Indirect modulation of dopamine D-2 receptors as potential pharmacotherapyfor schizophrenia: II. glutamate (ant)agonists

OBJECTIVE: To summarize the published preclinical and clinical data that su ggest the possible use of glutamate receptor agonists or antagonists as nov el antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from th e data sources were evaluated and all information deemed relevant was inclu ded. DATA SYNTHESIS: The standard antipsychotic drugs, whose clinical activity c orrelates with affinity for dopamine D-2 receptors, alleviate some of the p ositive symptoms of schizophrenia, but have limited impact on negative symp toms. Several lines of evidence implicate glutamate-receptor system dysfunc tion(s) in schizophrenia, either as causative or contributory factors. In a ddition, several standard antipsychotic drugs modulate glutamate or glutama te receptor activity, suggesting an alternative view of their mechanism of antipsychotic action. Preliminary studies have shown that drugs which modul ate glutamate brain concentrations have positive effects in animal models o f schizophrenia. CONCLUSIONS: A role for glutamate in the pathogenesis or pharmacotherapy of schizophrenia is suggested from anatomic (interactions between glutamaterg ic and dopaminergic systems in relevant brain regions), physiologic (implic ations of glutamate-receptor dysfunction), and pharmacologic (modulation of glutamate or glutamate receptors) evidence. Therefore, compounds that eith er as monotherapy or as an adjunct to dopamine D-2 receptor antagonists.