The glutamate/N-methyl-d-aspartate receptor (NMDAR) model of schizophrenia at 35: On the path from syndrome to disease

Abstract

At present, the diagnosis of schizophrenia is based entirely on phenotype with no established biologically based examinations for either overall diagnosis or pathophysiologically based subdivision. Moreover, the borders between schizophrenia and other illnesses such as affective psychosis are ill-defined and may not correspond to underlying biological mechanisms. At present, neurochemical models provide the strongest basis for etiologically based subdivision. Dopaminergic models, which date back to the discovery of chlorpromazine in the 1950's, are particularly relevant for forms of psychotic illness characterized by high positive symptoms, low negative symptoms and neurocognitive dysfunction, and rapid treatment response. Glutamatergic models focusing on N-methyl-d-aspartate receptor (NMDAR) dysfunction may be particularly relevant to poor outcome forms of the disorder. Event-related potential (ERP) biomarkers such as mismatch negativity (MMN) may distinguish between subgroups and facilitate development of effective glutamatergic agents. Advances in glutamate-based biomarker development are discussed along with remaining barriers to effective treatment development.