A landmark study presented at the 153rd Annual Meeting of the American Psychiatric Association found that the combination of a specific type of psychotherapy (CBASP) with an antidepressant drug called nefazodone (Serzone®) was a successful treatment for patients with chronic depression. Prior to this study, chronic depression was resistant to treatment and little research had been conducted in this area. These new results suggest that patients with chronic depression now have an effective treatment option.

Martin B. Keller, MD, the study's lead investigator, along with Mary E. Zucker, Professor and Chairman of the Department of Psychiatry and Human Behavior at Brown University Medical School, Providence, RI, presented results of the acute 12-week phase of treatment, which were recently published in the New England Journal of Medicine (Zajecka et al. 2000;342:1462-1470), and gave a preview of the longer-term results, which will not be published for several months. "After 12 weeks of therapy with this particular combination of psychotherapy and drug therapy, the response rates were so high that we were stunned," said Dr. Keller.

The study included 681 patients with chronic depression who received 12 weeks of acute-phase therapy at 12 different clinics. Patients were randomized to nefazodone alone, CBASP alone, or a combination of the two.

The study had a crossover design. Responders to the first form of therapy were assigned to continue on that therapy, but those who did not respond to their initial therapy were crossed over to a different group and continued for an additional 16 weeks. Treatment continued for another year with patients assigned to groups so that they could be compared to placebo groups and/or assessed by a psychiatric rating scale for depression (the HAM-D).

The results validate the importance of psychotherapy, which has been somewhat obscured by the emphasis on using drugs to treat disorders such as depression and anxiety. CBASP is a system of psychotherapy specially developed by James McCullough, MD, for chronic depression. The intervention consists of 16 to 20 sessions over a 12-week period. Up to 12 sessions are provided during the first six weeks, averaging two sessions per week. This is more psychotherapy than patients usually receive. The goal of CBASP is to help individuals assume responsibility for their conditions and behaviors and to understand how it affects others in their lives, explained Dr. Keller. He views this type of psychotherapy as a necessary component of the psychiatrist's repertoire and training only takes a few months.

Acute Phase Results

Over the first 12 weeks, the highest response was seen in the group treated with the combination of CBASP and nefazodone-85 percent of patients had a meaningful response as assessed by the HAM-D depression rating scale. Response in patients treated with the drug nefazodone alone was 55 percent and with CBASP alone, 52 percent. Remission (a complete response) occurred in 42 percent of the combination therapy group, 22 percent with nefazodone alone, and 24 percent with CBASP alone. Additionally, a partial response was seen in 43 percent, 33 percent, and 28 percent, respectively.

Results suggested that the effect of the drug kicked in first, and after four weeks, psychotherapy acted in synergy with the drug. During the first week, nefazodone alone was more effective than the combination therapy. After that, the benefits of psychotherapy in combination with drug treatment became evident. "It seemed to us that the effect of the two treatments was synergistic and somewhat independent. The response to combination therapy was the highest ever reported in the history of depression. We were amazed," Dr. Keller told attendees.

"The results of this study were extraordinary. We were gratified that the New England Journal of Medicine saw fit to publish them on a fast-track basis," said Dr. Keller.

Crossover Data

This phase included only nonresponders. Those who failed to respond to combination therapy were discontinued, and patients who did not respond to monotherapy with either nefazodone or CBASP were switched to the alternate group. Preliminary analysis of the crossover period suggested that there was an advantage for patients who were started on drug therapy with nefazodone first and then treated with psychotherapy, even if there was no apparent response to the drug. For those who did not respond to nefazodone and were crossed over to CBASP, total response rate was 64 percent; for those not responding to CBASP and crossing over to nefazodone, total response was 53 percent. "A 'first-blush' analysis of completers during the crossover period suggest[ed] that nefazodone and CBASP were equally effective as a single therapy. Among nonresponders to acute therapy, there was a 50 percent chance of a [patient response] to another form of therapy, which we feel is heartening," Dr. Keller told listeners.

Continuation Phase

Those who responded in the acute phase continued with a 52-week maintenance phase of therapy. Response rates during the maintenance phase were once again superior for combination therapy: 91 percent for the combination, 73 percent for CBASP, and 78 percent for nefazodone. Symptoms returned in 27 percent of patients in both the CBASP and nefazodone groups, but only returned in nine percent of patients who received combination therapy.

"This shows that if you can get patients through the acute phase, adverse events are reduced and the treatment is well tolerated during the maintenance phase," Dr. Keller added. "These results demonstrate that if patients with chronic depression are maintained on therapy, there is a gain in significant responders over time. Ninety percent of those in remission during the acute phase remained responders in all three groups, and about 10 percent of those in remission during the acute phase had a re-emergence of symptoms in all three groups," emphasized Dr. Keller.

About 80 percent of patients in all three groups completed a year's worth of therapy, with a very low incidence of side effects. Weight gain is a common concern in people taking antidepressants. However, weight gain was not a big problem with nefazodone. Only about 4 percent of each group gained weight over the year. In general, nefazodone is a good choice for chronic depression because it has beneficial effects on sleep and sexual function. Other antidepressants may cause sleep disturbances and lower libido and may affect the ability to achieve erection/orgasm. In the study, overall improvement in sexual function was seen in all three treatment groups, with the greatest results from combination therapy.

"In conclusion, this landmark trial demonstrated that chronic major depression can be effectively treated and that combination psychotherapy with CBASP and nefazodone achieved the best results," stated Dr. Keller.