Last night “60 Minutes” ran a piece about antidepressants and the placebo effect. This information was out there 2 years ago in this article that ran in Newsweek.
The Depressing News About Antidepressants
Jan 28, 2010 7:00 PM EST
Studies suggest that the popular drugs are no more effective than a placebo. In fact, they may be worse.
Although the year is young, it has already brought my first moral dilemma. In early January a friend mentioned that his New Year’s resolution was to beat his chronic depression once and for all. Over the years he had tried a medicine chest’s worth of antidepressants, but none had really helped in any enduring way, and when the side effects became so unpleasant that he stopped taking them, the withdrawal symptoms (cramps, dizziness, headaches) were torture. Did I know of any research that might help him decide whether a new antidepressant his doctor recommended might finally lift his chronic darkness at noon?
The moral dilemma was this: oh, yes, I knew of 20-plus years of research on antidepressants, from the old tricyclics to the newer selective serotonin reuptake inhibitors (SSRIs) that target serotonin (Zoloft, Paxil, and the granddaddy of them all, Prozac, as well as their generic descendants) to even newer ones that also target norepinephrine (Effexor, Wellbutrin). The research had shown that antidepressants help about three quarters of people with depression who take them, a consistent finding that serves as the basis for the oft-repeated mantra “There is no question that the safety and efficacy of antidepressants rest on solid scientific evidence,” as psychiatry professor Richard Friedman of Weill Cornell Medical College recently wrote in The New York Times. But ever since a seminal study in 1998, whose findings were reinforced by landmark research in The Journal of the American Medical Association last month, that evidence has come with a big asterisk. Yes, the drugs are effective, in that they lift depression in most patients. But that benefit is hardly more than what patients get when they, unknowingly and as part of a study, take a dummy pill—a placebo. As more and more scientists who study depression and the drugs that treat it are concluding, that suggests that antidepressants are basically expensive Tic Tacs.
Hence the moral dilemma. The placebo effect—that is, a medical benefit you get from an inert pill or other sham treatment—rests on the holy trinity of belief, expectation, and hope. But telling someone with depression who is being helped by antidepressants, or who (like my friend) hopes to be helped, threatens to topple the whole house of cards. Explain that it’s all in their heads, that the reason they’re benefiting is the same reason why Disney’s Dumbo could initially fly only with a feather clutched in his trunk—believing makes it so—and the magic dissipates like fairy dust in a windstorm. So rather than tell my friend all this, I chickened out. Sure, I said, there’s lots of research showing that a new kind of antidepressant might help you. Come, let me show you the studies on PubMed.
It seems I am not alone in having moral qualms about blowing the whistle on antidepressants. That first analysis, in 1998, examined 38 manufacturer-sponsored studies involving just over 3,000 depressed patients. The authors, psychology researchers Irving Kirsch and Guy Sapirstein of the University of Connecticut, saw—as everyone else had—that patients did improve, often substantially, on SSRIs, tricyclics, and even MAO inhibitors, a class of antidepressants that dates from the 1950s. This improvement, demonstrated in scores of clinical trials, is the basis for the ubiquitous claim that antidepressants work. But when Kirsch compared the improvement in patients taking the drugs with the improvement in those taking dummy pills—clinical trials typically compare an experimental drug with a placebo—he saw that the difference was minuscule. Patients on a placebo improved about 75 percent as much as those on drugs. Put another way, three quarters of the benefit from antidepressants seems to be a placebo effect. “We wondered, what’s going on?” recalls Kirsch, who is now at the University of Hull in England. “These are supposed to be wonder drugs and have huge effects.”
The study’s impact? The number of Americans taking antidepressants doubled in a decade, from 13.3 million in 1996 to 27 million in 2005.
To be sure, the drugs have helped tens of millions of people, and Kirsch certainly does not advocate that patients suffering from depression stop taking the drugs. On the contrary. But they are not necessarily the best first choice. Psychotherapy, for instance, works for moderate, severe, and even very severe depression. And although for some patients, psychotherapy in combination with an initial course of prescription antidepressants works even better, the question is, how do the drugs work? Kirsch’s study and, now, others conclude that the lion’s share of the drugs’ effect comes from the fact that patients expect to be helped by them, and not from any direct chemical action on the brain, especially for anything short of very severe depression.
As the inexorable rise in the use of antidepressants suggests, that conclusion can’t hold a candle to the simplistic “antidepressants work!” (unstated corollary: “but don’t ask how”) message. Part of the resistance to Kirsch’s findings has been due to his less-than-retiring nature. He didn’t win many friends with the cheeky title of the paper, “Listening to Prozac but Hearing Placebo.” Nor did it inspire confidence that the editors of the journal Prevention & Treatment ran a warning with his paper, saying it used meta-analysis “controversially.” Al-though some of the six invited commentaries agreed with Kirsch, others were scathing, accusing him of bias and saying the studies he analyzed were flawed (an odd charge for defenders of antidepressants, since the studies were the basis for the Food and Drug Administration’s approval of the drugs). One criticism, however, could not be refuted: Kirsch had analyzed only some studies of antidepressants. Maybe if he included them all, the drugs would emerge head and shoulders superior to placebos.
Kirsch agreed. Out of the blue, he received a letter from Thomas Moore, who was then a health-policy analyst at George Washington University. You could expand your data set, Moore wrote, by including everything drug companies sent to the FDA—published studies, like those analyzed in “Hearing Placebo,” but also unpublished studies. In 1998 Moore used the Freedom of Information Act to pry such data from the FDA. The total came to 47 company-sponsored studies—on Prozac, Paxil, Zoloft, Effexor, Serzone, and Celexa—that Kirsch and colleagues then pored over. (As an aside, it turned out that about 40 percent of the clinical trials had never been published. That is significantly higher than for other classes of drugs, says Lisa Bero of the University of California, San Francisco; overall, 22 percent of clinical trials of drugs are not published. “By and large,” says Kirsch, “the unpublished studies were those that had failed to show a significant benefit from taking the actual drug.”) In just over half of the published and unpublished studies, he and colleagues reported in 2002, the drug alleviated depression no better than a placebo. “And the extra benefit of antidepressants was even less than we saw when we analyzed only published studies,” Kirsch recalls. About 82 percent of the response to antidepressants—not the 75 percent he had calculated from examining only published studies—had also been achieved by a dummy pill.
The extra effect of real drugs wasn’t much to celebrate, either. It amounted to 1.8 points on the 54-point scale doctors use to gauge the severity of depression, through questions about mood, sleep habits, and the like. Sleeping better counts as six points. Being less fidgety during the assessment is worth two points. In other words, the clinical significance of the 1.8 extra points from real drugs was underwhelming. Now Kirsch was certain. “The belief that antidepressants can cure depression chemically is simply wrong,” he told me in January on the eve of the publication of his book The Emperor’s New Drugs: Exploding the Anti-depressant Myth.
The 2002 study ignited a furious debate, but more and more scientists were becoming convinced that Kirsch—who had won respect for research on the placebo response and who had published scores of scientific papers—was on to something. One team of researchers wondered if antidepressants were “a triumph of marketing over science.” Even defenders of antidepressants agreed that the drugs have “relatively small” effects. “Many have long been unimpressed by the magnitude of the differences observed between treatments and controls,” psychology researcher Steven Hollon of Vanderbilt University and colleagues wrote—”what some of our colleagues refer to as ‘the dirty little secret.’ ” In Britain, the agency that assesses which treatments are effective enough for the government to pay for stopped recommending antidepressants as a first-line treatment, especially for mild or moderate depression.
But if experts know that antidepressants are hardly better than placebos, few patients or doctors do. Some doctors have changed their prescribing habits, says Kirsch, but more “reacted with anger and incredulity.” Understandably. For one thing, depression is a devastating, underdiagnosed, and undertreated disease. Of course doctors recoiled at the idea that such drugs might be mirages. If that were true, how were physicians supposed to help their patients?
Two other factors are at work in the widespread rejection of Kirsch’s (and, now, other scientists’) findings about antidepressants. First, defenders of the drugs scoff at the idea that the FDA would have approved ineffective drugs. (Simple explanation: the FDA requires two well-designed clinical trials showing a drug is more effective than a placebo. That’s two, period—even if many more studies show no such effectiveness. And the size of the “more effective” doesn’t much matter, as long as it is statistically significant.) Second, doctors see with their own eyes, and feel with their hearts, that the drugs lift the black cloud from many of their depressed patients. But since doctors are not exactly in the habit of prescribing dummy pills, they have no experience comparing how their patients do on them, and therefore never see that a placebo would be almost as effective as a $4 pill. “When they prescribe a treatment and it works,” says Kirsch, “their natural tendency is to attribute the cure to the treatment.” Hence the widespread “antidepressants work” refrain that persists to this day.
Drug companies do not dispute Kirsch’s aggregate statistics. But they point out that the average is made up of some patients in whom there is a true drug effect of antidepressants and some in whom there is not. As a spokesperson for Lilly (maker of Prozac) said, “Depression is a highly individualized illness,” and “not all patients respond the same way to a particular treatment.” In addition, notes a spokesperson for Glaxo-Smith-Kline (maker of Paxil), the studies analyzed in the JAMA paper differ from studies GSK submitted to the FDA when it won approval for Paxil, “so it is difficult to make direct comparisons between the results. This study contributes to the extensive research that has helped to characterize the role of antidepressants,” which “are an important option, in addition to counseling and lifestyle changes, for treatment of depression.” A spokesperson for Pfizer, which makes Zoloft, also cited the “wealth of scientific evidence documenting