Progress in Neuro-Psychopharmacology and Biological Psychiatry
Effect of lamotrigine on plasma GABA levels in healthy 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.
Section snippets
Subjects
The authors studied 11 healthy male volunteers. All subjects were free of physical and psychiatric disorders as determined by a structured clinical interview for DSM-III-R diagnosis—nonpatient version (SCID-NP) (Spitzer et al., 1992), a medical history, and a physical examination. They were also free of a family history of an Axis I psychiatric disorder in first-degree relatives. All subjects were medication-free for at least 1 month prior to study. They gave written informed consents for
Results
Of the 11 study subjects, 1 subject withdrew his consent by the second study, and in the case of 1 subject, the plasma sample volume was not sufficient for duplicate analysis. We therefore excluded these two subjects from the data analysis. For the remaining nine subjects, the mean age±S.D. was 24.9±4.0 years and the mean body weight±S.D. was 79.1±16.4 kg. The mean baseline and posttreatment plasma GABA level±S.D. were 126.94±63.8 and 125.26±63.6 ng/ml, respectively. The baseline and
Discussion
There is some evidence suggesting that plasma GABA levels reflect brain GABA activity (Petty, 1994). For example, GABA levels in plasma were shown to be almost identical to levels in CSF (Loscher and Schmidt, 1984). This suggests that there is no active gradient between these two compartments. Furthermore, studies that measured plasma and CSF GABA simultaneously showed a significant correlation between the two in rats (Boheln et al., 1979), dogs (Loscher, 1982), and healthy humans (Uhlhaas et
Conclusions
The present finding of no treatment effect of lamotrigine on plasma GABA levels in male healthy volunteers does not provide support for the involvement of GABA in the mechanisms of lamotrigine. However, given the study limitations, including low treatment dose, short treatment interval, lack of measuring plasma level of lamotrigine, and small sample size, further studies with a higher lamotrigine dose and a longer treatment interval in a larger number of subjects are needed to ascertain further
Acknowledgements
Preliminary results from this study were presented at the 2001 Collegium International Neuro-Psychopharmacologicum (CINP), Regional Meeting, Hiroshima, Japan, October 2–5, 2001. The expert technical assistance of Ms. Gail Rauw is gratefully acknowledged. This research is partially supported by the Ministry of National Defense, Taiwan, ROC (Grant DOD-91-92 to Dr. Shiah).
References (42)
- et al.
Lamotrigine reduces spontaneous and evoked GABA(A) receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders
Neuropharmacology
(2002) - et al.
The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro
Neuropharmacology
(2000) - et al.
Analysis of CSF amino acids in young patients with generalised refractory epilepsy during an add-on study with lamotrigine
Epilepsy Res.
(1999) - et al.
Clinical experience using gabapentin adjunctively in patients with a history of mania or hypomania
J. Affective Disord.
(1998) - et al.
Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological cultures from rat cortex
Brain Res.
(1993) Valproate: a reapprasial of its pharmacodynamic properties and mechanisms of action
Prog. Neurobiol.
(1999)Use of topiramate, a new anti-epileptic as a mood stabilizer
J. Affective Disord.
(1998)- et al.
Open-label adjunctive topiramate in the treatment of bipolar disorders
Biol. Psychiatry
(2000) - et al.
Plasma GABA predicts acute response to divalproex in mania
Biol. Psychiatry
(1996) - et al.
GABA function in mood disorders: an update and critical review
Life Sci.
(1998)
Effect of lamotrigine on the electrically evoked release of endogenous amino acids from slices of dorsal horn of the rat spinal cord
Neuropharmacology
An assay of GABA in plasma and its application to phenelzine-treated patients
The relationship between GABA concentrations in brain and cerebrospinal fluid
Brain Res.
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar disorder
Arch. Gen. Psychiatry
A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group
J. Clin. Psychiatry
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group
J. Clin. Psychiatry
Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids
Neurochem. Res.
Topiramate as add-on treatment for patients with bipolar mania
Bipolar Disord.
The new generation of GABA enhancers. Potential in the treatment of epilepsy
CNS Drugs
Effects of drugs on rat brain, cerebrospinal fluid and blood GABA content
J. Neurochem.
A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders
J. Clin. Psychopharmacol.
Cited by (12)
Cortical excitability during prolonged antiepileptic drug treatment and drug withdrawal
2005, Clinical NeurophysiologyA capillary liquid chromatographic/tandem mass spectrometric method for the quantification of γ-aminobutyric acid in human plasma and cerebrospinal fluid
2005, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesLamotrigine
2015, Wyllie's Treatment of Epilepsy: Principles and Practice: Sixth EditionPost-traumatic stress disorder symptoms in a female patient following repeated teasing: Treatment with gabapentin and lamotrigine and the possible role of sensitization
2014, Clinical Psychopharmacology and NeuroscienceGABA-based evaluation of neurologic conditions: MR spectroscopy
2013, American Journal of Neuroradiology