Attenuation of the neuropsychiatric effects of ketamine with lamotrigine -Support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists

Background: The cognitive, behavioral, and mood effects of N-methyl-D-aspar tate (NMDA) receptor antagonists, such as phencyclidine and ketamine, have been used to study the effects of NMDA receptor dysfunction. Pharmacologica l modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnes ses 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 glut amate release, will reduce the neuropsychiatric effects of ketamine in huma ns. Method: Healthy subjects (n = 16) completed 4 test days involving the admin istration of lamotrigine, 300 mg by mouth, or placebo 2 hours prior to admi nistration 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 b aseline and after administration of the medications. Results: Lamotrigine significantly decreased ketamine-induced perceptual ab normalities as assessed by the Clinician;Administered Dissociative States S cale (P<.001); positive symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P<.001); negative symp toms as assessed by the Brief Psychiatric Rating Scale negative symptoms su bscale (P<.05); and learning and memory impairment as assessed by the Hopki ns Verbal Learning Test (P<.05). However, lamotrigine increased the immedia te mood-elevating effects of ketamine (P<.05). Conclusions: Glutamate release-inhibiting drugs may reduce the hyperglutama tergic consequences of NMDA receptor dysfunction implicated in the pathophy siologic processes of neuropsychiatric illnesses such as schizophrenia. Fur ther study is needed.