Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.

Over the past 20 years, glutamatergic models of schizophrenia have gained acceptance, based on phencyclidine (PCP) inducing psychosis by blocking NMDA-type glutamate receptors. This review examines two predictions: neurocognitive deficits in schizophrenia should mirror those from NMDAR dysfunction, and agents stimulating NMDAR function should be therapeutic. Studies show severe sensory dysfunction in schizophrenia, including impaired mismatch negativity and visual P1 potentials, similar to deficits from NMDAR antagonists like ketamine. Sensory dysfunction predicts impairments in higher-order cognition like emotion recognition. Treatment studies with glycine-site compounds (glycine, D-serine, D-cycloserine) and glycine transport inhibitors (RG1678) show significant beneficial effects on persistent symptoms, suggesting novel treatment and prevention approaches.

Study at a glance

Abstract

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.