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GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT FOR DISORDERS OF THE NERVOUS SYSTEM WORKSHOP SUMMARY Diana E. Pankevich, Miriam Davis, and Bruce M. Altevogt Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This project was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; AstraZeneca Pharmaceuticals, Inc.; CeNeRx Biopharma; the Department of Health and Human Services’ National Institutes of Health (NIH, Contract No. N01-OD-4-213) through the National Institute on Aging, National Insti- tute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Eye Institute, NIH Blueprint for Neuroscience Research, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke; Eli Lilly and Company; Foundation for the National Institutes of Health; GE Healthcare, Inc.; GlaxoSmithKline, Inc.; Johnson & Johnson Pharmaceutical Research and Development, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkin- son’s Research; the National Multiple Sclerosis Society; the National Science Foundation (Contract No. OIA-0753701); Pfizer Inc.; and the Society for Neuroscience. The views presented in this publication are those of the editors and attributing authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-21221-2 International Standard Book Number-10: 0-309-21221-9 Additional copies of this report are available from The National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334- 3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover courtesy of: Dr. Ehud Isacoff, University of California–Berkeley. Suggested citation: IOM (Institute of Medicine). 2011. Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: A Workshop Summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding en- gineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT FOR DISORDERS OF THE NERVOUS SYSTEM PLANNING COMMITTEE* DANIEL JAVITT (Cochair), New York University CHI-MING LEE (Cochair), AstraZeneca Pharmaceuticals HUDA AKIL, University of Michigan MARK BEAR, Massachusetts Institute of Technology JOHN DUNLOP, Pfizer RICHARD FRANK, GE Healthcare, Inc. WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke MENELAS PANGALOS, AstraZeneca Pharmaceuticals WILLIAM POTTER, Foundation for NIH Neuroscience Biomarker Steering Committee RAE SILVER, Columbia University NORA VOLKOW, National Institute on Drug Abuse STEVIN ZORN, Lundbeck Research STEPHEN ZUKIN, AstraZeneca Pharmaceuticals Study Staff BRUCE M. ALTEVOGT, Project Director, Institute of Medicine SARAH L. HANSON, Associate Program Officer (until June 2010) SARA SHNIDER, Christine Mirzayan Science and Technology Policy Graduate Fellow (until May 2010) LORA K. TAYLOR, Senior Project Assistant, Institute of Medicine * Institute of Medicine planning committees are solely responsible for organizing the work- shop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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INSTITUTE OF MEDICINE FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS* ALAN LESHNER (Chair), American Association for the Advancement of Science HUDA AKIL, University of Michigan MARC BARLOW, GE Healthcare, Inc. MARK BEAR, Massachusetts Institute of Technology DAVID BREDT, Eli Lilly and Company DANIEL BURCH, CeNeRx Biopharma DENNIS CHOI, Simons Foundation (until March 2011) TIMOTHY COETZEE, National Multiple Sclerosis Society DAVID COHEN, Columbia University JOHN DUNLOP, Pfizer Inc. EMMELINE EDWARDS, NIH Neuroscience Blueprint RICHARD FRANK, GE Healthcare, Inc. MYRON GUTTMAN, National Science Foundation RICHARD HODES, National Institute on Aging KATIE HOOD, Michael J. Fox Foundation for Parkinson’s Research STEVEN E. HYMAN, Harvard University THOMAS INSEL, National Institute of Mental Health DANIEL JAVITT, Nathan Kline Institute for Psychiatric Research STORY LANDIS, National Institute of Neurological Disorders and Stroke HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC EVE MARDER, Brandeis University DAVID MICHELSON, Merck Research Laboratories JONATHAN MORENO, University of Pennsylvania School of Medicine KATHIE L. OLSEN, Association of Public and Land-Grant Universities ATUL PANDE, GlaxoSmithKline, Inc. MENELAS PANGALOS, AstraZeneca Pharmaceuticals STEVEN PAUL, Weill Cornell Medical College WILLIAM POTTER, FNIH Neuroscience Biomarker Steering Committee PAUL SIEVING, National Eye Institute RAE SILVER, Columbia University JUDITH SIUCIAK, Foundation for the National Institutes of Health MARC TESSIER-LAVIGNE, Rockefeller University * Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vi

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WILLIAM THIES, Alzheimer’s Association NORA VOLKOW, National Institute on Drug Abuse KENNETH WARREN, National Institute on Alcohol Abuse and Alcoholism FRANK YOCCA, AstraZeneca Pharmaceuticals STEVIN H. ZORN, Lundbeck USA CHARLES ZORUMSKI, Washington University School of Medicine IOM Staff BRUCE M. ALTEVOGT, Forum Director SARAH L. HANSON, Associate Program Officer (until June 2010) DIANA E. PANKEVICH, Associate Program Officer (since October 2010) LORA K. TAYLOR, Senior Project Assistant ANDREW POPE, Director, Board on Health Sciences Policy vii

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: Mark Geyer, University of California–San Diego John Krystal, Yale School of Medicine Herb Meltzer, Vanderbilt University School of Medicine Kalpana Merchant, Eli Lilly & Company Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Dr. Joseph T. Coyle, Harvard Medical School. Appointed by the Institute of Medicine, he was responsible for making certain that an independent ex- amination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Re- sponsibility for the final content of this report rests entirely with the author- ing committee and the institution. ix

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Contents 1 INTRODUCTION 1 Glutamate Biomarkers, 2 Workshop Goals, 3 2 OVERVIEW OF THE GLUTAMATERGIC SYSTEM 5 Glutamate Receptors, 7 Glutamate Transporters, 9 3 GLUTAMATE BIOMARKERS 11 Biomarkers of Engagement and Efficacy, 12 Physiological Biomarkers, 13 Cognitive Biomarkers, 20 Imaging Biomarkers, 22 4 TREATMENT IMPLICATIONS OF BIOMARKERS 27 Target Developments, 27 Patient Stratification, 28 Side-Effect Reduction, 30 5 CHALLENGES AND OPPORTUNITIES 33 Challenges, 34 Opportunities, 34 Summary, 37 xi

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xii CONTENTS APPENDIXES A References 39 B Registered Attendees 45 C Agenda 49