Psychopharmacology

, Volume 169, Issue 3, pp 215–233

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

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

DOI: 10.1007/s00213-003-1582-z

Cite this article as:
Krystal, J.H., D'Souza, D.C., Mathalon, D. et al. Psychopharmacology (2003) 169: 215. doi:10.1007/s00213-003-1582-z

Abstract

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.

Keywords

SchizophreniaGlutamateN-Methyl-D-aspartate (NMDA)KetamineCerebral cortexNeural networkCognitive functionMedications development

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • John H. Krystal
    • 1
    • 2
    • 3
  • 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