Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?
N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine and phencyclidine, induce perceptual abnormalities, psychosis-like symptoms, and mood changes in healthy humans and patients with schizophrenia. The similarity between NMDA receptor antagonist-induced psychosis and schizophrenia has led to the widespread use of the drugs to provide models to aid the development of novel treatments for the disorder. This review investigates the predictive validity of NMDA receptor antagonist models based on a range of novel treatments that have now reached clinical trials. Furthermore, it considers the extent to which the different hypotheses that have been proposed to account for the psychotomimetic effects of NMDA receptor antagonist have been validated by the results of these trials. Finally, the review discusses some of the caveats associated with use of the models and some suggestions as to how a greater use of translational markers might ensure progress in understanding the relationship between the models and schizophrenia.
Large
Charles H
CH
Psychiatry CEDD, GlaxoSmithKline, Via Fleming 4, 37135 Verona, Italy. Charles.H.Large@gsk.com
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D011605:Psychoses, Substance-Induced / Q000188:drug therapy* / Q000523:psychology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000502:physiology
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D004298:Dopamine