Yale Bulletin and Calendar

September 23, 2005|Volume 34, Number 4

Study resolves 'conflicting'
theories about schizophrenia

A study by School of Medicine researchers reconciles two different theories about schizophrenia.

The report, published in the September issue of the Archives of General Psychiatry, highlights the interplay of two brain signaling systems, glutamate and dopamine, in psychosis and cognitive function.

The study helps resolve a longstanding research debate between the "dopamine hypothesis" and the "glutamate hypothesis" or "PCP Model" of schizophrenia, says Dr. John Krystal, professor and deputy chair for research in the Department of Psychiatry, and lead author of the study.

"Both systems appear to be involved," he notes.

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 blocks the NMDA subtype of glutamate receptors.

The Yale 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 impairment of 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 says.

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

-- By Jacqueline Weaver

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