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Two studies this month delve deeper into our understanding of schizophrenia. A study by John Krystal and colleagues from Yale in the Archives of General Psychiatry, attempted to delineate the interplay of two brain signaling systems, glutamate and dopamine, in psychosis and cognitive function.
Two theories have been debated as a model for understanding schizophrenia: 1) the "dopamine hypothesis" that suggests that suggests that dopamine neurons are hyperactive in persons with schizophrenia and that effects of the dopamine-releasing drug, amphetamine, can mimic aspects of the illness; and, 2) the "glutamate hypothesis" or "PCP Model," which maintains that certain schizophrenia-related deficits in the function of glutamate, could be reproduced in healthy people by the administration of drugs such as ketamine, which block the NMDA subtype of glutamate receptors.
The study included 41 healthy subjects who were given amphetamine, ketamine and then saline, in varying sequence. The researchers found the transient psychotic state produced by each drug was similar but not identical and that ketamine produced a more "complete" schizophrenia-like state than amphetamine. They also found that cognitive impairments produced by ketamine, specifically working memory, were reduced by the administration of amphetamine.
Their findings implicate both N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. They conclude that "glutamate and dopamine may differentially contribute to psychosis, thought disorder, and euphoria. Regarding medication development for cognitive dysfunction, the pattern of the interactive effects of ketamine and amphetamine is consistent with the hypothesis that facilitation of prefrontal cortical dopamine levels would attenuate some cognitive impairments associated with deficits in N-methyl-D-aspartate receptor function."
Genetics and Schizophrenia
 We have known for a long time that there is a genetic component to schizophrenia, but finding which specific gene(s) are responsible has been elusive. The disease is complex, with multiple genes and environmental factors thought to be responsible for its manifestation.
A recent study by researchers at Rutgers published in PLoS Medicine revisited a connection between a gene called CAPON (carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase) and schizophrenia in families where the disease is common. Brzustowicz and colleagues examined postmortem brain samples for differences in CAPON gene activity between normal individuals and those with mental illness. And in their set of 35 samples each from individuals with schizophrenia, individuals with bipolar disorder, and individuals without mental illness, they found such differences.
The scientists found that the CAPON gene is a template for two different proteins, a short form and a long form. The brain samples from patients with schizophrenia and bipolar disorder had higher levels of the short form than brain samples from patients without psychiatric illness. Moreover, these higher levels of the short version were predominantly seen in people with variants of the CAPON gene that had been previously linked to schizophrenia.
These results lend more support to the idea that CAPON is involved in schizophrenia. Given the cumulative evidence, it seems clear that further study of CAPON is justified. The findings by Brzustowicz and colleagues suggest that we need to learn more about the short version of CAPON, and specifically its presence and function in the brain.
Genes, Cognition, and Psychosis Program (GCAP) of the NIMH
More on Dr Brzustowicz genetic work
PubMed review of CAPON studies
Dopamine Hypothesis of Schizophrenia
Schizophrenia and Glutamate
10:38:52 AM 
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