Yale School of Medicine researchers published a report this month in the Archives of General Psychiatry that highlights the interplay of two brain signaling systems, glutamate and dopamine, in psychosis and cognitive function.

The study helps resolve a long-standing research debate between the "dopamine hypothesis" and the "glutamate hypothesis" or "PCP Model," said John Krystal, M.D., professor, deputy chair for research in the Department of Psychiatry, and lead author of the study. "Both systems appear to be involved," he said.

The first theory 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. The second theory maintains that certain schizophrenia-related deficits in the function of glutamate, the dominant stimulatory transmitter, 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.

"This study lends support to the hypothesis that drugs that facilitate the function of particular dopamine receptors might play a role in treating cognitive impairments associated with schizophrenia," Krystal said.

The study was conducted at the VA Connecticut Healthcare System with support from the National Alliance for Research on Schizophrenia and Affective Disorders, the National Institute of Mental Health and the Department of Veterans Affairs.

Co-authors include Edward Perry Jr., M.D., Ralitza Gueorguieva, Aysenil Belger, Steven Madonick, M.D., Anissa Abi-Dargham, M.D., Thomas Cooper, Lisa MacDougall, Walid Abi-Saab, M.D., and Cyril D'Souza, M.D.

Archives of General Psychiatry 62: 985-995 (September 2005)

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