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 drug's efficacy has been hotly debated. Some believe that the short-term benefits are modest 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. That's the topic of this week's healthcare triage It's not that we lack research.

Many--many!--studies of antidepressants can be found in the peer-reviewed 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 labeling. Companies have to submit the results of registered trials of the FDA regardless of those results. These trials also tend to have less data massaging, such as the cherry-picking of outcomes, that 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, meaning that the antidepressant performed better than the placebo. The other half were negative.

But if you looked only in the published literature, you 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. 22 were never published, and 11 were published, but repackaged so that they appeared positive.

The second meta-analysis published that year also used FDA data instead of using 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 in the participants. The results suggested yes.

The effectiveness of antidepressants was limited for those with moderate depression, and small--which is better--for those with severe depression. The take-home message from these two studies was that the effectiveness of antidepressants has been overstated, and that the benefit might be limited to far fewer patients than that were actually using the drugs. These points and more were made in a paper written by John Ioannidis in the journal Philosophy, Ethics, and Humanities in Medicine in 2008.

He argued that the study of designs and population selected especially the short length of many studies bias them to positive results. He argued that while many studies achieve statistical significance, they failed to achieve clinical significance. He argued that we knew too little about the 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", sewed lingering doubts about the use of antidepressants in the conduct of medical research. But, recently, the most comprehensive antidepressant study to date was published, and it appears to be a thorough effort to overcome the hurdles of the past. Researchers--including Dr.

Ioannidis this time--searched the medical literature, regulatory agency websites, and international registries for both published and unpublished double blinded randomized controlled trials all the way from the beginning 'til 2016. They looked for both placebo controlled and head-to-head trials of twenty-one 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 comparer.

They examine not only how well the drugs worked, but also how tolerated their treatments were--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 communications or hand-searching review articles. The authors went an extra step and asked for unpublished data even 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 seem to have substantially different results than larger trials. It also did not appear that industry sponsoring of trials correlated with significant differences in response or dropout rates.

But--and this is a big but-- the vast majority of trials are funded by industry. As a result, this meta-analysis may not have had enough data on non-industry trials to accurately determine if a difference exists. There were also signs of novelty bias.

Antidepressants seem to perform better when they are newly released in the market, but seem to lose efficacy and acceptability in later years, which is odd. The bad news is that even though there were statistically significant differences, the effect sizes were still mostly modest. The benefits also applied only to people who are suffering from major depression, specifically in the short-term.

In other words, this study provides evidence that when people are found to have acute major depression, treatment with antidepressants works to improve outcomes in the first two months of therapy. Because we lack good data, we still don't know how well antidepressants work for those with milder symptoms that fall short of major depression--especially if patients have been on the drugs for months or even years. Many people probably fall into that category, yet are still regularly prescribed antidepressants for extended periods of time.

We also don't know how much of the benefit received from such use is a placebo effect versus one caused somehow biologically by the drug. I asked Dr. Ioannidis if the results of this new study were as radical as many news articles had suggested.

He confirmed that this was a much larger meta-analysis, with about 10 times more information than the ones from a decade ago, with more unpublished data and more antidepressants covered. He's also hopeful the future studies will be even better at informing individual level responses which might help to see if some patients benefit substantially, even when others don't seem to benefit at all. But, he thought that some of the exuberance in the news media might be overblown.

I'm quoting him: "I am afraid that some news stories gave very crude interpretations that may be misleading, especially when their titles were too absolute like 'The Drugs Work', 'The Debate Is Over', and so forth." "The clinical as opposed to statistical significance of the treatment effects that we detected will continue to be contested, and it is still important to find ways that one can identify the specific patients who get the maximum benefit." Even with so much research on antidepressants, there are still many unanswered questions. It's unclear if drug companies will be interested in the results, or indeed, why they would be. The drugs are already being widely used and no regulatory agency is requiring more data.

If patients want answers, they're gonna need to demand the research themselves. Hey, did you enjoy this video? It really does help if you like or subscribe to the show right down there.

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