May 7, 1999

Newer antidepressant drugs are generally no better at treating depression and no more likely to be discontinued due to side effects than earlier drugs including tricyclic antidepressants, according to a recent review by the federal Agency for Health Care Policy and Research (AHCPR).

The AHCPR review also found that there are too few data to evaluate the relative efficacy for depression of psychotherapy versus medication, despite a recent meta-analysis in Psychotherapy and Psychosomatics that concluded that psychotherapy worked as well as medication.

"This issue of old-versus-new antidepressants and completeness of response is very complicated, to say the least," remarked Charles B. Nemeroff, M.D., Ph.D., vice chair of APA's Committee on Research on Psychiatric Treatments and chair of the department of psychiatry and behavioral sciences at the Emory University School of Medicine in Atlanta. For example, several studies have suggested that clomipramine, an older generation drug, is more effective than several different SSRIs in severe depression, he noted.

In a typical trial of 100 patients given a single SSRI, 30 percent show complete remission, 40 percent a "clinically significant response-that is, better but not well," said Nemeroff, and 30 percent have no response. "Others might quibble about the exact numbers, but this means that 70 percent of patients are only partial responders or nonresponders. We need to do better."

The AHCPR analyzed more than 300 randomized trials of newer pharmacotherapies and reached the following conclusions:

• More than 80 studies found newer drugs more effective than placebo for treating adults with major depression; 32 percent of patients in double-blind placebo trials improved on placebo, versus 50 percent given one of the newer antidepressants.



• The efficacy of newer antidepressants is comparable with that for both first- and second-generation tricyclic antidepressants.



• Dropout rates for newer and older antidepressants are similar.



• St. John's Wort, the best studied herbal antidepressant, is more effective than placebo for short-term treatment of mild to moderately severe depressive disorders, but this conclusion is tempered by the scarcity of trials. It is not clear whether St. John's Wort is as effective as standard antidepressant drugs.

  The AHCPR study also compared newer antidepressants and psychosocial therapies and concluded that there remain substantial gaps in knowledge.




• There were no trials comparing newer drugs with educational or supportive counseling and only one small trial comparing psychotherapy directly with a newer antidepressant in adults. The data are too limited to determine whether newer antidepressants are more or less effective than psychosocial therapies.



• Only two studies were found that evaluated newer antidepressants in children or adolescents, yielding too few data to guide clinicians managing depression in those age groups.



• A number of studies evaluated newer antidepressants for patients comorbid for depression and other conditions including alcoholism, chronic fatigue syndrome, HIV-related illness, heart disease, renal failure, and stroke. The results, however, "are conflicting and insufficient to reliably determine the efficacy of newer agents compared with placebo or older agents," the report concludes.



• Fewer than 10 percent of trials report on the participants' ethnic background, rendering the data inadequate to determine whether efficacy varies across ethnic groups.

Cynthia Mulrow, M.D., the study's lead investigator, is a professor of medicine and geriatrics at the University of Texas Health Science Center in San Antonio. Although SSRIs are the "therapies of choice" for many clinicians, said Mulrow, there are many other options, "and no particular class of drugs is routinely more effective than others."

The analysis "shows the importance of evaluating the evidence on the full range of treatments-new and old, conventional and alternative-so that clinicians have all the information available when making treatment decisions about their patients," said AHCPR Administrator John Eisenberg, M.D.

"The reason clinicians generally prefer the newer medications is that there is virtually no risk of lethal overdose," observed Alexander Bodkin, M.D., director of McLean Hospital's clinical psychopharmacology research program in Belmont, Mass. "An equally important consideration is the relative tolerability of the side effects encountered." The problem with basing such broad conclusions on a cumulative analysis of placebo-controlled studies is that it "completely misses the ease of managing side effects since that is excluded by the very methodology of placebo-controlled studies," Bodkin added.

Although AHCPR concluded that there are too few data to determine whether psychosocial therapies may work as well as or better than medications new or old, a separate review headed by psychologist David Antonuccio, Ph.D., of the University of Nevada School of Medicine, and colleagues reached different conclusions. The authors reviewed meta-analyses of hundreds of depression treatment studies conducted between 1958 and the present and concluded that psychotherapy alone may be as effective as pharmacotherapy in treating depression.

"The evidence suggests that psychological interventions are at least as effective as pharmacotherapy in treating depression, even if severe, especially when patient-rated measures are used and long-term follow-up is considered," the authors said. The article appeared in the January-February issue of Psychotherapy and Psychosomatics.

Among the contentions raised by the authors: industry-funded research studies that result in negative findings are sometimes not published; placebo washout procedures may bias results; the integrity of the double-blind procedure is questionable in some drug trials; preliminary evidence suggests that patients treated successfully with cognitive behavioral therapy (CBT) show similar biological changes as those who respond to medication. The authors also questioned whether the risks of medications outweigh the benefits and further note that biochemical theories of depression remain unproven.

Researcher Nemeroff disagreed with the conclusions drawn by Antonuccio and colleagues. Nemeroff noted, for example, that in one ongoing multicenter trial comparing the antidepressant nefazodone and cognitive behavioral therapy for treatment of chronic depression, those treated with a combination of medication and psychotherapy have fared better than those treated with either psychotherapy or medication alone. Nemeroff is managing the trials at one site.

The AHCPR report is available online at www.ahcpr.gov/clinic/deprsumm.htm. The Psychotherapy and Psychosomatics article may be accessed through the publisher's Web site at www.karger.com/journals/pps/pps_jh.htm.