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, an d prior chronicity predicts future chronicity. However, few studies directl y inform the acute or maintenance phase treatments of chronic depressions a nd even less is known about the effects of treatment on psychosocial functi oning. Method: We describe the design and rationale for 2 parallel double-blind, r andomized, multicenter acute and maintenance phase treatment trials. One fo cused on DSM-III-R major depression currently in a chronic (2 2 years) majo r depressive episode, the other on DSM-III-R major depression with concurre nt 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, fol lowed by a 16-week continuation treatment phase for subjects with a satisfa ctory therapeutic response. Patients receiving sertraline who successfully completed the continuation phase entered a 76-week maintenance trial to com pare sertraline with placebo; those taking imipramine continued without a p lacebo substitution. As part of the acute trial, subjects completing but fa iling to respond to the initial 12-week acute phase medication were crossed over (double-blind) to the alternative medication for a 12-week acute phas e trial. We obtained naturalistic follow-up data (up to 18 months) for subj ects exiting the protocol at any time. Conclusion: Multiphase protocols for chronic depression can test efficacy b y 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 tria l or the preferred medication sequence in a potential multistep treatment p rogram.