Medication and Therapy Combined for Chronic Depression
ABSTRACT & COMMENTARY
Source: 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 2000;342(20):1462-1470.
Chronic depression is a particularly treatment-resis- tant form of major depressive disorder which, by definition, lasts for at least two years. Rates of full response to treatment (with either antidepressants or psychotherapy) are generally less than 50%. In light of this, a large proportion of patients experience residual symptomatology, which increases the risk for future relapses. Furthermore, patients with chronic depression have been shown to have marked impairments in psychosocial and occupational functioning, and have disproportionately high rates of health care resource use.
The current study by Keller and colleagues was a 12-week, multicenter, randomized trial that compared treatment with the antidepressant medication nefazodone (Serzone), treatment with a structured form of psychotherapy known as the cognitive behavioral-analysis system of psychotherapy (CBASP), and treatment with a combination of the two modalities in adult outpatients with chronic major depression. Subjects with a 24-item Hamilton Rating Scale for Depression (HAM-D) score of at least 20 were eligible for the study. Subjects with severe borderline personality disorder, a principal diagnosis of panic, generalized anxiety, or post-traumatic stress disorder were excluded from the study, as were patients with a substance-related abuse or dependence disorder.
Six hundred eighty-one subjects were randomized to one of three treatment arms: treatment with nefazodone (300-600 mg/d), treatment with CBASP (16-20 sessions), or treatment with both nefazodone and CBASP. The HAM-D was administered at baseline and at weekly intervals by blind clinical raters. Psychotherapy was performed by trained psychiatrists, psychologists, or social workers. The HAM-D score was the primary outcome measure. Response was defined as a reduction in HAM-D of at least 50% from baseline, with a score of 15 or less at week 10 and week 12 for completers, and at the time of withdrawal for those who did not complete the study. Two hundred twenty-six subjects were randomized to nefazodone, 228 to CBASP, and 227 to combined treatment. For all groups, 76% of subjects completed the study. The mean final daily dose of nefazodone was 466 (± 144 mg) in the nefazodone group and 460 (± 139 mg) in the combined-treatment group. The average number of psychotherapy sessions was 16.0 in the CBASP group and 16.2 in the combined treatment group.
For the primary outcome measure, the response rate from baseline to week 12 was significantly higher in the combined treatment group than in the nefazodone or CBASP groups.
Among subjects who completed the study, the overall rate of response was 52% in the CBASP group, 55% in the nefazodone group, and 85% in the combined treatment group. In addition, subjects in the combined treatment group showed remission rates of 42% compared to 24% in the CBASP group and 22% in the nefazodone group.
The rate of discontinuation due to adverse events was 14% in the nefazodone group, 1% in the CBASP group, and 7% in the combined treatment group. The most commonly observed adverse events associated with nefazodone were consistent with known side effects of the drug, and included headache, somnolence, dry mouth, and nausea.
COMMENT BY ANN CALLAHAN, MD
Keller et al have presented a large-scale, well-designed study showing that the combination of nefazodone and a structured form of psychotherapy (the cognitive behavioral-analysis system of psychotherapy) is superior to treatment with either modality alone for patients with chronic depression. In relative terms, two important findings emerged from their data for combination treatment compared to the single treatment regimens. First, the overall rate of response was increased by more than 30%, and second, twice as many patients reached full remission status.
Patients with chronic depression have been shown to have significantly lower rates of response to antidepressant therapy than patients with nonchronic forms of major depression; however, their response to psychotherapy is unclear due to a paucity of systematic studies. In addition, there are a lack of conclusive data establishing the efficacy of combined-treatment with an antidepressant drug and psychotherapy. In light of these facts, the findings take on particular importance and are quite encouraging.
A few limitations exist that deserve discussion. First, there was no placebo arm in this study. However, in numerous studies patients with chronic depression have been shown to have low rates of placebo response, thus this factor becomes less important. Second, the study was only 12 weeks in duration; it remains to be seen whether the benefits of combination treatment will be sustained over longer periods of time.
Finally, the degree of difficulty involved in implementing combination treatment in general clinical practice cannot be ignored. Two factors emerge that may reduce overall generalizability of these data. First, restrictive inclusion criteria caused some patients with certain comorbid psychiatric disorders to be excluded from the study. Given the fact that chronic depression frequently co-exists with disorders such as substance abuse, severe personality disorder, and post-traumatic stress disorder, the study population differed to some degree from a typical group that would be seen in a clinical setting. More important, it is likely that this treatment regimen will be difficult to implement in clinical practice. Specifically, the delivery of CBASP may present a variety of difficulties. For example, psychotherapy must be performed by specially trained professionals. At present, these individuals are few and far between. Second, in this day of managed care medicine, the cost of such treatment may be prohibitive. (Dr. Callahan is the former chief of Clinical Psychopharmacology, Brown University Veterans Affairs Medical Center, Providence, RI).
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