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-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.


METHODS
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.
Anand
A
A
Department of Psychiatry, Yale University School of Medicine, West Haven, CT 06516, USA. amit.anand@yale.edu
Charney
D S
DS
Oren
D A
DA
Berman
R M
RM
Hu
X S
XS
Cappiello
A
A
Krystal
J H
JH
D000328:Adult; D000339:Affect / Q000187:drug effects; D010054:Brief Psychiatric Rating Scale / Q000706:statistics & numerical data; D003072:Cognition Disorders / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005971:Glutamates / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007649:Ketamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077213:Lamotrigine; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control; D010468:Perceptual Disorders / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D012565:Schizophrenic Psychology; D014227:Triazines / Q000494:pharmacology*; D014706:Verbal Learning / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D010919:Placebos; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D007649:Ketamine; D000077213:Lamotrigine