Doantidepressants work?

More people in the United States are on antidepressants, as a percentage of the population, than any other country in the world. And yet the drugs’ efficacy has been hotly debated.

Some believe that the short-term benefits are much more modest than widely thought, and that harms may outweigh benefits in the long run. Others believe that they work, and that they can be life-changing.

Settling this debate has been much harder than you might think.

It’s not that we lack research. Many, many studies of antidepressants can be found in the peerreviewed literature. The problem is that this has been a prime example of publication bias: positive studies are likely to be released, with negative ones more likely to be buried in a drawer.

In 2008, a group of researchers made this point by doing a meta-analysis of antidepressant trials that were registered with the Food and Drug Administration as evidence in support of approvals for marketing or changes in labelling. Companies had to submit the results of registered trials to the F D A regardless of the result. These trials also tend to have less data massaging — such as the cherry-picking of outcomes — than might be possible in journals.

The researchers found 74 studies, with more than 12,500 patients, for drugs approved between 1987 and 2004. About half of these trials had “positive” results, in that the antidepressant performed better than a placebo; the other half were “negative.” But if you looked only in the published literature, you’d get a much different picture. Nearly all of the positive studies are there. Only three of the negative studies appear in the literature as negative. Twenty-two were never published, and 11 were published but repackaged so that they appeared positive.

A second meta-analysis published that year also used F D A data instead of the peer-reviewed literature, but asked a different question. Researchers wondered if the effectiveness of a study was related to the baseline levels of depression of its participants. The results suggested yes. The effectiveness of antidepressants was limited for those with moderate depression, and small for those with severe depression.

The take-home message from these two studies was that the effectiveness of antidepressants had been overstated, and that the benefit might be limited to far fewer patients than were actually using the drugs.

These points, and more, were made in a paper written by John Ioannidis in the journal Philosophy, Ethics, andHumanities in Medicine in 2008. He argued that the study designs and populations selected, especially the short length of many studies, biased them to positive results. He argued that while many studies achieved statistical significance, they failed to achieve clinical significance. He argued that we knew too little about long-term harms, and that we were being presented with biased information by looking only at published data.

This paper—“Effectiveness of Antidepressants: An Evidence Myth Constructed From a Thousand Randomized Trials?” — sowed lingering doubts about the use of antidepressants and the conduct of medical research. But recently, the most comprehensive antidepressants study to date was published, and it appears to be a thorough effort to overcome the hurdles of the past.

Researchers, including Ioannidis this time, searched the medical literature, regulatory agency websites and international registers for both published and unpublished double-blind randomised controlled trials, all the way till the beginning of 2016.

They looked for both placebo-controlled and head-to-head trials of 21 antidepressants used to treat adults for major depressive disorder. They used a “network meta-analysis technique,” which allows multiple treatments to be compared both within individual trials directly and across trials indirectly to a common comparator. They examined not only how well the drugs worked, but also how tolerated the treatment was — what they called acceptability.

They found 522 trials that included more than 116,000 participants. Of those, 86 were unpublished studies found on trial registries and company websites. An additional 15 were discovered through personal communication or by handsearching review articles. The authors went an extra step and asked for unpublished data on the studies they found, getting it for more than half of the included trials.

The reassuring news is that all of the antidepressants were more effective than placebos. They varied modestly in terms of efficacy and acceptability, so each patient and doctor should discuss potential benefits and harms of individual drugs.

Further good news is that smaller trials did not have substantially different results from larger trials.