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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
