Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats

Abstract

Lamotrigine is a novel anticonvulsant drug which also stabilises mood in bipolar illness via an unknown mechanism. We report the concentration-dependent inhibition of 5-hydroxytryptamine (5-HT) uptake in both human platelets and rat brain synaptosomes (IC₅₀s were 240 and 474 μM, respectively) by lamotrigine. Synaptosomal uptake of noradrenaline (IC₅₀ 239 μM) and dopamine (IC₅₀ 322 μM) was also inhibited. Tetrodotoxin failed to modulate 5-HT uptake suggesting that sodium channel blockade does not mediate the lamotrigine effect. Lithium, sodium valproate, zonisamide, and carbamazepine all possess anti-manic activity but only the latter inhibited 5-HT uptake. The inhibition of the p-chloroamphetamine-induced 5-HT syndrome in rats suggests that lamotrigine also inhibits 5-HT uptake in vivo. These effects probably reflect an affinity for biogenic amine transporters. However, at present, it remains uncertain whether, at clinically effective doses, these effects contribute significantly to the efficacy of lamotrigine in bipolar illness.

Introduction

Li⁺ has been the mainstay of treatment for bipolar illness for several decades but in recent years the inadequacy of this therapy for many patients has become increasingly apparent (Silverstone and Romans, 1997). In the search for alternatives, carbamazepine and sodium valproate have emerged as useful adjuncts to lithium (Post et al., 1996). Although these therapies do offer some protection against bipolar depression when used prophylactically, lithium, carbamazepine, and sodium valproate are all relatively ineffective against acute bipolar depression (Kalin, 1996).

Lamotrigine (3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine; Lamictal) is a new generation broad-spectrum anticonvulsant (Goa et al., 1993) which is believed to mediate its anticonvulsant activity by the use- and voltage-dependent blockade of Na⁺ channels (Xie et al., 1995). Preliminary reports indicate that lamotrigine may also be useful in the treatment of bipolar illness with efficacy against depressive breakthroughs and rapid cycling bipolar disorder (Calabrese et al., 1996; Corn et al., 1996; Walden et al., 1996). The 5-hydroxytryptamine (5-HT) system is widely implicated in the pathophysiology of depression (Owens and Nemeroff, 1994) and current antidepressant therapy is largely based upon boosting 5-HT neurotransmission by inhibiting biogenic amine reuptake (Moller and Volz, 1996). We have used rat brain synaptosomes and washed human platelets to test the hypothesis that lamotrigine inhibits biogenic amine uptake in vitro. These in vitro studies are complemented by an examination of the effect of lamotrigine in the p-chloroamphetamine-induced 5-HT behavioural syndrome in rats (Tricklebank, 1985; Adell et al., 1989; Hutson and Curzon, 1989). Attenuation of the syndrome is a recognised marker for inhibition of 5-HT uptake in vivo (Fuller, 1980; Fuller and Snoddy, 1986).