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Combination Therapy Effective in Chronic Depression



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Am Fam Physician. 2000 Nov 1;62(9):2125-2128.

Major depression tends to be a chronic condition, with prolonged episodes and incomplete remissions. About 3 percent of the U.S. population is affected at any given time, contributing significantly to poor work performance, increased hospitalizations and frequent suicide attempts. Antidepressants have proved to be effective as both initial and maintenance therapy. Despite the lack of proven efficacy from clinical trials, practice guidelines from the psychiatric literature recommend a combination of pharmacotherapy and psychotherapy as the treatment of choice in patients with chronic depression. However, data supporting the superiority of combination therapy are inconclusive. Keller and colleagues compared the effectiveness of monotherapy with pharmacotherapy or psychotherapy and combination therapy in the treatment of chronic forms of major depression.

Adult patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for chronic major depressive disorder were followed at several university outpatient sites for 18 months. Inclusion criteria consisted of a score of at least 20 on a 24-item Hamilton Rating Scale for Depression (HRSD) at initial screening and, after a two-week drug-free period, at baseline. Many exclusion criteria were applied, including a history of seizures, head trauma, schizophrenia, bipolar disorder, anxiety disorder and substance abuse. Patients who met the study criteria were randomized to receive nefazodone, psychotherapy, or a combination treatment. The medical therapy was started at 200 mg per day and increased to a maximum dosage of 600 mg per day, depending on response and tolerability. A cognitive behavioral-analysis system of psychotherapy included two weekly sessions for the first four weeks, followed by a single weekly session through week 12. The primary outcome of the study was the score on the HRSD. Remission was defined as an HRSD score of eight or less at weeks 10 and 12. The same criterion was applied to patients who did not complete the study. A satisfactory therapeutic response to treatment was defined as at least a 50 percent reduction in the HRSD from baseline to weeks 10 through 12, but with a total score of 15 or less. Patients who did not meet these criteria were considered to have no response to the respective therapies.

A total of 1,035 patients was initially screened, with 681 randomized to one of the three treatment modalities. Demographic and clinical data were the same across groups. Mean patient age was approximately 43 years, and approximately 65 percent of the patients were women. Evaluation of all patients in a modified intention-to-treat sample indicated that the mean dosage of nefazodone was 466 mg, and the average number of psychotherapy treatments was nearly 16. Mean dosage and number of therapy sessions were slightly higher in patients who completed the study. The overall response rate in patients who received either modality alone was 48 percent, but it increased to 73 percent in patients who received combination treatment. Among patients who completed the study, response rates were 55 percent for nefazodone and 52 percent for psychotherapy alone, and 85 percent for combination treatment. Remission also was significantly higher (P < 0.001) in all patients receiving combination therapy, regardless of whether or not they completed the study.

The authors conclude that combination therapy is significantly more effective than either medical therapy or psychotherapy alone.

Keller MB, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. May 18, 2000;342:1462–70.

editor's note: Intuitively, it seems that the results of this study should be not be surprising to family physicians. However, the authors cite three prior studies in which the results of combination therapy were inconclusive. It is hoped that studies such as this one will encourage third-party payers to cover the costs of outpatient psychotherapy—a benefit that has been severely restricted or eliminated during the past decade.—j.t.k.

 

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