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Effect of lamotrigine on plasma GABA levels in healthy humans
Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 419 – 423 www.elsevier.com/locate/pnpbp
Effect of lamotrigine on plasma GABA levels in healthy humans I-Shin Shiah
a,b,*
, Lakshmi N. Yathamc, Yuh-Cherng Gaua, Glen B. Bakerd
a
Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Gung Road, Sec. 2, Nei-Hu District, 114, Taipei, Taiwan b National Defense Medical Center, Taipei, Taiwan, ROC c Department of Psychiatry, Division of Mood Disorders, The University of British Columbia, Vancouver, BC, Canada d Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada Accepted 22 January 2003
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 gaminobutyric 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. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Lamotrigine; Anticonvulsants; GABA; Plasma GABA
1. 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, 2000; Frye et al., 2000; Bowden et al., 2003). Although evidence suggests
Abbreviations: GABA, g-aminobutyric acid; HPLC, high-pressure liquid chromatography; MRS, magnetic resonance spectroscopy; CNS, central nervous system; CSF, cerebrospinal fluid; IPSCs, inhibitory postsynaptic currents. * Corresponding author. Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Gung Road, Sec. 2, Nei-Hu District, 114, Taipei, Taiwan. Tel.: +886-2-8792-7431; fax: +886-2-8791-2161. E-mail address: [email protected] (I.-S. Shiah).
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. g-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
0278-5846/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(03)00028-9
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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, 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.
2. Methods 2.1. 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-IIIR 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 psy-
chiatric disorder in first-degree relatives. All subjects were medication-free for at least 1 month prior to study. They gave written informed consents for participation in the study, and the study was approved by the local ethics committee. 2.2. Procedure All study subjects reported to the research unit for baseline blood sampling. After the subjects were weighed, a venous blood sample was obtained from each individual for a baseline plasma GABA level. Then the subjects took 100 mg/day of lamotrigine for 1 week on an outpatient basis. During the 7 days, subjects were asked to record adverse events related to lamotrigine. The adverse events reported in the questionnaire were classified as mild, moderate, and severe and were defined by ‘‘not affecting usual activity,’’ ‘‘mild disruption in usual activity,’’ and ‘‘major disruption in usual activity,’’ respectively. Subjects took the last dose of lamotrigine at 2200 h on the seventh day, and the posttreatment blood sampling for plasma GABA was carried out on the eighth day. 2.3. Biochemical assays Venous blood samples were collected into tubes containing EDTA, stored on ice and centrifuged within 60 min. Plasma was separated and then was stored at 80 °C for assay at a later time. GABA levels were determined using the high-pressure liquid chromatography (HPLC) procedure of Baker et al. (1998). In this method, samples are acidified by the addition of 1:10 the volume of 4N perchloric acid on ice and centrifuged to remove protein. The supernatant is retained, basified, and shaken with the liquid ion-pairing agent di-(2-ethylhexyl)phosphate. The aqueous layer is retained and briefly centrifuged. The sample is then reacted with fluoraldehyde (o-phthaldialdehyde, OPA) reagent and injected onto an HPLC system attached to a fluorescence detector and an integrator. All plasma samples were assayed in the same batch, and all assays were performed by a lab technician blind to the study conditions. 2.4. Statistical analysis Computer analysis of the data was carried out using the Statistical Package for Social Sciences (SPSS) for Windows1. The Kolmogorov – Smirnov (K-S) test was used to ascertain the normality of plasma GABA data distribution ( P-values for K-S tests on plasma GABA data were all larger than .1). A paired t test was used to determine if there was a significant difference in plasma GABA levels before and after treatment with lamotrigine. Relationships between variables were assessed by means of Pearson’s correlation coefficient. All significance levels reported were two-tailed and were set at P < .05.
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3. 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 posttreatment plasma GABA levels were not significantly different (t = 0.146, df = 8, P=.89) (Fig. 1). However, there was a significant positive correlation in plasma GABA levels before and after treatment with lamotrigine (Pearson’s r=.86, P < .004, n = 9) (Fig. 2). In addition, there was no significant correlation between age (Pearson’s r = – 0.34, P=.93, n = 9) or body weight (Pearson’s r = .26, P=.51, n = 9) and baseline plasma GABA levels. No significant correlation was found between age (Pearson’s r=.13, P=.74, n = 9) or body weight (Pearson’s r = .33, P=.39, n = 9) and posttreatment plasma GABA levels. As mentioned, one subject dropped out from the study after withdrawing his consent. The other 10 subjects completed the course of lamotrigine for 1 week and gave their reports on the adverse events of lamotrigine with open questionnaires. The adverse events to lamotrigine included drowsiness (10% with mild and moderate degree, respectively), headache (10% with moderate degree), tachycardia (10% with moderate degree). Interestingly, one subject reported having nightmares for 5 days after taking lamotrigine, and he rated the symptom as moderate in degree. Five out of the ten subjects did not report any significant side effects. None of the study
Fig. 1. Mean ( ± S.E.M.) plasma GABA levels in healthy male humans before and after 1 week of lamotrigine treatment (100 mg/day). The treatment of lamotrigine did not significantly alter the plasma GABA levels (Paired t test, P=.89).
Fig. 2. Plasma GABA levels before (baseline) and after treatment with lamotrigine (posttreatment) in healthy male humans. The line indicates a significant positive correlation between the baseline and posttreatment GABA levels (Pearson’s correlation, P < .004).
subjects developed skin rashes during the period of lamotrigine administration.
4. 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 al., 1986). In addition, pharmacological manipulations change both plasma and brain GABA levels in a similar magnitude (Ferkany et al., 1978; Loscher, 1979). Our finding of no significant change in plasma GABA levels after 1 week of lamotrigine treatment is consistent with the finding of Eriksson and O’Connor (1999) that there was no significant change in CSF GABA levels in patients with resistant epilepsy before and after a mean of 5 months of lamotrigine treatment, thus not supporting the involvement of GABA in the mechanisms of lamotrigine. However, it is in contrast to the MRS finding of increased cerebral GABA levels in healthy volunteers who received lamotrigine for 4 weeks (Kuzniecky et al., 2002). There are several possible explanations for the discrepancy between the studies. First, plasma and CSF GABA may not be as sensitive as cerebral GABA measured by MRS for detecting the alteration in GABA function induced by lamotrigine. If that is the case, lamotrigine appears to have an enhancing effect on central GABA function, and the exact mechanisms underlying such an effect need to be further investigated. Regarding this, Cunningham and Jones (2000) reported that lamotrigine increased both the amplitude and frequency of spontaneous GABAA receptor-mediated inhibitory postsynaptic currents
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(IPSCs) and suggested that the drug was acting presynaptically to enhance GABA release. However, the results from several other neurochemical and electrophysiological studies are contradictory (Leach et al., 1986; Lees and Leach, 1993; Teoh et al., 1995; Waldmeier et al., 1995; Braga et al., 2002). Teoh et al. (1995) reported that lamotrigine reduced GABA release evoked by electrical stimulation in rat spinal dorsal horn slices. In rat cerebral cortical slices, lamotrigine reduced GABA release evoked by the sodium channel activator, veratrine (Leach et al., 1986; Waldmeier et al., 1995). There is also some indication from whole-cell patch clamp recordings that lamotrigine may reduce spontaneous release of GABA from cultured cortical neurons (Lees and Leach, 1993). Recently, it was reported that lamotrigine reduced GABAA receptor-mediated synaptic transmission in intact circuits of the basolateral amygdala (Braga et al., 2002). Given the above conflicting results, further studies are clearly needed to ascertain further the role of GABA in the mechanism of action of lamotrigine. Second, the doses and duration of lamotrigine treatment were different for the three studies. We used 100 mg/day of lamotrigine for 1-week treatment, Eriksson and O’Connor (1999) used 1– 12 mg/kg/day of lamotrigine for a mean of 5 months treatment (range 2 –12 months), and Kuzniecky et al. (2002) used 7.1 mg/kg/day of lamotrigine for a 4-week treatment. We cannot exclude the possibility that higher doses and/or longer duration of lamotrigine will result in significant alterations in plasma GABA levels. Third, the numbers and the compositions of the study populations were also different between the studies. We had nine male healthy volunteers (mean age 24.9 years, range 18 – 30 years) who completed the lamotrigine treatment and were included in the data analysis. Eriksson and O’Connor (1999) studied 22 children and young adults with a mean age 8.9 years (range 2.5 –20.5 years) with generalized refractory seizure. Most of their study subjects received at least two other anticonvulsants prior to lamotrigine treatment. In the MRS study conducted by Kuzniecky et al. (2002), a total of 17 healthy young adults were studied (10 men, 7 women, mean age 28.7 years). Of the 17 subjects, 6 received topiramate, 6 received gabapentin, and 5 received lamotrigine. Fourth, we did not measure the plasma concentration of lamotrigine to check for the drug compliance of subjects, which may have confounded our results. Finally, it must be pointed out that our mean plasma GABA levels for healthy subjects are higher than those obtained in control subjects in the previous studies reporting on plasma GABA (Loscher and Schmidt, 1981; Petty et al., 1996; Loscher, 1999). The mean values are also higher than those obtained in subjects who we have previously studied in Edmonton using the same technique. The reason for this is not clear. However, the healthy subjects used in the present study appear to be considerably younger than most control groups in the previous studies (Loscher and Schmidt, 1981; Petty et al., 1996; Loscher, 1999), and they are also younger than those previously investigated in Edmonton.
5. 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 if lamotrigine enhances GABA activity in humans.
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).
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Effect of lamotrigine on plasma GABA levels in healthy humans I-Shin Shiah
a,b,*
, Lakshmi N. Yathamc, Yuh-Cherng Gaua, Glen B. Bakerd
a
Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Gung Road, Sec. 2, Nei-Hu District, 114, Taipei, Taiwan b National Defense Medical Center, Taipei, Taiwan, ROC c Department of Psychiatry, Division of Mood Disorders, The University of British Columbia, Vancouver, BC, Canada d Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada Accepted 22 January 2003
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 gaminobutyric 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. D 2003 Elsevier Science Inc. All rights reserved. Keywords: Lamotrigine; Anticonvulsants; GABA; Plasma GABA
1. 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, 2000; Frye et al., 2000; Bowden et al., 2003). Although evidence suggests
Abbreviations: GABA, g-aminobutyric acid; HPLC, high-pressure liquid chromatography; MRS, magnetic resonance spectroscopy; CNS, central nervous system; CSF, cerebrospinal fluid; IPSCs, inhibitory postsynaptic currents. * Corresponding author. Department of Psychiatry, Tri-Service General Hospital, No. 325, Cheng-Gung Road, Sec. 2, Nei-Hu District, 114, Taipei, Taiwan. Tel.: +886-2-8792-7431; fax: +886-2-8791-2161. E-mail address: [email protected] (I.-S. Shiah).
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. g-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
0278-5846/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(03)00028-9
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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, 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.
2. Methods 2.1. 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-IIIR 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 psy-
chiatric disorder in first-degree relatives. All subjects were medication-free for at least 1 month prior to study. They gave written informed consents for participation in the study, and the study was approved by the local ethics committee. 2.2. Procedure All study subjects reported to the research unit for baseline blood sampling. After the subjects were weighed, a venous blood sample was obtained from each individual for a baseline plasma GABA level. Then the subjects took 100 mg/day of lamotrigine for 1 week on an outpatient basis. During the 7 days, subjects were asked to record adverse events related to lamotrigine. The adverse events reported in the questionnaire were classified as mild, moderate, and severe and were defined by ‘‘not affecting usual activity,’’ ‘‘mild disruption in usual activity,’’ and ‘‘major disruption in usual activity,’’ respectively. Subjects took the last dose of lamotrigine at 2200 h on the seventh day, and the posttreatment blood sampling for plasma GABA was carried out on the eighth day. 2.3. Biochemical assays Venous blood samples were collected into tubes containing EDTA, stored on ice and centrifuged within 60 min. Plasma was separated and then was stored at 80 °C for assay at a later time. GABA levels were determined using the high-pressure liquid chromatography (HPLC) procedure of Baker et al. (1998). In this method, samples are acidified by the addition of 1:10 the volume of 4N perchloric acid on ice and centrifuged to remove protein. The supernatant is retained, basified, and shaken with the liquid ion-pairing agent di-(2-ethylhexyl)phosphate. The aqueous layer is retained and briefly centrifuged. The sample is then reacted with fluoraldehyde (o-phthaldialdehyde, OPA) reagent and injected onto an HPLC system attached to a fluorescence detector and an integrator. All plasma samples were assayed in the same batch, and all assays were performed by a lab technician blind to the study conditions. 2.4. Statistical analysis Computer analysis of the data was carried out using the Statistical Package for Social Sciences (SPSS) for Windows1. The Kolmogorov – Smirnov (K-S) test was used to ascertain the normality of plasma GABA data distribution ( P-values for K-S tests on plasma GABA data were all larger than .1). A paired t test was used to determine if there was a significant difference in plasma GABA levels before and after treatment with lamotrigine. Relationships between variables were assessed by means of Pearson’s correlation coefficient. All significance levels reported were two-tailed and were set at P < .05.
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3. 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 posttreatment plasma GABA levels were not significantly different (t = 0.146, df = 8, P=.89) (Fig. 1). However, there was a significant positive correlation in plasma GABA levels before and after treatment with lamotrigine (Pearson’s r=.86, P < .004, n = 9) (Fig. 2). In addition, there was no significant correlation between age (Pearson’s r = – 0.34, P=.93, n = 9) or body weight (Pearson’s r = .26, P=.51, n = 9) and baseline plasma GABA levels. No significant correlation was found between age (Pearson’s r=.13, P=.74, n = 9) or body weight (Pearson’s r = .33, P=.39, n = 9) and posttreatment plasma GABA levels. As mentioned, one subject dropped out from the study after withdrawing his consent. The other 10 subjects completed the course of lamotrigine for 1 week and gave their reports on the adverse events of lamotrigine with open questionnaires. The adverse events to lamotrigine included drowsiness (10% with mild and moderate degree, respectively), headache (10% with moderate degree), tachycardia (10% with moderate degree). Interestingly, one subject reported having nightmares for 5 days after taking lamotrigine, and he rated the symptom as moderate in degree. Five out of the ten subjects did not report any significant side effects. None of the study
Fig. 1. Mean ( ± S.E.M.) plasma GABA levels in healthy male humans before and after 1 week of lamotrigine treatment (100 mg/day). The treatment of lamotrigine did not significantly alter the plasma GABA levels (Paired t test, P=.89).
Fig. 2. Plasma GABA levels before (baseline) and after treatment with lamotrigine (posttreatment) in healthy male humans. The line indicates a significant positive correlation between the baseline and posttreatment GABA levels (Pearson’s correlation, P < .004).
subjects developed skin rashes during the period of lamotrigine administration.
4. 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 al., 1986). In addition, pharmacological manipulations change both plasma and brain GABA levels in a similar magnitude (Ferkany et al., 1978; Loscher, 1979). Our finding of no significant change in plasma GABA levels after 1 week of lamotrigine treatment is consistent with the finding of Eriksson and O’Connor (1999) that there was no significant change in CSF GABA levels in patients with resistant epilepsy before and after a mean of 5 months of lamotrigine treatment, thus not supporting the involvement of GABA in the mechanisms of lamotrigine. However, it is in contrast to the MRS finding of increased cerebral GABA levels in healthy volunteers who received lamotrigine for 4 weeks (Kuzniecky et al., 2002). There are several possible explanations for the discrepancy between the studies. First, plasma and CSF GABA may not be as sensitive as cerebral GABA measured by MRS for detecting the alteration in GABA function induced by lamotrigine. If that is the case, lamotrigine appears to have an enhancing effect on central GABA function, and the exact mechanisms underlying such an effect need to be further investigated. Regarding this, Cunningham and Jones (2000) reported that lamotrigine increased both the amplitude and frequency of spontaneous GABAA receptor-mediated inhibitory postsynaptic currents
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(IPSCs) and suggested that the drug was acting presynaptically to enhance GABA release. However, the results from several other neurochemical and electrophysiological studies are contradictory (Leach et al., 1986; Lees and Leach, 1993; Teoh et al., 1995; Waldmeier et al., 1995; Braga et al., 2002). Teoh et al. (1995) reported that lamotrigine reduced GABA release evoked by electrical stimulation in rat spinal dorsal horn slices. In rat cerebral cortical slices, lamotrigine reduced GABA release evoked by the sodium channel activator, veratrine (Leach et al., 1986; Waldmeier et al., 1995). There is also some indication from whole-cell patch clamp recordings that lamotrigine may reduce spontaneous release of GABA from cultured cortical neurons (Lees and Leach, 1993). Recently, it was reported that lamotrigine reduced GABAA receptor-mediated synaptic transmission in intact circuits of the basolateral amygdala (Braga et al., 2002). Given the above conflicting results, further studies are clearly needed to ascertain further the role of GABA in the mechanism of action of lamotrigine. Second, the doses and duration of lamotrigine treatment were different for the three studies. We used 100 mg/day of lamotrigine for 1-week treatment, Eriksson and O’Connor (1999) used 1– 12 mg/kg/day of lamotrigine for a mean of 5 months treatment (range 2 –12 months), and Kuzniecky et al. (2002) used 7.1 mg/kg/day of lamotrigine for a 4-week treatment. We cannot exclude the possibility that higher doses and/or longer duration of lamotrigine will result in significant alterations in plasma GABA levels. Third, the numbers and the compositions of the study populations were also different between the studies. We had nine male healthy volunteers (mean age 24.9 years, range 18 – 30 years) who completed the lamotrigine treatment and were included in the data analysis. Eriksson and O’Connor (1999) studied 22 children and young adults with a mean age 8.9 years (range 2.5 –20.5 years) with generalized refractory seizure. Most of their study subjects received at least two other anticonvulsants prior to lamotrigine treatment. In the MRS study conducted by Kuzniecky et al. (2002), a total of 17 healthy young adults were studied (10 men, 7 women, mean age 28.7 years). Of the 17 subjects, 6 received topiramate, 6 received gabapentin, and 5 received lamotrigine. Fourth, we did not measure the plasma concentration of lamotrigine to check for the drug compliance of subjects, which may have confounded our results. Finally, it must be pointed out that our mean plasma GABA levels for healthy subjects are higher than those obtained in control subjects in the previous studies reporting on plasma GABA (Loscher and Schmidt, 1981; Petty et al., 1996; Loscher, 1999). The mean values are also higher than those obtained in subjects who we have previously studied in Edmonton using the same technique. The reason for this is not clear. However, the healthy subjects used in the present study appear to be considerably younger than most control groups in the previous studies (Loscher and Schmidt, 1981; Petty et al., 1996; Loscher, 1999), and they are also younger than those previously investigated in Edmonton.
5. 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 if lamotrigine enhances GABA activity in humans.
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).
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