COGNITIVE, BEHAVIORAL, AND MOTOR EFFECTS OF THE NMDA ANTAGONIST KETAMINE IN HUNTINGTONS-DISEASE

Background: Excitotoxicity may contribute to neuronal degeneration in Huntington's disease (HD). N-methyl-D-aspartate (NMDA) receptor antago nists can prevent neuronal degeneration caused by excitotoxicity, but their effects in HD patients are not known. Methods: We investigated t he 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 te st day and compared with placebo infusions on a second, identical test ing day. Linear mixed-effects models and randomization tests were used to identify whether, and at which dose, a significant change from bas eline occurred in outcome variables. Results: We demonstrated that ket amine is well tolerated at low and intermediate subanesthetic doses. I ntermediate ketamine doses produced specific decline in memory and ver bal 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 in creasing NMDA receptor blockade in HD patients. The clinical effects a ppearing with higher levels of NMDA receptor blockade can identify the range of doses used in clinical trials of NMDA receptor antagonists.