The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens-Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo-controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders.