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 impairments. Shortcomings of most previous investigations include failure to maintain steady-state infusion conditions, test multiple doses and/or measure antagonist plasma concentrations. This double-blind, placebo-controlled, randomized within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine hz healthy males (n = 15) demonstrated dose-dependent 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 Scale 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 declarative memory, occurring at or below plasma concentrations producing other 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 Neuropsychopharmacology Published by Elsevier Science lire.