Glutamate Models of Psychosis: from Theory to Treatment
Bita Moghaddam
University of Pittsburgh

Disturbances in glutamate-mediated neurotransmission are implicated in a range of psychiatric disorders including schizophrenia, substance abuse, and mood disorders. Glutamatergic involvement in of schizophrenia was initially based on the ability of N-methyl-D-aspartate receptor antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of glutamate-related gene expression and metabolic pathways in pscyhosis. Our animal models modeling studies have long implicated excess glutamate in cortical and hippocampal regions in the pathophysiology of schizophrenia.Although the idea of hyperfunctionality of glutamate synapses is counterintuitive to some traditional views on glutamate neurotransmission and schizophrenia (e.g. that glutamate is hypofunctional in schizophrenia), the mechanism has gained acceptance because it is now consistent with a number of clinical findings in schizophrenia. At a theoretical level, this hyperfunctionality may serve as a common pathway for the diverse genetic causes of the illness and is consistent with inflammatory and neurotoxic processes including apoptosis that may mediate cortical and hippocampal atrophy. Based on our findings, reducing glutamate neurotransmission in schizophrenia through modulatory mechanisms such as agonists of metabotropic glutamate receptor 2 (mGlu2) has been in the pipeline for more than a decade. While the approach of reducing glutamate availability may not provide long-term efficacy for treating psychosis and other symptoms in chronically ill patients, recent work suggests that it may be a useful approach as a prevention strategy in individuals at high risk for schizophrenia or during the early stages of the illness.