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Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults

From the Department of Neurology and Center for Nuclear Imaging Research, University of Alabama at Birmingham Epilepsy Center.

Address correspondence and reprint requests to Dr. Ruben Kuzniecky, Department of Neurology, UAB Station, Birmingham, AL 35294.

Background: Anticonvulsant drugs have multiple mechanisms of action. Recent in vivo MRS studies suggest that cerebral -aminobutyric acid (GABA) increases occur with the administration of certain anticonvulsants in humans.

Objective: To investigate the effect of topiramate, gabapentin, and lamotrigine on cerebral GABA concentrations in healthy volunteers and correlate the GABA concentrations with serum drug levels.

Methods: Seventeen healthy adults were randomly assigned to receive topiramate, gabapentin, and lamotrigine and underwent GABA measurements using a 4.1-T magnet from a 13.5-mL volume over the occipital region. GABA concentrations and serum levels were measured at 3 and 6 hours following administration of an acute single dose of one of the drugs. Thereafter, drugs were titrated over 4 weeks to target doses, with GABA measurements performed at 2 and 4 weeks.

Results: Cerebral GABA concentrations rose 70% in the acute phase compared with baseline for topiramate. GABA rose 48% at 6 hours with gabapentin but not with lamotrigine. With long-term dosing and once target doses were achieved at 4 weeks, significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%).

Conclusion: This study demonstrates that single doses of topiramate and gabapentin increase cerebral GABA concentrations acutely (hours) in healthy individuals, but all drugs at clinically utilized doses increase cerebral GABA at 4 weeks. These results suggest that the mechanisms of action of anticonvulsant drugs are more complex and are likely to be multiple in nature.

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