Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models.

Schizophrenia has long been understood as a disorder of dopamine neurotransmission, but this framework has limited research to dopamine-rich brain regions. About twenty years ago, an alternative model emerged based on how dissociative anesthetics like PCP and ketamine induce psychosis by blocking NMDA-type glutamate receptors. Unlike dopamine, glutamate is widespread in the brain and central to sensory processing and cortical analysis, suggesting that schizophrenia involves diffuse but process-specific cortical dysfunction. NMDA receptors also interact with other neurotransmitter systems and have binding sites for endogenous compounds like glycine and D-serine. This glutamatergic theory opens new treatment approaches, many now entering clinical evaluation.

Study at a glance

Abstract

Clinical concepts of mental illness have always been modulated by underlying theoretical considerations. For the past fifty years, schizophrenia has been considered primarily a disease of dopaminergic neurotransmission. Although this conceptualization has helped greatly in explaining the clinical effects of psychostimulants and guiding the clinical use of both typical and atypical antipsychotics, it has nevertheless shaded how we look at the disorder from both a pathophysiological and therapeutic perspective. For example, most explanatory research in schizophrenia has focused on dopamine-rich regions of the brain, with little investigation of regions of the brain that are relatively dopamine poor. Starting approximately twenty years ago, an alternative formulation of schizophrenia was proposed based upon actions of the "dissociative anesthetic" class of psychotomimetic agents, including phencyclidine (PCP), ketamine and various designer drugs. These compounds induce psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting an alternative model for pathogenesis in schizophrenia. As opposed to dopamine, the glutamatergic system is widely distributed throughout the brain and plays a prominent role in sensory processing as well as in subsequent stages of cortical analysis. Glutamatergic theories of schizophrenia, thus, predict that cortical dysfunction will be regionally diffuse but process specific. In addition, NMDA receptors incorporate binding sites for specific endogenous brain compounds, including the amino acids glycine and D-serine and the redox modulator glutathione, and interact closely with dopaminergic, cholinergic and γ-aminobutyric acid (GABA)-ergic systems. Glutamatergic theories, thus, open new potential approaches for treatment of schizophrenia, most of which are only now entering clinical evaluation.