The development of a skin rash is often associated with a rapid escalation of lamotrigine dose. We used lamotrigine to treat 259 patients with Diagnostic and Statistical Manual of Mental Disorders, 4th edition, bipolar depression using either the standard titration schedule (n=132) or a slower titration schedule (n=127) and compared the clinical efficacy and safety of both groups. Clinical efficacy of lamotrigine treatment was assessed using changes in the Clinical Global Impression Scale for Bipolar Disorder-Modified scores during the course of the 12-week treatment. A significant reduction of the Clinical Global Impression Scale for Bipolar Disorder-Modified score was observed in both groups and the effect size was large for both groups (standard, 0.75; slower, 0.71). A mixed-effect model of repeated measurement revealed an increased rate of improvement in the standard titration group that was significant during the first 5 weeks (P<0.001) but became nonsignificant by the final 7 weeks of treatment. The statistically significant reduction in the development of rashes (P=0.005) was a major advantage for patients in the slower titration group. Although the standard titration schedule generally led to faster recovery from depressive symptoms, the slower titration schedule may be an option for patients with a high risk of rash development.