Cognitive, behavioral, and motor effects of the NMDA antagonist ketarnine in Huntington’s disease zy D.L. Murman, MD; B. Giordani, PhD; A.M. Mellow, MD, PhD; J.R. Johanns, MS; R.J.A. Little, PhD; M. Hariharan, PhD; and N.L. Foster, MD Article abstract-Buckground: Excitotoxicity may contribute to neuronal degeneration in Huntington’s disease (HD). N-methyl+-aspartate (NMDA) receptor antagonists can prevent neuronal degeneration caused by excitotoxicity, but their effects in HD patients are not known. zyxwvutsrq 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. NEUROLOGY 1997;49:153-161 Neuronal death may be caused by a cellular process termed “excitotoxicity”in several neurologic disorders, including Huntington’s disease (HD).1-3 Excitotoxicity is caused by excess stimulation, or response to stimula- tion, of excitatory amino acid receptors, especially the N-methyl-D-aspartate (NMDA) receptor s ~ b t y p e . ~ - ~ This process of neuronal degeneration can be blocked in cell culture and animal models with NMDA receptor antag~nists.~-lO Thus, blockade of NMDA receptors may provide a therapeutic approach to the prevention of neuronal loss in human neurodegenerative diseases, such as HD. An NMDA receptor antagonist that is safe for experimental studies in humans is ketamine. In normal control subjects, ketamine produces specific, dose-dependent impairment of memory and verbal zyxwv flu- ency, in addition to alterations in thought content and sensory perception.11-14 The effect of NMDA receptor blockade in HD patients is not known. HD patients may have unique responses to NMDA receptor blockade because of disease-related loss of NMDA receptors in the striatum. Substantial loss of NMDA receptors occurs in the striatum of HD pa- tients and may contribute to symptoms of this disea~e.~~-~~ For example, impairment of excitatory amino acid connections between the frontal lobes and striatum contribute to impairment of executive functions, such as verbal fluency, in HD.19,20 Simi- larly, a relative deficiency of corticostriatal, excita- tory amino acid activity may produce psychosis in schizophrenia and could contribute to the increased frequency of psychosis in this disorder.21,22 Other symptoms of HD, such as chorea, may result from overactivity of excitatory amino acid-mediated path- ways produced by loss of inhibitory neural connections in the ~ t r i a t u m . ~ ~ , ~ ~ Thus, blockade of NMDA-mediated pathways in HD with NMDA receptor antagonists could exacerbate cognitive and behavioral symptoms, but could improve symptoms of chorea. In this study, we gave HD patients escalating doses of the NMDA receptor antagonist ketamine and measured acute changes in cognitive, behav- ioral, and motor function. The escalating-dose design allowed comparison of the threshold dose at which ketamine produced significant changes in outcome measures in HD patients. Ketamine is ideal for this design, because it is given in controlled infusions, is measurable in serum, is safe in humans when given at subanesthetic doses, and has known effects in nor- mal control s ~ b j e c t s . ~ ~ - ~ ~ We hypothesized that HD patients receiving ketamine would be sensitive to psychiatric effects and impairment of executive func- tion, but would have improvement in chorea with increasing NMDA receptor blockade. Methods. Patients. Ten HD patients (four men and six women) were tested after obtaining informed consent. The 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. Supported in part by NIH Grant MH47144 (to N.L.F.), the Michigan Alzheimer’s Disease Research Center (AG086711, and the General Clinical Research Center (M01-RR00042) at the University of Michigan. Received March 8, 1996. Accepted in final form January 17, 1997. Address correspondence and reprint requests to Dr. Norman L. Foster, Department of Neurology, University of Michigan, Ann Arbor, MI 48109. Copyright zyxwvu 0 1997 by the American Academy of Neurology 153