Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis

N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are reported to induce schizophrenia-like symptoms in humans, including cognitive impairmen ts. Shortcomings of most previous investigations include failure to maintai n steady-state infusion conditions, test multiple doses and/or measure anta gonist plasma concentrations. This double-blind, placebo-controlled, random ized within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine hz healthy males (n = 15) demonstrated dose-d ependent increases in Brief Psychiatric Rating Scale positive (F[3,42] = 21 .84; p < 0.0001) and negative symptoms (F[3, 42] = 2.89; p = 0.047), and Sc ale for the Assessment of Negative Symptoms (SANS) total scores (F[3,42] = 10.55; p < 0.0001). Ketamine also produced a robust dose-dependent decrease in verbal declarative memory performance (F[3, 41] = 5.11; p = 0.004), ann preliminary evidence for a similar dose-dependent decrease in nonverbal de clarative memory, occurring at or below plasma concentrations producing oth er symptoms. Increasing NMDA receptor hypofunction is associated with early occurring memory impairment followed by other schizophrenia-like symptoms. [Neuropsychopharmacology 20:106-118, 1999] (C) 1998 American College of Ne uropsychopharmacology Published by Elsevier Science lire.