Imagine, for a moment, a friend who boasts successes—whether in cards or in love, in stock picks or in sport fishing—while leaving out the losses and the lonely nights, the busts and empty buckets. Depending on how well you know him or her, you might come to a rather inflated sense of your friend’s talents. Now imagine that this individual is actually an enormous multi-billion dollar business running clinical trials on antidepressants, and that it was selectively publishing successful trials, while kicking the less-successful ones under the carpet. You might similarly come to have an inflated sense of the potency of the drugs it was producing.



That’s basically what happened over the last few decades, though it took a Freedom of Information Request to figure it all out. Kramer discusses two studies, both published in 2008, that used data from studies that had never been published to shed light on the real efficacy of antidepressants. Kirsch was the lead author of one (“Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration”), published in the journal PLOS One. The other, by Erick H. Turner and colleagues, (“Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy”), was published in the New England Journal of Medicine. The Turner study explicitly examined the extent to which publication bias affected the “apparent efficacy” of antidepressants, and it made headlines. Briefly, these investigators obtained trial data submitted to the FDA for 12 antidepressants approved between 1987 and 2004. Overall, of the 74 studies they found, almost one third had never been published. They then classified the studies based on how the FDA had reviewed them: “positive” (the drug worked), “negative” (it didn’t), or “questionable” (somehow mixed). They found that the vast majority of positive studies—37 out of 38—were published. On the contrary, of the 36 negative and questionable studies, “3 were published as not positive, whereas the remaining 33 either were not published (22 studies) or were published, in our opinion, as positive (11) and therefore conflicted with the FDA’s conclusion.” This is disturbing, to say the very least. Selective publication fundamentally distorts our perception of whether the drugs work at all, much less how they work. Still—and as Kramer underscores—the study still found, at the end of the day, that the drugs were effective, just substantially less so than what one would believe on the basis of the published literature.

The 2008 study by Kirsch and colleagues didn’t compare unpublished and published study, but instead simply included both together in order to determine, more accurately, the actual effect of antidepressants. Ultimately, what they found (again, drawing on study data arrived at through a Freedom of Information Request) was that there was a statistically significant effect of antidepressants but that it wasn’t very impressive (indeed, it was below the standard considered to be of “clinical significance” by the British National Health Service), though this depended on the severity of depression. This last finding—that the effect of antidepressants depended on the severity of depression—was confirmed in another widely-reported meta-analysis by Jay C. Fournier and colleagues that appeared in 2010 in the Journal of the American Medical Association (also discussed and critiqued by Kramer). In this study, whereas evidence for efficacy was “nonexistent to negligible” for patients with more moderate forms of depression, there was evidence that the drugs were fairly potent for those with “very severe symptoms.” (Kramer cites other studies that he contends dispel this so-called “severity hypothesis”).

It was in the context of the unfurling of these somewhat scandalous studies that the debate over antidepressants burst onto the public stage. In 2011, Marcia Angell, physician and former editor-in-chief of the New England Journal of Medicine, wrote a two-part, wide-ranging essay in the New York Review of Books that reviewed several critical books about mental illness, one of which was a book by Kirsch that built on his 2008 study. Angell, however, went beyond a discussion of antidepressant efficacy to excoriate the diffuse corruption of the psychiatric field by industry money, the expansion of psychiatric diagnostic categories to encompass ever-larger numbers of people, and the downgrading of non-drug therapies. “[B]y emphasizing drug treatment,” she notes, “psychiatry became the darling of the pharmaceutical industry, which soon made its gratitude tangible.” The same year, Kramer issued something of a rebuttal, a long article headlined “In Defense of Antidepressants” that appeared in the New York Times.