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 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.
Newcomer
J W
JW
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Farber
N B
NB
Jevtovic-Todorovic
V
V
Selke
G
G
Melson
A K
AK
Hershey
T
T
Craft
S
S
Olney
J W
JW
D000328:Adult; D000818:Animals; D003071:Cognition / Q000187:drug effects; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology; D011939:Mental Recall / Q000187:drug effects; D011605:Psychoses, Substance-Induced / Q000523:psychology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine