Objective: To examine whether lamotrigine has a unique role in the treatment of bipolar disorder, we evaluated the results of recent clinical trials and molecular and cell biological studies on lamotrigine.

Data sources: Using keywords such as bipolar disorder, lamotrigine, clinical trial, outcomes studies, and mechanisms, we conducted a search for English-language articles on MEDLINE and Index Medicus and also on abstracts presented in recent research conferences.

Data synthesis: Several studies have strongly suggested that lamotrigine is effective for the acute treatment of bipolar depression as well as for long-term maintenance treatment of bipolar disorder. Stevens-Johnson syndrome is a concern, but the incidence of this side effect may not be as high as previously believed, if dosing is slowly titrated. The action mechanisms underlying the mood-stabilizing effects of lamotrigine are unknown at present but recent studies have produced interesting leads. Lamotrigine modulates various ion channels, altering neuronal excitability. The use-dependent inhibition of neuronal firing by lamotrigine is potentially important because it could result in attenuating supranormal neuronal activities that are possibly associated with bipolar disorder. Lamotrigine inhibits the release of glutamate, similarly to lithium, and its possible association with mood-stabilizing or antidepressant effects needs to be further examined. Unlike lithium or valproic acid, however, lamotrigine does not down-regulate the expression of protein kinase C or MARCKS, suggesting that lamotrigine employs different intracellular mechanisms for long-term changes in neuro-biology from those of lithium or valproic acid.

Conclusion: The efficacy of lamotrigine for bipolar depression may provide us with new options in the treatment of bipolar disorder. Examining the effects of lamotrigine on various molecular mechanisms in correlation with its unique efficacy on bipolar depression may enhance our understanding of action mechanisms of the mood stabilizers.

• MH61912-01/MH/NIMH NIH HHS/United States