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

John W. Newcomer, Nuri B. Farber, Vesna Jevtovic-Todorovic, Gregg Selke, Angela Kelly Melson, Tamara Hershey, Suzanne Craft, John W. Olney

Research output: Contribution to journalArticlepeer-review

501 Scopus citations


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 in 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), and 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 impairments followed by other schizophrenia-like symptoms. Copyright (C) 1999 American College of Neuropsychopharmacology.

Original languageEnglish
Pages (from-to)106-118
Number of pages13
Issue number2
StatePublished - Feb 1999


  • Cognition
  • Glutamate
  • Ketamine
  • Memory
  • NMDA
  • Schizophrenia


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