Preliminary communication
Effects of lamotrigine on the 5-HT1A receptor function in healthy human males

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Abstract

Background: Lamotrigine, a new anticonvulsant, has recently been reported to be effective in treating patients with bipolar mania, depression, and schizoaffective disorder, suggesting that it is perhaps a mood stabilizer with antimanic and antidepressant properties. However, the mechanism of action underlying its efficacy in mood disorders is still unknown. Methods: To explore the role of 5-HT1A receptors in the mechanism of action of lamotrigine, we measured the body temperature and plasma cortisol responses to a challenge with a selective 5-HT1A receptor agonist ipsapirone in ten healthy human males. Each subject received 0.3 mg/kg of ipsapirone hydrochloride tablets at time “0”. Body temperature readings and blood samples for cortisol levels were obtained at 0, 30, 60, 90, 120, 150, 180 min. The ipsapirone challenge tests were repeated after 1 week treatment with lamotrigine (100 mg/day). Results: Treatment with lamotrigine for 1 week did not significantly alter the hypothermic or cortisol responses to ipsapirone. Limitations: The limitations of this study included small sample size, low treatment dose, short treatment interval, and lack of placebo control. Conclusions: Our findings might suggest that 5-HT1A receptor function is not involved in the mechanism of action of lamotrigine in humans. Further placebo-controlled studies with a higher lamotrigine dose and a longer treatment interval in a larger number of subjects are needed to verify this.

Introduction

Lamotrigine is a new 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 recently been reported to be effective in a mixed cohort of patients with bipolar mania, depression, and schizoaffective disorder, suggesting that it is perhaps a mood stabilizer like lithium with antimanic and antidepressant properties (Calabrese et al., 1996). Although evidence suggests that the antiepileptic action of lamotrigine may be due to its inhibition of voltage-sensitive sodium channel and suppression of subsequent release of glutamate (Gilman, 1995), the mechanism of action underlying its efficacy in mood disorders remains unknown.

In healthy humans, 5-HT1A receptor agonists – such as buspirone, gepirone, and ipsapirone – increase plasma cortisol and decrease body temperature. Buspirone and gepirone also increase plasma prolactin and growth hormone (Cowen et al., 1990). Data from animal studies suggest that hormonal responses to 5-HT1A receptor agonists are mediated via post-synaptic 5-HT1A receptors (Van De Kar, 1991) whereas hypothermic response to 5-HT1A receptor agonists is mediated by pre-synaptic 5-HT1A autoreceptors, although a mixed pre- and post-synaptic activation has also been suggested for mediation of hypothermia in rats (Glaser and De Vry, 1992). Therefore, measurement of hypothermic and hormonal responses to 5-HT1A receptor agonists would be an in vivo approach to study pre- and post-synaptic 5-HT1A receptors in human subjects (Lesch, 1991).

Using this paradigm, blunted hypothermic responses to buspirone (Cowen et al., 1994) and ipsapirone (Lesch et al., 1990a) have been demonstrated in depressed patients compared to normal controls, suggesting a subsensitivity of 5-HT1A autoreceptors in depression. Furthermore, a subsensitivity of postsynaptic 5-HT1A receptors in depression has also been suggested by the studies that showed a reduction in cortisol responses to ipsapirone (Lesch et al., 1990b, Meltzer and Maes, 1995), and a reduction in prolactin response to buspirone (Moeller et al., 1994) in patients with depression. In the only one study of the 5-HT1A function in mania, Yatham (1994)found no significant difference in prolactin response to buspirone between 11 manic patients and 11 healthy controls. Since buspirone also possess dopamine antagonist activity which may partly explain its capacity to increase prolactin, the results of the study can not exclude the possibility that 5-HT1A receptor function is involved in mania. More recently, we demonstrated that the mood stabilizer, divalproex sodium (DVP), significantly attenuated ipsapirone-induced hypothermia in healthy humans, suggesting that this medication may enhance 5-HT neurotransmission by down-regulating pre-synaptic 5-HT1A autoreceptors (Shiah et al., 1997).

Given that 5-HT1A receptor function is involved in depression, and possibly in mania, and that mood stabilizers may exert their actions by altering the 5-HT1A receptor function, we were particularly interested in determining whether 5-HT1A receptors play a role in the mechanism of action of lamotrigine. We, therefore, examined the effects of lamotrigine on the pre- and post-synaptic 5-HT1A receptor function by measuring hypothermic and cortisol responses to ipsapirone in healthy male volunteers before and after 1 week treatment with lamotrigine.

Section snippets

Methods

We studied ten healthy male volunteers (mean age±S.D.: 24.4±4.0 years). All subjects were free of physical and psychiatric disorders as determined by a structured clinical interview for DSM-III-R diagnosis-non-patient version (SCID-NP; Spitzer et al., 1992) 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 testing. They gave written informed consents for

Results

There was no significant difference in the baseline body temperature of ten subjects before and after lamotrigine treatment (36.7±0.2 vs 36.8±0.3°C; t=−0.31, d.f.=9, P=0.77). As shown in Fig. 1, ipsapirone administration led to a significant drop in body temperature. This, however, was not altered by lamotrigine treatment for 1 week. Repeated measures ANOVA on temperature data showed a significant time effect (F=6.09, df=54,6, P<0.001) but no significant treatment effect (F=1.33, df=9,1, P

Discussion

This study replicates earlier findings that ipsapirone, a 5-HT1A receptor agonist, significantly decreases body temperature and increases plasma cortisol levels in healthy humans (Lesch et al., 1990a, Lesch et al., 1990b), supporting a role for 5-HT1A receptors in regulating body temperature and hypothalamic-pituitary-adrenal (HPA) axis activation in humans (Cowen et al., 1990). Treatment with lamotrigine for 1 week did not significantly alter hypothermic or cortisol responses to ipsapirone.

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