Abstract
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 pharmacotherapeutic strategies also may have neuroprotective or neurotrophic consequences that influence the course of schizophrenia.
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Acknowledgements
This review is based on a presentation to the symposium, “Is D2 Antagonism Required for Antipsychotic Activity?” This symposium was sponsored by Hoescht Marion Roussell, Inc. and held in Washington DC, February 17–18, 1999. The authors thank Cameron Carter, MD, Robert W. Greene, Ph.D, Graham Williams, Ph.D, Patricia Goldman-Rakic, Ph.D, Franz Vollenweider, MD, and Richard Mohs, Ph.D for discussions related to elements of the presentation. The work described in this review was supported by funds from the Department of Veterans Affairs to their Merit Review Program, Alcoholism Research Center, Schizophrenia Biological Research Center, and National Center for PTSD. It was also supported by the National Institute of Mental Health through Grants MH-30929 and MH-44866 and by an unrestricted educational grant from Hoechst Marion Roussel. Dr. Krystal received additional funding via an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Affective Disorder, an award from the Patrick and Catherine Weldon Donaghue Medical Research Foundation, and the Civilian Defense and Research Foundation.
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Krystal, J., Belger, A., D'Souza, D. et al. Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists. Neuropsychopharmacol 21 (Suppl 2), S143–S157 (1999). https://doi.org/10.1016/S0893-133X(99)00102-5
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DOI: https://doi.org/10.1016/S0893-133X(99)00102-5
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