New Data Rebut Claims About Antidepressants

A re-analysis of more than 40 studies refutes an earlier meta-analysis purporting to show that effectiveness of antidepressants was limited to severe depression.

The antidepressants fluoxetine and venlafaxine were found to be efficacious for major depressive disorder in all age groups, although more so in youth and adults than in geriatric patients, and baseline severity was not significantly related to degree of treatment advantage over placebo.

These results came from a re-analysis of data from more than 40 randomized, controlled trials of fluoxetine hydrochloride and venlafaxine hydrochloride in youth, adult, and geriatric subjects.

The re-analysis was published online on March 5 in the Archives of General Psychiatry. The findings contradict a 2008 study in the journal PLoS (Public Library of Science) by Kirsch and colleagues that garnered much publicity for indicating that antidepressants appeared to be effective only for severe depression.

The Archives study differed crucially from the 2008 PLoS article because it employed statistical models that allowed for patient-level data, incorporating baseline severity scores as both a discrete and a continuous variable and tracking change in symptoms over time to measure rates of relapse and remission; in contrast, the PLoS article simply looked at the average change of everyone in a study over the course of the study.

“Unlike a typical meta-analysis, we got all the patient-level data as well as data at every point that patients were measured within a study,” lead author Robert Gibbons, Ph.D., told Psychiatric News. “Previous meta-analyses worked with study-level data, looking at average change from baseline to the end of the study and found that only those studies with more severely depressed patients showed a significant change.

“We used a much more rigorous approach using intermediate data,” he said. “We were able to look at patient-level changes across time and compute response and remission rates. And we found that there was no significant difference in the amount of change depending on whether one was more sick or less sick at baseline.”

He is a professor of biostatistics in the departments of medicine, health studies, and psychiatry at the University of Chicago.

In the study, Children’s Depression Rating Scale–Revised scores, Hamilton Rating Scale for Depression scores for adult and geriatric populations, and estimated response and remission rates at six weeks were analyzed for 2,635 adults, 960 geriatric patients, and 708 youth receiving fluoxetine; for 2,421 adults receiving immediate-release venlafaxine; and for 2,461 adults receiving extended-release venlafaxine.

Gibbons and colleagues found that patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo.

Geriatric patients had the smallest drug-placebo differences, an 18.5 percent greater rate of improvement, 9.9 percent for response and 6.5 percent for remission. By contrast, child and adolescent patients had the largest overall drug placebo differences, a 29.0 percent greater rate of improvement, 24.1 percent for response and 30.1 percent for remission.

Psychiatrist Michael Thase, M.D., who has conducted research in this area and was familiar with the methods and results of the Gibbons study, said it effectively refutes one of the more controversial conclusions of the PLoS paper, namely, that antidepressants are only effective in patients with severe depression.

“Gibbons and colleagues were able to use statistical models that take into account each person’s level of pretreatment severity and how those people’s symptoms change across time, whereas Kirsch and colleagues worked with only study-level data,” Thase told Psychiatric News. “Average change from baseline gives you some information but much less than using individual patient data. Moreover, Gibbons and colleagues were able to compute response and remission rates, which are the more meaningful difference in outcome for people.”

Thase, a professor of psychiatry in the Perelman School of Medicine at the University of Pennsylvania, spoke at APA’s 2010 annual meeting in New Orleans about efficacy of antidepressants. At that meeting, he said modern randomized, controlled studies of antidepressants demonstrate increasing effects of placebo because of patient selection and study design—a fact that has obscured the real value of antidepressants (Psychiatric News, July 2, 2010).

Thase added that the PLoS analysis used last-observation-carried-forward—a statistical convention that “carries forward” the last scores of a patient who drops out of a study, as if it were an endpoint. “It’s a conservative convention to account for missing data that typically punishes the arm of active treatment in a study because drugs have side effects, so some greater percentage of people usually drop out of the active treatment before they have a chance to respond.”

An abstract of “Benefits From Antidepressants: Synthesis of 6-Week Patient-Level Outcomes From Double-Blind Placebo-Controlled, Randomized Trials of Fluoxetine and Venlafaxine” is posted at http://archpsyc.ama-assn.org/cgi/content/abstract/archgenpsychiatry.2011.2044.