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Novel Molecular Targets for Mood Disorders and Psychosis: Proceedings of a Workshop (2021)

Chapter: Appendix B: Workshop Agenda

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Previous Chapter: Appendix A: References

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Suggested Citation: "Appendix B: Workshop Agenda." 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.

B

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:

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.
Examine key clinical and ethical 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 setting—and regulatory challenges and opportunities.

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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
2:00pm EST	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 on Mental Illness
	ASHLEY CLAYTON, Yale University
2:30pm	Introductory talk: Scientific perspective on the history of drug treatments for mood disorder and psychosis
2:30pm	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 University
	CARLOS ZARATE, NIMH
4:35pm	Audience Q&A
4:50pm	Day 1 synthesis and closeout
4:50pm	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? Which molecular pathways are presumed to be involved?
10:20am	GABARs: Mechanisms of action for GABA-A modulators in depression
10:20am	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
11:15am	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
1:00pm	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
1:15pm	GABRIELLA GOBBI, McGill University
1:25pm	TAAR1/5-HT1_AR agonists in schizophrenia treatment
1:25pm	KENNETH KOBLAN, Sunovian Pharmaceuticals
1:35pm	M1/M4 acetylcholine muscarinic receptor targets
1:35pm	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
2:55pm	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
4:05pm	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
4:55pm	LINDA BRADY, NIMH, Workshop Chair
5:00pm	END OF WORKSHOP