The Treatment of Chronic Depression, Part 1: Study Design and Rationale for Evaluating the Comparative Efficacy of Sertraline and Imipramine as Acute, Crossover, Continuation, and Maintenance Phase Therapies

Background: Chronic depressions are common, disabling, and undertreated, and prior chronicity predicts future chronicity. However, few studies directly inform the acute or maintenance phase treatments of chronic depressions and even less is known about the effects of treatment on psychosocial functioning.

Method: We describe the design and rationale for 2 parallel double-blind, randomized, multicenter acute and maintenance phase treatment trials. One focused on DSM-III-R major depression currently in a chronic (≥ 2 years) major depressive episode, the other on DSM-III-R major depression with concurrent DSM-III-R dysthymia ("double depression").

Results: Considering the critical knowledge deficits, we designed a 12-week acute phase safety and efficacy trial of sertraline versus imipramine, followed by a 16-week continuation treatment phase for subjects with a satisfactory therapeutic response. Patients receiving sertraline who successfully completed the continuation phase entered a 76-week maintenance trial to compare sertraline with placebo; those taking imipramine continued without a placebo substitution. As part of the acute trial, subjects completing but failing to respond to the initial 12-week acute phase medication were crossed over (doubleblind) to the alternative medication for a 12-week acute phase trial. We obtained naturalistic follow-up data (up to 18 months) for subjects exiting the protocol at any time.

Conclusion: Multiphase protocols for chronic depression can test efficacy by randomized contrasts as well as shed light on key clinical issues such as the degree of response or attrition expected at particular times in a trial or the preferred medication sequence in a potential multistep treatment program.