Therapeutic implications of the hyperglutamatergic effects of NMDA antagonists

John H. Krystal, Aysenil Beiger, D. Cyril D’Souza, Amit Anand, Dennis S. Charney, George K. Aghajanian, Bita Moghaddam

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor produce transient effects in healthy human subjects that resemble symptoms observed in some schizophrenic patients. NMDA antagonists also impair aspects of human corticolimbic information processing in a fashion that resembles deficits associated with schizophrenia, as measured by electrophysiologic and functional neuroimaging paradigms. Although all current antipsychotics block dopamine-2 (D2) receptors, recent studies question the centrality of D2-receptor stimulation to the NMDA-antagonist psychosis. For example, pretreatment with haloperidol fails to attenuate the psychotic effects of ketamine in healthy human subjects. Also, pretreatment with amphetamine fails to increase these effects of ketamine. Both preclinical and clinical studies suggest that subanesthetic doses of NMDA antagonists activate glutamate neurons in the cerebral cortex and hippocampus. Recent preclinical and clinical studies also suggest that drugs that attenuate glutamate release, including group II/III metabotropic glutamate-receptor agonists, drugs that block voltage-dependent ion channels, and serotonin-2A (5-HT2A)-receptor antagonists may attenuate NMDA antagonist effects. To the extent that NMDA antagonist effects provide insight into the pathophysiology of schizophrenia, these novel pharmacologic strategies and others may provide a rationale for the exploration of new treatments that do not involve D2-receptor blockade. If schizophrenia, like NMDA-antagonist effects, involves hyperglutamatergic states, then these novel harmacotherapeutic strategies also may have neuroprotective or neurotrophic consequences that influence the course of schizophrenia.

Original languageEnglish (US)
Pages (from-to)S143-S157
Issue number6
StatePublished - Dec 1999
Externally publishedYes


  • 5-HT2A
  • 907
  • Attention
  • Cognitive function
  • Frontal cortex
  • Glutamate
  • Ketamine
  • LY354740
  • Lamotrigine
  • M100907
  • MDL 100
  • NMDA
  • Pharmacotherapy
  • Schizophrenia
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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