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

Daniel C. Javitt, Stephen R. Zukin, Uriel Heresco-Levy, Daniel Umbricht

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)958-966
Number of pages9
JournalSchizophrenia Bulletin
Volume38
Issue number5
DOIs
StatePublished - Sep 2012

Keywords

  • cognition
  • glycine
  • glycine transport inhibitors
  • negative symptoms
  • neurophysiology
  • NMDA receptors
  • schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health

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