Despite the development of better-tolerated antidepressants and more effective applications of nondrug modalities like cognitive-behavioral therapy, depressive disorders are often chronic or recurrent. The investigators of a new multiphase study of chronic depression indicate that rates of chronicity for naturalistically treated depressive episodes range from 7% to 12% in prospective studies with five to 10 years of follow-up. The rates of symptoms "persisting through decades" among inpatients with major depression are approximately 7% to 20% (Rush et al., 1998).
In describing the rationale for their studies of chronic depression, A. John Rush, M.D., professor of psychiatry at University of Texas Southwestern Medical Center at Dallas, and colleagues observed, "Among patients who do respond to treatment or who spontaneously remit, many suffer subsequent relapses or recurrences or both."
The impaired functioning, lower quality of life and increased health care utilization associated with mood disorders are particularly evident when a disorder is chronic. There is a correlation between improved psychosocial functioning and symptomatic improvement of acute depression. However, less is known about the changes in functioning that follow a response to treatment in patients who have suffered chronic depression.
The researchers point out that there has been relatively little evaluation of chronic depression, with most studies addressing short-term treatment of acute episodes. Selective serotonin reuptake inhibitor (SSRI) antidepressants are generally preferred to the tricyclic antidepressants (TCA) because of fewer discomforting side effects. However, the authors found no studies of their maintenance use in patients with chronic depression, and only a few studies of TCA maintenance regimens for recurrent, but not chronic, depression.
"The stark fact is that treatments for the most chronic and disabling forms of depression have not been well evaluated in efficacy trials," the authors observed.
In view of the paucity of data, the researchers undertook a multiphase investigation of treatment for patients with chronic depression. Separate reports have now been published on the initial 12 weeks of treatment (Keller et al., 1998a; Miller et al., 1998) and on a 76-week maintenance phase (Keller et al., 1998b).
Martin Keller, M.D., chair of the department of psychiatry and human behavior at Brown University, Providence, R.I., and co-authors concurred with Rush et al. concerning the necessity for additional research of chronic depression. "One of the most widely accepted tenets of modern psychopharmacology is the value of maintenance treatment of major depression," they note, "and yet this de facto consensus treatment strategy remains largely an article of faith" (Keller et al., 1998b).
Maintenance Phase Study
In an era when treatment decisions and reimbursement of treatment costs are increasingly evidence-based, Keller and colleagues sought to substantiate the utility of maintenance antidepressant treatment. Their maintenance phase study is a randomized, placebo-controlled test of the safety and sustained prophylactic efficacy of maintenance treatment with the SSRI sertraline (Zoloft). The subjects are patients who had responded in the 12-week acute treatment phase (published separately), and evidenced continued response through an additional four-month continuation phase.
The study included 209 patients (49.1%) of 426 who completed the 12 weeks of acute treatment with sertraline and met full or satisfactory response criteria. Out of these, 169 (81%) subsequently completed the continuation phase with good response. The maintenance study comprised 161 of these patients, randomized to receive either sertraline (77 patients) or placebo (84 patients) for an additional 76-week treatment period.
The patients in this multiphase study had initially presented with chronic depression of at least two years' duration, or "double depression," with dysthymic disorder and concurrent diagnoses of major depression. Their baseline depression severity, prior to the acute treatment phase, correlated with a minimum score of 18 on the 24-item Hamilton Depression Scale (HAM-D). At the time of their enrollment in the maintenance phase, after 28 weeks of acute and continued treatment, the patients were either in full remission or evidencing a satisfactory therapeutic response.
Criteria for full remission was a HAM-D total score of 7 or less and a Clinical Global Impression (CGI) improvement score of 1 or 2 (much or very much improved). Response was deemed satisfactory if the HAM-D score had been reduced by at least 50% to 15 or less, and the CGI-improvement and CGI-severity scores were each 3 or less.
During the 76-week maintenance phase, patients received either placebo or sertraline in flexible daily doses of 50 mg to 200 mg. Physician-rated efficacy measures, administered monthly, were the 24-item version of the HAM-D, the Montgomery-Asberg Depression Rating Scale, the Cornell Dysthymia Scale, and the CGI-Severity and CGI-Improvement Scales. Patient-rated assessments were the Beck Depression Inventory and the Patient Global Evaluation, also completed monthly.
An exacerbation of depressive symptoms triggered an appointment within one week and follow-up within the following week. The dosage of sertraline could be increased to a maximum of 200 mg daily and, if improvement did not occur, the patient could be discontinued from the study. Of the 77 patients receiving sertraline, 42 withdrew from the study; and 60 of the 84 patients receiving placebo withdrew. Eleven of the 42 sertraline-treated patients who withdrew from the study did so for lack of efficacy, eight for a violation of the research protocol, eight due to an adverse drug reaction and 15 for other reasons or being lost to follow-up. Ultimately, 35 patients receiving sertraline and 24 receiving placebo completed the 76-week maintenance trial.
As expected, the maintenance SSRI resulted in significantly better outcomes on all symptom measures than did placebo. Although the likelihood for recurrence of depression with active treatment had been lessened by paring down this study population to patients who had achieved and maintained initial response to treatment, a comparison of the probability for recurrence did distinguish sertraline from placebo beginning at the eighth week. The SSRI provided patients with significantly better prophylaxis than placebo at all assessment points thereafter.
A number of possible factors contributing to the depression recurrence were examined, with a longer duration of dysthymia the only significant predictor. The investigators did note a trend, albeit not statistically significant, of recurrence risk correlating with a higher acute baseline CGI-Severity score.
Keller and colleagues concluded from their findings that the maintenance SSRI regimen for patients with chronic depression "protects against recurrence or reemergence of depression and considerably extends the time in remission for this high-risk population."
Keller MB, Gelenberg AJ, Hirschfeld RMA et al. (1998a), The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 59(11):598-607.
Keller MB, Kocsis JH, Thase ME et al. (1998b), Maintenance phase efficacy of sertraline for chronic depression. JAMA 280(19):1665-1672.
Miller IW, Keitner GI, Schatzberg AF et al. (1998), The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine. J Clin Psychiatry 59(11):608-619.
Rush AJ, Koran LM, Keller MB (1998), 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. J Clin Psychiatry 59(11):589-597.