, Volume 169, Issue 3–4, pp 215–233 | Cite as

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development

  • John H. KrystalEmail author
  • D. Cyril D'Souza
  • Daniel Mathalon
  • Edward Perry
  • Aysenil Belger
  • Ralph Hoffman


There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.


Schizophrenia Glutamate N-Methyl-D-aspartate (NMDA) Ketamine Cerebral cortex Neural network Cognitive function Medications development 



The authors acknowledge the support from the Department of Veterans Affairs via the Schizophrenia Biological Research Center, Alcohol Research Center, VA National Center for PTSD, Career Development Program (D.M.), Cooperative Studies Career Development Program (E.P.), and Merit Review Program (J.K.). The work outlined in this review has also been supported by the National Institute of Mental Health (5P50 MH44866-12), National Institute on Alcohol Abuse and Alcoholism (KO2 AA 00261-01), and the National Alliance for Research on Schizophrenia and Affective Disorders. The authors gratefully acknowledge the helpful input of colleagues with whom we have discussed topics related to this review including Bita Moghaddam, Ph.D., Judith Ford, Ph.D., John Lisman, Ph.D., and Robert Greene, M.D., Ph.D.


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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • John H. Krystal
    • 1
    • 2
    • 3
    Email author
  • D. Cyril D'Souza
    • 1
    • 2
    • 3
  • Daniel Mathalon
    • 1
    • 2
    • 3
  • Edward Perry
    • 1
    • 2
    • 3
  • Aysenil Belger
    • 5
  • Ralph Hoffman
    • 2
    • 3
    • 4
  1. 1.Schizophrenia Biological Research Center (116-A)VA Connecticut Healthcare SystemWest HavenUSA
  2. 2.Department of PsychiatryYale UniversityNew HavenUSA
  3. 3.Abraham Ribicoff Research FacilitiesConnecticut Mental Health CenterNew HavenUSA
  4. 4.Department of PsychiatryYale-New Haven HospitalNew HavenUSA
  5. 5.Department of PsychiatryUniversity of North CarolinaChapel HillUSA

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