Methodologic issues in maintenance therapy clinical trials.

In the early 1980s, the National Institute of Mental Health supported a multicenter, randomized, controlled, clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate, imipramine hydrochloride, a lithium-imipramine combination, and placebo in preventing the recurrence of affective disorders. The objective of this report is to present a reanalysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials. We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study. Our findings have important implications for the design, conduct, and interpretation of results of maintenance therapy clinical trials in general.