Effect of lamotrigine on plasma GABA levels in healthy humans

Abstract

Lamotrigine, a new anticonvulsant, has been reported to be useful in treating bipolar depression, rapid cycling, and other phases of bipolar disorder. However, the mechanism of action underlying its efficacy in mood disorders is still not known. Since there is evidence for γ-aminobutyric acid (GABA) involvement in the pathophysiology and treatment response of patients with bipolar disorder, this study was designed to examine the effect of lamotrigine on plasma GABA levels in healthy humans. Eleven healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. Each subject received lamotrigine 100 mg/day for 1 week. Blood samples for assay of plasma levels of GABA were taken from each subject before and after administration of lamotrigine. Plasma GABA levels were analyzed using high-pressure liquid chromatography (HPLC) with fluorescence detection after derivatization with o-phthaldialdehyde (OPA). We found no significant difference in the plasma GABA levels of the study subjects before and after treatment with lamotrigine. The finding of this study suggests that lamotrigine in the dose used in this study does not appear to enhance GABA levels in humans.

Introduction

Lamotrigine is a new generation broad-spectrum anticonvulsant which has been approved for use as an adjunct drug in treatment of refractory partial seizure with or without generalized tonic/clonic seizures (Messenheimer, 1995). This medication has also been reported to be useful in treating bipolar depression, rapid cycling, and other phases of bipolar disorder, suggesting that it is perhaps a mood stabilizer like lithium with antimanic and antidepressant properties Calabrese et al., 1999, Calabrese et al., 2000, Frye et al., 2000, Bowden et al., 2003. Although evidence suggests that the antiepileptic action of lamotrigine may be due to its inhibition of voltage-sensitive sodium channels and suppression of subsequent release of glutamate (Gilman, 1995), the mechanism of action underlying its efficacy in bipolar disorders remains unknown.

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain, and low GABA function has been implicated in the pathophysiology of bipolar disorder (Shiah and Yatham, 1998). Several anticonvulsants that enhance GABA activity are useful in the treatment of bipolar disorder (Yatham et al., 2002). For example, valproic acid has been shown to be an effective mood stabilizer. This medication has a better side effect profile than lithium and carbamazepine and is well tolerated by patients (Kusumakar et al., 1997). It is thought to enhance GABA function via a combination of inhibition of GABA degradation and an enhancement of GABA synthesis, resulting in the elevation of levels in the synaptic cleft (Chapman et al., 1982). Topiramate, a novel anticonvulsant, has been shown to be useful as an adjunct to other mood stabilizers in refractory mania and in ultrarapid or ultradian cycling disorder Marcotte, 1998, Chengappa et al., 1999, McElroy et al., 2000. Recent magnetic resonance spectroscopy (MRS) studies showed that topiramate significantly increases cerebral GABA levels in healthy humans (Kuzniecky et al., 1998) and in patients with epilepsy Petroff et al., 1999, Petroff et al., 2001. In addition, open-label studies and case reports suggested the usefulness of gabapentin Ghaemi et al., 1998, Knoll et al., 1998, Letterman and Markowitz, 1999 and tiagabine Kaufman, 1998, Schaffer and Schaffer, 1999 in bipolar disorder. These two anticonvulsants appear to enhance GABA turnover in the central nervous system (CNS) as well. Gabapentin acts by enhancing GABA synthesis, whereas tiagabine elevates synaptic GABA levels by inhibiting GABA uptake into neurons and glia (Czuczwar and Patsalos, 2001).

Given the possibility that the enhancing effects of anticonvulsants on GABA may contribute to their therapeutic action in bipolar disorder, it would be of interest to know if GABA also plays a role in the mechanism of action of lamotrigine. There are now two clinical studies that have examined the effect of lamotrigine on GABA function Eriksson and O'Connor, 1999, Kuzniecky et al., 2002. Using MRS, Kuzniecky et al. (2002) showed that cerebral GABA levels increase acutely (hours) in healthy volunteers who received an acute single dose of topiramate and gabapentin, but not in those receiving lamotrigine. However, all three anticonvulsants at clinically therapeutic doses significantly increase cerebral GABA concentrations at 4 weeks. Their results suggest that lamotrigine may have an enhancing effect on GABA function in addition to its blocking effect on sodium channels and suppression effect on glutamate release. In contrast, Eriksson and O'Connor (1999) measured cerebrospinal fluid (CSF) GABA levels in 22 patients with generalized therapy-resistant epilepsy before and after a mean of 5 months of lamotrigine treatment. They found that lamotrigine decreased seizure incidence and severity in 12 of the 22 patients without changing CSF GABA levels. Their negative finding thus did not support GABA involvement in the mechanisms of lamotrigine. Given the above conflicting results, we were particularly interested in ascertaining further if lamotrigine has an enhancing effect on GABA function in humans by measuring plasma GABA, another index of central GABA function.