Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?

NMDA receptor antagonists like ketamine and phencyclidine produce psychosis-like symptoms in healthy people and those with schizophrenia, making them useful as models for developing new schizophrenia treatments. This review examines whether these models have predictive validity based on results from recent clinical trials of novel treatments. It also assesses how different hypotheses about the drugs' psychotomimetic effects hold up against trial data. The authors discuss limitations of the models and suggest that incorporating translational markers could improve understanding of how these models relate to schizophrenia.

Study at a glance

Abstract

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.