Therapeutic implications of the hyperglutamatergic effects of NMDA antagonists

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate recepto r produce transient effects in healthy human subjects that resemble symptom s observed in some schizophrenic patients. NMDA antagonists also impair asp ects of human corticolimbic information processing in a fashion that resemb les deficits associated with schizophrenia, as measured by electrophysiolog ic and functional neuroimaging paradigms. Although all current antipsychoti cs block dopamine-2 (D-2) receptors, recent studies question the centrality of D-2-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 fai ls to increase these effects of ketamine. Both preclinical and clinical stu dies suggest that subanesthetic doses of NMDA antagonists activate glutamat e neurons in the cerebral cortex and hippocampus. Recent preclinical and cl inical studies also suggest that duties that attenuate glutamate release, i ncluding group II/III metabotropic glutamate-receptor agonists, drugs that block voltage-dependent ion channels, and serotonin-2A (5-HT2A)-receptor an tagonists may attenuate NMDA antagonist effects. To the extent that NMDA an tagonist effects provide insight into the pathophysiology of schizophrenia, these novel pharmacologic strategies and others may provide a rationale fo r the exploration of new treatments that do not involve D-2-receptor blocka de. If schizophrenia, like NMDA-antagonist effects, involves hyperglutamate rgic states, then these novel pharmacotherapeutic strategies also may have neuroprotective or neurotrophic consequences that influence the course of s chizophrenia. [Neuropsychopharmacology 22:S143-S157, 1999] (C) 1999 America n College of Neuropsychopharmacology. Published by Elseiver Science Inc.