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Abstract
Several clinical studies have investigated the use of the anticonvulsant lamotrigine (LTG) as a treatment for bipolar affective disorder. Evidence suggests that this drug may have a broad spectrum of utility in this illness, having both mood-stabilising (antimanic) and acute antidepressant properties. This makes this molecule of particular interest in helping to understand the underlying disease processes. In this review, we describe the cellular and molecular actions of LTG that may contribute to its action in bipolar disorder. LTG preferentially inhibits neuronal hyperexcitability and modifies synaptic plasticity via use- and voltage-dependent inhibition of neuronal voltage-activated Na^sup +^ channels and possibly high-voltage-activated Ca^sup 2+^ channels. As a consequence, it reduces excessive transmitter release in the brain. Indirectly, these effects would be expected to regulate aberrant intracellular and intercellular signalling in critical regions of the limbic forebrain where hyperactivity may occur in mania, and thus may be directly relevant to its mood-stabilising properties. Whether other molecular actions of LTG, for example on monoamine disposition, could contribute to its antidepressant activity, are less clear at present but warrant further investigation.
Key Words
Lamotrigine
Bipolar disorder
Anticonvulsant
Valproate
Carbamazepine
Sodium channel
Calcium channel
Patch clamp recording
Hippocampus
Monoamine
Introduction
Bipolar affective disorder is a severe, chronic and potentially life-threatening illness of recurrent episodes of depression with one or more episodes of mania. The aetiology and pathophysiology of the illness are poorly understood. It is clearly heterogeneous, with a substantial, but complex contribution from genetic inheritance [for recent reviews, see 1, 2]. The complexity of the phenotypes, where different behavioural, cognitive and psychomotor facets of the disorder present in temporally unpredictable and often worsening patterns make it an extremely difficult disease to treat clinically and to understand biologically. There are no animal models that can simulate all of these complexities. Moreover, in the absence of any clear molecular pathophysiology which can be used to interpret drug action, there is generally limited understanding of the mechanisms of action of moodstabilising drugs currently used to treat the disorder, including lithium and the anticonvulsants, mainly valproate (VAP) and carbamazepine (CBZ) [3, 4]. Nevertheless, advances in molecular neurobiology, particularly our understanding of mechanisms of synaptic plasticity and signal transduction, together with neuroimaging, genetics, and an appreciation of the pharmacology of...