Yale Study Reconciles Two Models Of Schizophrenia

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 theDepartment of Psychiatry, and lead author of the study. "Both systemsappear to be involved," he said.

The first theory suggests that dopamine neurons are hyperactive inpersons with schizophrenia and that effects of the dopamine-releasingdrug, amphetamine, can mimic aspects of the illness. The second theorymaintains that certain schizophrenia-related deficits in the functionof glutamate, the dominant stimulatory transmitter, could be reproducedin 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 foundthe transient psychotic state produced by each drug was similar but notidentical and that ketamine produced a more "complete"schizophrenia-like state than amphetamine. They also found thatcognitive impairments produced by ketamine, specifically workingmemory, were reduced by the administration of amphetamine.

"This study lends support to the hypothesis that drugs that facilitatethe function of particular dopamine receptors might play a role intreating cognitive impairments associated with schizophrenia," Krystalsaid.

The study was conducted at the VAConnecticut Healthcare System with support from the National Alliancefor Research on Schizophrenia and Affective Disorders, the NationalInstitute of Mental Health and the Department of Veterans Affairs.

Co-authors include Edward Perry Jr., M.D., Ralitza Gueorguieva, AysenilBelger, 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)