Popular antidepressants including Prozac and Paxil have little impact on most patients, according to a comprehensive review of newly released data from trials that were conducted before the drugs were approved in the U.S.
Researchers from the U.K., U.S. and Canada analyzed results for fluoxetine (better known by the brand name Prozac), venlafaxine (Effexor), nefazodone (Serzone) and paroxetine (Paxil or Seroxat) all members of a class of drugs known as selective serotonin reuptake inhibitors (SSRIs). The researchers' paper, published this week in the journal PLoS Medicine, claims that only patients who are diagnosed "at the upper end of the very severely depressed category" get any meaningful benefit from the widely prescribed drugs. For the others, the paper says, antidepressants are barely more effective than a placebo (although patients suffering from depression, like those suffering from chronic pain, generally do see a substantial placebo benefit).
There are plenty of studies about antidepressants. What makes this one so important the results were front-page news across the U.K. on Tuesday is that the researchers were able to track down comprehensive unpublished trial results from the drug makers themselves before the drugs were authorized for sale in the U.S., and include them in their review of the literature. The U.S. Food and Drug Administration (FDA) must receive records of all relevant pharmaceutical-company trials, both published and unpublished, before it will approve a drug. Under the Freedom of Information Act, the researchers writing in PLoS Medicine were recently able to obtain those FDA records of industry-sponsored clinical trials. They yield data, they believe, that lets them avoid a bias that often plagues reviews of previous research: the tendency for conclusive positive results to be published, sometimes more than once, and thus over-represented, while mediocre results can be ignored or even swept under the rug.
Drug companies claim the review is still flawed, however. One massive problem: there are many more recent studies than those surveyed in the article, which looked only at pre-approval trials conducted before 1999. Nicholas Francis, a U.K. spokesman for Eli Lilly and Company, which produces Prozac, says that the new study "does not take into account that today more than 12,000 patients have participated in Prozac clinical trials and thousands of scientific papers have referenced Prozac, supporting its use in the treatment of depression." Some 50 million people worldwide have taken Prozac, and in a company statement Lilly said it "is proud of the difference Prozac has made to millions of people living with depression." Similarly, paroxetine producer GlaxoSmithKline warns, "This analysis has only examined a small subset of the total data available ... and this one study should not be used to cause unnecessary alarm and concern for patients." As a spokeswoman for Wyeth, Effexor's maker, points out, these were, after all, the same data the FDA reviewed before approving the drugs for public use.
There are really two issues at the heart of the controversy. One is the difference between "statistical significance" a measure of whether the drug's effects are reliable, and that patient improvement is not just due to chance and "clinical significance," whether those effects actually are big enough to make a difference in the life of a patient. The researchers behind this new paper did find that SSRI drugs have a statistically significant impact for most groups of patients: that is, there was some measurable impact on depression compared to the placebo effect. "But a very tiny effect may not have a meaningful difference in a person's life," says Irving Kirsch, lead author on the paper and a professor of psychology at the University of Hull in England. As it happens, only for the most severely depressed patients did that measurable difference meet a U.K. standard for clinical relevance and that was mostly because the very depressed did not respond as much to placebos. The drug trials showed SSRI patients improved, on average, by 1.8 points on the Hamilton Depression Rating Scale, a common tool to rate symptoms such as low mood, insomnia, and lack of appetite. The U.K. authorities use a drug-placebo difference of three points to determine clinical significance.
The more troubling question concerns what kind of data is appropriate for analyzing a drug's efficacy. The companies are correct in claiming there is far more data available on SSRI drugs now than there was 10 or 20 years ago. But Kirsch maintains that the results he and colleagues reviewed make up "the only data set we have that is not biased." He points out that currently, researchers are not compelled to produce all results to an independent body once the drugs have been approved; but until they are, they must hand over all data. For that reason, while the PLoS Medicine paper data may not be perfect, it may still be among the best we've got.