NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.
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.
Krystal
John H
JH
Schizophrenia Biological Research Center (116-A), VA Connecticut Healthcare System, 950 Campbell Ave., West Haven, CT 06516, USA. john.krystal@yale.edu
D'Souza
D Cyril
DC
Mathalon
Daniel
D
Perry
Edward
E
Belger
Aysenil
A
Hoffman
Ralph
R
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008959:Models, Neurological; D009434:Neural Pathways / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine