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Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease

From the Departments of Neurology (Drs. Murman and Foster), Psychiatry(Drs. Giordani, Mellow, and Hariharan), and Biostatistics (J.R. Johanns and Dr. Little), University of Michigan, Ann Arbor, MI.

Address correspondence and reprint requests to Dr. Norman L. Foster, Department of Neurology, University of Michigan, Ann Arbor, MI 48109.

Background: Excitotoxicity may contribute to neuronal degeneration in Huntington's disease (HD). N-methyl-D-aspartate (NMDA) receptor antagonists can prevent neuronal degeneration caused by excitotoxicity, but their effects in HD patients are not known.

Methods: We investigated the acute cognitive, behavioral, and motor effects of the NMDA-receptor antagonist ketamine in HD patients. Double-blind infusions of 0.10, 0.40, and 0.60 mg/kg/hr ketamine were given to 10 HD patients on one test day and compared with placebo infusions on a second, identical testing day. Linear mixed-effects models and randomization tests were used to identify whether, and at which dose, a significant change from baseline occurred in outcome variables.

Results: We demonstrated that ketamine is well tolerated at low and intermediate subanesthetic doses. Intermediate ketamine doses produced specific decline in memory and verbal fluency. Higher subanesthetic doses caused a significant increase in psychiatric symptoms and impairment of eye movements.

Conclusions: These results describe the spectrum of clinical effects produced by increasing NMDA receptor blockade in HD patients. The clinical effects appearing with higher levels of NMDA receptor blockade can identify the range of doses used in clinical trials of NMDA receptor antagonists.

Supported in part by NIH Grant MH47144 (to N.L.F.), the Michigan Alzheimer's Disease Research Center (AG08671), and the General Clinical Research Center (M01-RR00042) at the University of Michigan.

Received March 8, 1996. Accepted in final form January 17, 1997.

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