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Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine
Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function
John H. Krystal, MD;
Edward B. Perry, Jr, MD;
Ralitza Gueorguieva, PhD;
Aysenil Belger, PhD;
Steven H. Madonick, MD;
Anissa Abi-Dargham, MD;
Thomas B. Cooper, MA;
Lisa MacDougall, MA;
Walid Abi-Saab, MD;
D. Cyril D’Souza, MD
Arch Gen Psychiatry. 2005;62:985-994.
Background In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition.
Objectives To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals.
Design Placebo-controlled, randomized, double-blind psychopharmacologic trial.
Setting and Participants Forty-one healthy individuals recruited from the community who completed up to 4 test days.
Main Outcome Measures On each test day, participants received amphetamine (a 1-minute infusion of amphetamine sulfate, 0.25 mg/kg, or saline) and ketamine (a 1-minute intravenous infusion of ketamine, 0.23 mg/kg, followed by a 1-hour infusion of 0.5 mg/kg or an identical saline bolus and infusion). The order of amphetamine and ketamine infusions was randomized.
Results At the doses studied, ketamine and amphetamine produced positive symptoms and euphoria. However, perceptual changes were produced only by ketamine, and hostility, grandiosity, and somatic concern were stimulated only by amphetamine. Amphetamine and ketamine produced conceptual disorganization, but only ketamine produced concrete ideation and unusual mannerisms. Ketamine produced negative symptoms and disrupted delayed recall. Ketamine and amphetamine showed 3 types of interactive effects: (1) amphetamine attenuated the impairment of working memory produced by ketamine; (2) amphetamine and ketamine had additive effects on thought disorder, arousal, and euphoria; and (3) amphetamine and ketamine had less-than-additive effects on psychosis.
Conclusions These findings implicate N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. However, 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.
Author Affiliations: Department of Psychiatry (Drs Krystal, Perry, Belger, and D’Souza and Ms MacDougall) and Division of Biostatistics, Department of Epidemiology and Public Health (Dr Gueorguieva), Yale University School of Medicine, New Haven, Conn; Schizophrenia Biological Research Center (116-A), VA Connecticut Healthcare System, West Haven (Drs Krystal, Perry, Belger, and D’Souza and Ms MacDougall); Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven (Drs Krystal, Perry, Gueorguieva, and D’Souza and Ms MacDougall); Institute of Living, Hartford, Conn (Dr Madonick); New York State Psychiatric Institute, Columbia University Department of Psychiatry, New York (Dr Abi-Dargham and Mr Cooper); and Abbott Laboratories, Abbott Park, Ill (Dr Abi-Saab). Dr Belger is now with the Department of Psychiatry, University of North Carolina, Chapel Hill.
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