Rationale for Using Lithium in Combination With Other Mood Stabilizers in the Management of Bipolar Disorder

Bipolar disorder is a complex illness, and no single agent has been proven in randomized, placebo-controlled trials to effectively prevent and/or control all aspects of the illness—acute mania, rapid cycling, and breakthrough depression. However, for the most important issue, prophylaxis of episodes, lithium has more evidence of efficacy than any other agent. Like lithium, typical antipsychotics,carbamazepine, divalproex, and the atypical antipsychotic olanzapine are effective in thetreatment of mania. Carbamazepine, divalproex, and olanzapine seem effective in preventing manicepisodes but, like lithium, are less effective in preventing depression. Few trials have been conductedin the more difficult-to-treat characteristics of bipolar disorder, specifically, rapid cycling and breakthrough depression. For patients with rapid cycling, carbamazepine or divalproex therapy may improvesymptoms, but only lamotrigine has been shown to reduce cycling, mostly in the bipolar IIgroup, in a randomized, placebo-controlled study. For the treatment of depressive episodes, lithiumand olanzapine have shown modest efficacy in controlled trials, and among the mood stabilizers, lamotrigine has the most robust effect. Because manic symptoms may respond best to one agent anddepressive symptoms to another, combination therapy may be the optimal treatment for many patientswith bipolar disorder. For example, lithium augmentation may improve overall response rates to treatmentwith carbamazepine or divalproex, and the lithium-lamotrigine combination should provideeffective prevention of both mania and depression. Also, each mood stabilizer may be given at lowerdoses when given in combination, resulting in a reduced side effect burden and improved compliance.