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Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists

Amit Anand, MD; Dennis S. Charney, MD; Dan A. Oren, MD; Robert M. Berman, MD; X. Sylvia Hu, PhD; Angela Cappiello, MD, PhD; John H. Krystal, MD

Arch Gen Psychiatry. 2000;57:270-276.

Background  The cognitive, behavioral, and mood effects of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine, have been used to study the effects of NMDA receptor dysfunction. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia. Preclinical studies indicate that some ketamine effects may be mediated through increased glutamate release. In this study, we tested the hypothesis that lamotrigine, a drug reported to inhibit glutamate release, will reduce the neuropsychiatric effects of ketamine in humans.

Method  Healthy subjects (n = 16) completed 4 test days involving the administration of lamotrigine, 300 mg by mouth, or placebo 2 hours prior to administration of ketamine (0.26 mg/kg by intravenous bolus and 0.65 mg/kg per hour by intravenous infusion) or placebo in a randomized order under double-blind conditions. Behavioral and cognitive assessments were performed at baseline and after administration of the medications.

Results  Lamotrigine significantly decreased ketamine-induced perceptual abnormalities as assessed by the Clinician-Administered Dissociative States Scale (P<.001); positive symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P<.001); negative symptoms as assessed by the Brief Psychiatric Rating Scale negative symptoms subscale (P<.05); and learning and memory impairment as assessed by the Hopkins Verbal Learning Test (P<.05). However, lamotrigine increased the immediate mood-elevating effects of ketamine (P<.05).

Conclusions  Glutamate release–inhibiting drugs may reduce the hyperglutamatergic consequences of NMDA receptor dysfunction implicated in the pathophysiologic processes of neuropsychiatric illnesses such as schizophrenia. Further study is needed.

From the Department of Psychiatry, Yale University School of Medicine (Drs Anand, Charney, Oren, Berman, Cappiello, and Krystal), and the Abraham Ribicoff Research Facilities, Connecticut Mental Health Center (Drs Charney, Berman, and Krystal), New Haven; and the Veterans Affairs Connecticut Healthcare System, West Haven (Drs Anand, Charney, Oren, Cappiello, and Krystal).

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