPROVE NEGATIVE AND COGNITIVE SYMPTOMS IN SCHIZOPHRENIA
  • THE ADDED COMPLEXITY OF POLYPHARMACY
• 6. Regulatory Considerations for the Next Generation of Psychiatric Drugs
  • THE APPROVAL OF ESKETAMINE
  • THE APPROVAL OF BREXANOLONE
• 7. Ethical and Legal Principles Related to the Clinical Use of Psychoactive Drugs
  • TRANSLATING ETHICAL PRINCIPLES TO THE CLINICAL USE OF PSYCHOACTIVE DRUGS
  • PSILOCYBIN THERAPY: CLINICAL USE AND LEGAL CHALLENGES
• 8. Potential Next Steps and Future Opportunities
  • NOVEL APPROACHES NEEDED TO ADDRESS UNANSWERED QUESTIONS
  • FINAL THOUGHTS ON THE FUTURE OF THERAPY FOR PSYCHIATRIC DISORDERS
• References
• Workshop Agenda

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.

Digital Object Identifier: https://doi.org/10.17226/26218

Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.

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