Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine.
Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the antipsychotic efficacy of the atypical antipsychotic agent clozapine. Clinical data on the interaction between clozapine's mechanism of action and NMDA receptor function have been lacking secondary to a paucity of pharmacologic probes of the NMDA system. We have utilized a double-blind, placebo-controlled infusion paradigm with subanesthetic doses of the NMDA antagonist ketamine to test the hypothesis that clozapine would blunt ketamine-induced psychotic symptoms in schizophrenic patients. Ten schizophrenic patients underwent ketamine infusions while antipsychotic drug free and also during treatment with clozapine. Antipsychotic drug-free patients experienced increases in ratings of positive and negative symptoms. Clozapine treatment significantly blunted the ketamine-induced increase in positive symptoms. These data suggest that NMDA receptor function may be involved in the unique antipsychotic efficacy of clozapine.
Malhotra
A K
AK
Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1380, USA.
Adler
C M
CM
Kennison
S D
SD
Elman
I
I
Pickar
D
D
Breier
A
A
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D003024:Clozapine