Children and adolescents who are the offspring of a bipolar parent and who first present with major depressive disorder (MDD) are at high risk for eventually developing bipolar disorder. In this report, the authors describe a group of 9 such high-risk children and adolescents with MDD, aged 7-16 years, who were randomized to receive treatment with either paroxetine monotherapy or combination paroxetine-divalproex sodium therapy. In the long-term management of depressive symptomatology in these patients, neither treatment appeared to be particularly effective. As a result, future treatment studies in this population appear to be warranted, not only due to the putative impending risk of developing bipolar disorder, but also the manifest risk of current depressive episodes.