Experts Dispute Report Critical of Antidepressants

In late February some headlines heralded bad news for those being treated for depression: “Prozac does not work,” declared one headline from the UK Guardian, “and nor do similar drugs....”

The news was in reaction to a metaanalysis of trials of selective serotonin reuptake inhibitors submitted to the U.S. Food and Drug Administration (FDA) from 1987 to 1999. The report appeared in the February 26 PLOS Medicine.

“These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression,” the authors wrote, “but show significant effects for only the most depressed patients.”

Given their findings, Irving Kirsch, Ph.D., and colleagues concluded that“ there seems to be little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit.”

In an editorial appearing on the Web site of the British Medical Journal, Eric Turner, M.D., an assistant professor of psychiatry at Oregon Health and Science University, and Robert Rosenthal, Ph.D., a distinguished professor of psychology at the University of California, Riverside, noted that the data derived from their analysis of 12 antidepressant trials submitted to the FDA was similar to that derived from Kirsch.

“Although these two sets of results were in excellent agreement, our interpretations of them were quite different. In contrast to Kirsch and colleagues' conclusion that antidepressants are ineffective, we concluded that each drug was superior to placebo,” the letter stated.

In the meta-analysis of FDA clinical trials, Kirsch obtained data from 35 randomized clinical trials, including five of fluoxetine, six of venlafaxine, eight of nefazodone, and 16 of paroxetine in which all patients had been diagnosed with major depressive disorder. The trials were conducted and submitted to the FDA in an effort by manufacturers to have their medication approved.

The researchers analyzed the findings in two ways: they calculated a standardized mean difference between the drug and placebo and the effect size of both groups.

The researchers examined all available information on the drugs, including results from the trials that drug manufacturers did not publish during the licensing period, which they obtained through a Freedom of Information Act request. This gave them access to nine trials deemed adequate and well controlled by the FDA, but that according to the report failed to achieve a statistically significant benefit for drug over placebo.

The results were then compared with the criterion for clinical significance as measured by the United Kingdom's National Institute for Clinical Excellence (NICE). That criterion is a three-point difference between placebo and treatment groups on the Hamilton Rating Scale of Depression (HRSD) scores or a standardized mean difference of .50.

The HRSD was used to measure depression levels at baseline and throughout the duration of the trials.

Kirsch and colleagues found that the weighted mean improvement on the HRSD in the groups receiving antidepressants was 9.60, and for those receiving placebo was 7.80, yielding a drug-placebo difference of 1.8 on the HRSD, which though statistically significant, did not meet NICE's three-point drug-placebo criterion for clinical significance.

In addition, the standardized mean difference for the drug groups was 1.24 and was .92 for placebo groups, which meant that the difference between improvement in the drug groups and placebo groups was .32, which fell below the .50 standardized mean difference criterion suggested by NICE.

In their editorial, Turner and Rosenthal pointed out that the criterion set by NICE is “problematic, because it transforms effect size, a continuous measure, into a yes or no measure, thereby suggesting that drug efficacy is either totally present or absent, even when comparing values as close together as 0.51 and 0.49.”

They also noted that the NICE criterion is not a definitive measure, but a value that could be problematic as a litmus test for drug efficacy.

In the article, Kirsch and his colleagues noted that drug efficacy did not change as a function of initial depression severity, whereas placebo efficacy decreased as initial depression severity increased. “Efficacy reaches clinical significance only in trials involving the most extremely depressed patients,” the authors wrote, “due to a decrease in the response to placebo rather than to an increase in the response to medication.”

In an interview with Psychiatric News, one of the authors of the report, Blair Johnson, Ph.D., noted that the average trial's placebo effect was closer to 100 percent of the size of the average drug effect at lower observed rates of depression (that is, a score of about 17 on the HRSD) and dropped to about 50 percent at the higher observed levels of depression (that is, a score of about 30 on the HRSD).

Johnson is a professor of psychology at the University of Connecticut.

According to Darrel Regier, M.D., M.P.H., executive director of the American Psychiatric Institute for Research and Education and director of APA's Division of Research, there is nothing new in the findings to guide clinical decision making for those prescribing antidepressants.

“We knew from the National Institute of Mental Health Collaborative Treatment of Depression study in the 1980s that mild to moderate depression could be treated as effectively with cognitive-behavioral therapy or interpersonal therapy as with tricyclic antidepressants, but that those with more severe depression responded better to the medication.”

In addition, Regier pointed out, “the FDA is well aware of the high placebo effect in depression treatment and requires at least two credible placebo controls to grant an indication for an antidepressant medication.”

After safety and effectiveness are determined by the FDA, Regier noted, clinicians need to know how to treat their patients most effectively.

The Sequenced Alternatives to Relieve Depression (STAR^*D) study demonstrated that many patients “don't respond to the first antidepressant at a rate much higher than is found with placebo,” but that different steps of treatment produced cumulative remission rates of 67 percent.

In their editorial, Turner and Rosenthal wrote that they view the antidepressant “ 'glass' as far from full, but we disagree that it is completely empty.”

They recommended to clinicians that “when considering the potential benefits of treatment with antidepressants, be circumspect but not dismissive.”

Regier, in his assessment of Kirsch's article, agreed.

Regier noted that for some reason Kirsch and colleagues are continuing a quest to convince patients and physicians that antidepressants are largely ineffective. In fact, there were a large number of online responses to the article, many of which were critical of the study and its conclusions. Commenters covered topics such as charges of author bias, descriptions of measurement and methodology shortcomings with the original antidepressant studies and the meta-analysis, discussions of the complexity of understanding the placebo effect in clinical trials, and patient perspectives on the efficacy of antidepressants. The comments and Johnson's response are posted at<http://medicine.plosjournals.org/perlserv/?request=read-response&doi=10.1371/journal.pmed.0050045#r2188>.

Regier also said, “Fortunately for patients suffering from these very real and disabling disorders, clinicians who follow a logical sequence of treatment trials informed by research such as STAR^*D are able to maximize treatment effectiveness with a combination of medications and psychotherapies.”

“Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration” is posted at<http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050045>. Turner and Rosenthal's editorial, “Efficacy of Antidepressants,” is posted at<www.bmj.com/cgi/content/full/336/7643/516>.▪