Clozapine Blunts N-Methyl-d-Aspartate Antagonist-Induced Psychosis: A Study with Ketamine

Abstract

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.

Introduction

Clozapine is the only antipsychotic agent with superior efficacy in partially responsive and treatment-refractory schizophrenic patients (Kane et al 1988; Pickar et al 1992; Breier et al 1994). Although clozapine has some relatively unique pharmacologic properties (low dopamine D2 receptor affinity, high D4 receptor affinity, high serotonin (5-HT)₂ receptor affinity) among antipsychotic drugs (Meltzer 1994), there are limited data demonstrating that these properties are related to clozapine’s antipsychotic efficacy (Meltzer 1996; Malhotra and Pickar 1996). Recently, several lines of evidence have suggested that the glutamatergic N-methyl-d-aspartate (NMDA) receptor is involved in clozapine’s mechanism of action.

Unlike typical neuroleptics, clozapine increases glutamate levels in prefrontal cortex (Daly and Moghaddam 1993, stimulates glutamate release in nucleus accumbens (Yamamoto and Cooperman 1994), and alters electrophysiological responses evoked through the glutamatergic corticostriatal pathway (Lidsky et al 1993). Clozapine, but not typical neuroleptics, potently blocks the effects of NMDA antagonists on prepulse inhibition (Bakshi et al 1994) and stereotypy induction, two common preclinical models of psychosis. Finally, Olney and Farber (1994)have reported that clozapine is the most effective antipsychotic agent in preventing the neurotoxicity of NMDA antagonists on rat cerebrocortical neurons.

Clinical data on the interaction between NMDA receptor function and antipsychotic efficacy have been limited by the lack of a suitable method for probing the NMDA system in humans. Recently, however, we and others have used subanesthetic doses of the NMDA antagonist ketamine to examine NMDA function in clinical populations (Krystal et al 1994; Lahti et al 1995; Malhotra et al 1996a). In healthy volunteers, ketamine produces a syndrome of thought disorder, perceptual abnormalities, blunted affect, and explicit memory impairment (Malhotra et al 1996a; Krystal et al 1994). In antipsychotic drug-free schizophrenics, ketamine activates the positive, negative, and cognitive symptoms of schizophrenia (Lahti et al 1995; Malhotra et al 1996b). Data on the effects of antipsychotic agents on ketamine response are limited to one study that found that the typical neuroleptic haloperidol did not block ketamine’s effects on psychotic symptoms in 6 schizophrenics (Lahti et al 1995). Clozapine’s effects were not examined in this patient group.

Examination of ketamine response in clozapine-treated patients may provide data on the interaction between the NMDA receptor and clozapine’s efficacy. In the present study, we examined the effects of a placebo-controlled, double-blind infusion of ketamine on psychotic symptoms in a group of antipsychotic drug (APD)-free and clozapine-treated schizophrenic patients. The hypothesis to be tested was that clozapine, in comparison to the APD-free condition, would blunt ketamine-induced psychotic symptoms.