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Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders. Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: Workshop Summary. Washington (DC): National Academies Press (US); 2011.

Cover of Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System

Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: Workshop Summary.

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Glutamate dysfunction has been associated with a wide array of nervous system diseases and disorders. Glutamate-related disorders include neuropsychiatric disorders such as schizophrenia, neurodegenerative diseases such as Alzheimer's, substance abuse, pain disorders, and traumatic brain and spinal cord injuries. These conditions are widespread, affecting a large portion of the U.S. population, and remain difficult to treat (Narrow et al., 2002; Wang and Ding, 2008; Writer and Schillerstrom, 2009). Glutamate's contribution to such a wide range of nervous system disorders is best explained by a single fact: Glutamate is the most pervasive neurotransmitter in the central nervous system (CNS). Despite this fact, no validated biological markers, or biomarkers, currently exist for measuring glutamate pathology in CNS disorders or injuries. A workshop titled Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System was convened by the Institute of Medicine Forum on Neuroscience and Nervous System Disorders to explore promising current and emerging technologies with potential as reliable glutamate biomarkers, and to outline strategies to accelerate development, validation, and implementation of these biomarkers as powerful tools to advance drug development for nervous system disorders associated with glutamatergic dysfunction.

Although glutamate has a staggering array of functions, none of the top-selling CNS drugs is indicated directly for rectifying dysfunction at the glutamate synapse. Currently, three prescription drugs approved by the Food and Drug Administration (FDA)—memantine, ketamine, and D-cycloserine2—have implications for diseases of glutamate or glutamate-related pathology. Many workshop participants agreed that the lack of glutamate biomarkers is the largest obstacle to increasing glutamate-specific drug development. In spite of this problem, scientific progress is close to a tipping point that will yield novel glutamate biomarkers as long as concerted efforts are undertaken by academic, government, and industry researchers, as well as by health policy makers. The stakes, in their view, are too great to disregard.


Biomarkers are defined as quantitative measurements that provide information about biological processes, a disease state, or response to treatment (IOM, 2008). Although many biomarkers are being investigated expressly for glutamate neurotransmission, none to date has been validated for use in clinical trials, much less clinical practice. The development and adoption of glutamate or glutamate-related biomarkers (hereinafter called “glutamate biomarkers”) is crucial because biomarkers streamline research and development of new therapies that have the potential to increase understanding of glutamate-related disorders and make them easier to prevent and/or treat. Daniel Javitt, director of schizophrenia research at the Nathan Kline Institute for Psychiatric Research and cochair of the workshop, stressed that development of glutamate biomarkers has the potential to increase the understanding of glutamate dysfunction in CNS disease.

Biomarkers would provide a mechanism to:

  • monitor response to treatment;
  • identify people at risk for disease;
  • measure and predict disease progression or prognosis;
  • identify molecules sufficiently important to the disease that they are strong targets for treatment or prevention;
  • offer a choice of outcome measures in “proof-of-concept” studies to spur investment and lead to larger clinical trials;
  • provide mechanisms for patient stratification; and
  • find surrogate outcome measures to shorten the length of clinical trials.

To find a potential biomarker, research first must demonstrate that the biomarker has the capacity to reliably distinguish between healthy individuals and those with disease. The process begins with an array of studies, depending on the nature and application of the biomarker and later with replication by other laboratories, all of which require years of investigation. A “potential” biomarker, however, is not automatically designated a “validated” biomarker. The process of validation, for regulatory purposes and thus for clinical trials, requires even more types of studies and various levels of evidence, depending on the use of the biomarker (e.g., measuring drug outcomes) and other FDA requirements (FDA, 2004, 2010; Goodsaid and Frueh, 2007).


In June 2010, the Forum hosted a workshop that examined the potential for development of glutamate biomarkers, and explored next steps that would advance drug development. Established in 2006, the Forum aims to foster dialogue among a broad range of stakeholders—practitioners, policy makers, private industry, community members, academics, and others—and to provide these stakeholders with opportunities to tackle issues of mutual interest and concern. The Forum's neutral venue provides a place for broad-ranging discussions that can help in the coordination and cooperation of all stakeholders to enhance understanding of neuroscience and nervous system disorders. This workshop featured more than 20 presentations describing new approaches to biomarker development while recognizing that the research remains in the hypothesis testing and replication stages.

Specific objectives of the workshop were as follows:

  • Briefly outline the need for glutamate-related biomarkers both for understanding the causes of neuropsychiatric disorders and neurodegenerative diseases associated with glutamatergic dysfunction and for accelerating drug development for these disorders.
  • Discuss the most promising current and emerging technologies and analytical methods for assessing glutamatergic neurotransmission, and identify the research gaps for their development into biomarkers.
  • Outline approaches for biomarker validation in pre-clinical and clinical studies, including relevant animal models and translational challenges.
  • Discuss the implementation and regulatory barriers to incorporating glutamatergic biomarkers into drug development for neuropsychiatric disorders and neurodegenerative diseases and approaches to overcome them.
  • Identify the next steps in establishing principles and procedures to accelerate biomarker development, validation, and implementation in clinical trials, including frameworks for partnerships and collaboration.

The report that follows highlights the presentations by the expert panelists, and the open panel discussions that took place during the workshop. This report is not intended to be a thorough review of all published literature but an accounting of speaker presentations and commentary by panelists and workshop attendees.



This workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, are not necessarily endorsed or verified by the forum or The National Academies, and should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and panelists are noted in the report, many qualified their comments as being based on personal experience over the course of a career, and not being presented formally on behalf of their organization (unless specifically noted).


Memantine is indicated for cognitive dysfunction in Alzheimer's disease, ketamine is an anesthetic, and D-cycloserine is indicated for anxiety disorders, schizophrenia, and chronic pain.

Copyright © 2011, National Academy of Sciences.
Bookshelf ID: NBK62184


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