Mood changes, cognitive deficits, and psychosis have been reported during corticosteroid therapy. However, minimal data are available on the treatment of these side effects. This pilot study examined the effect of 12 weeks of open- label lamotrigine treatment (dose: mean = 340 mg/day, SD = 65) on mood and cognition in five patients receiving prescription corticosteroids continuously for at least 6 months before study entry. The participants showed significant improvement in cognition with lamotrigine. Two subjects who met criteria for a current major depressive episode at baseline had baseline-to-exit reductions in scores on the Hamilton Depression Rating Scale of more than 20 points. These pilot data suggest that lamotrigine may be associated with improved mood and performance on cognitive tasks in steroid-treated patients. Larger controlled trials are needed to confirm these preliminary findings.