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

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.

Fig. 1.

Relative distribution of N-methyl-D-aspartate (NMDAR) (A) and dopamine D2 (B) and D1 (C) receptors in brain. As opposed to dopamine receptors, NMDAR receptors are diffusely distributed throughout brain in both cortical and subcortical regions (D), consistent with recent findings of generalized brain dysfunction in schizophrenia. From Allen Brain Atlas (www.brain-map.org).

Fig. 2.

Sensory contributions to cognitive dysfunction in schizophrenia. In the auditory system, structural and functional disturbances at the level of primary auditory cortex correlate with impairments in higher auditory auditory function such as auditory emotion recognition (A). In the visual system, deficits in early visual activation lead to impairments in frontal activation during tasks such as perceptual closure (B) or AX-type continuous performance task (C) performance.

Fig. 3.

Effect of NMDAR glycine-site agonists on motor symptoms (tardive dyskinesia) as reflected in Abnormal Involuntary Movement Scale (AIMS) score. Data are from studies of glycine or D-serine. Across all studies, D-serine treatment led to a highly significant (t = 4.86, df = 192, P < .00001, d = .83) improvement in AIMS symptom, suggesting benefit of NMDAR agonist on motor and neuropsychological symptoms in schizophrenia.

Fig. 4.

Schematic diagram of glutamate synapses showing potential sites of interaction for modulation of NMDAR function. mGlu, metabotropic glutamate receptor; nACh7, alpha7 nicotinic receptor; EAAT, excitatory amino acid transporter; GlyT1, glycine type 1 transporter; SerT, high-affinity D-serine transporter; Xc–, cystine/glutamate antiporter; Glu, glutamate; Gly, glycine; D-ser, D-serine; GSH, glutathione. Adapted from Javitt et al.