AntiDepressants Don’t Work:5 Things You Need to Know Now! Studies suggest that the popular drugs are no moreeffective than a placebo. In fact, they may be worse
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for those with very severe, more chronic conditions, it's harder to knock down and placebos are less adequate," says Hollon. Why that should be remains a mystery, admitscoauthor Robert DeRubeis of the University of Pennsylvania.Like every scientist who has stepped into the treacherous waters of antidepressantresearch, Hollon, DeRubeis, and their colleagues are keenly aware of the disconnect between evidence and public impression. "Prescribers, policy-makers, and consumersmay not be aware that the efficacy of [antidepressants] largely has been established onthe basis of studies that have included only those individuals with more severe forms of depression," something drug ads don't mention, they write. People with anything less thanvery severe depression "derive little specific pharmacological benefit from takingmedications. Pending findings contrary to those reported here … efforts should be madeto clarify to clinicians and prospective patients that … there is little evidence to suggestthat [antidepressants] produce specific pharmacological benefit for the majority of patients."Right about here, people scowl and ask how anti-depressants—especially those that raisethe brain's levels of serotonin—can possibly have no direct chemical effect on the brain.Surely raising serotonin levels should right the synapses' "chemical imbalance" and liftdepression.Unfortunately, the serotonin-deficit theory of depression is built on a foundation of tissue paper. How that came to be is a story in itself, but the basics are that in the 1950sscientists discovered, serendipitously, that a drug called iproniazid seemed to help some people with depression. Iproniazid increases brain levels of serotonin and norepinephrine.Ergo, low levels of those neurotransmitters must cause depression. More than 50 yearson, the presumed effectiveness of antidepressants that act this way remains the chief support for the chemical-imbalance theory of depression. Absent that effectiveness, thetheory hasn't a leg to stand on.Direct evidence doesn't exist. Lowering people's serotonin levels does not change their mood. And a new drug, tianeptine, which is sold in France and some other countries (butnot the U.S.), turns out to be as effective as Prozac-like antidepressants that keep thesynapses well supplied with serotonin. The mechanism of the new drug? It
lowers
brainlevels of serotonin. "If depression can be equally affected by drugs that increase serotoninand by drugs that decrease it," says Kirsch, "it's hard to imagine how the benefits can bedue to their chemical activity."Perhaps antidepressants would be more effective at higher doses? Unfortunately, in 2002Kirsch and colleagues found that high doses are hardly more effective than low ones,improving patients' depression-scale rating an average of 9.97 points vs. 9.57 points—adifference that is not statistically significant. Yet many doctors increase doses for patientswho do not respond to a lower one, and many patients report improving as a result.There's a study of that, too. When researchers gave such nonresponders a higher dose, 72 percent got much better, their symptoms dropping by 50 percent or more. The catch?
Only half the patients really got a higher dose. The rest, unknowingly, got the original,"ineffective" dose. It is hard to see the 72 percent who got much better on ersatz higher doses as the result of anything but the power of expectation: the doctor upped my dose,so I believe I'll get better.Something similar may explain why some patients who aren't helped by oneantidepressant do better on a second, or a third. This is often explained as "matching" patient to drug, and seemed to be confirmed by a 2006 federal study called STAR*D.Patients still suffering from depression after taking one drug were switched to a second;those who were still not better were switched to a third drug, and even a fourth. No placebos were used. At first blush, the results offered a ray of hope: 37 percent of the patients got better on the first drug, 19 percent more on their second, 6 percent moreimproved on their third try, and 5 percent more on their fourth. (Half of those whorecovered relapsed within a year, however.)So does STAR*D validate the idea that the key to effective treatment of depression ismatching the patient to the drug? Maybe. Or maybe people improved in rounds two,three, and four because depression sometimes lifts due to changes in people's lives, or because levels of depression tend to rise and fall over time.With no one in STAR*D receiving a placebo, it is not possible to conclude with certaintythat the improvements in rounds two, three, and four were because patients switched to adrug that was more effective for them. Comparable numbers might have improved if theyhad switched to a placebo. But STAR*D did not test for that, and so cannot rule it out.It's tempting to look at the power of the placebo effect to alleviate depression and stick an"only" in front of it—as in, the drugs work
only
through the placebo effect. But there isnothing "only" about the placebo response. It can be surprisingly enduring, as a 2008study found: "The widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking," scientistswrote in the
Journal of Psychiatric Research
.The strength of the placebo response drives drug companies nuts, since it makes showingthe superiority of a new drug much harder. There is a strong placebo component in theresponse to drugs for pain, asthma, irritable-bowel syndrome, skin conditions such ascontact dermatitis, and even Parkinson's disease. But compared with the placebocomponent of antidepressants, the placebo response accounts for a smaller fraction of the benefit from drugs for those disorders—on the order of 50 percent for analgesics, for instance.Which returns us to the moral dilemma. In any year, an estimated 13.1 million to 14.2million American adults suffer from clinical depression. At least 32 million will have thedisease at some point in their life. Many of the 57 percent who receive treatment (the restdo not) are helped by medication. For that benefit to continue, they need to believe intheir pills. Even Kirsch warns—in boldface type in his book, which is in stores this week —that patients on antidepressants not suddenly stop taking them. That can cause serious
withdrawal symptoms, including twitches, tremors, blurred vision, and nausea—as wellas depression and anxiety. Yet Kirsch is well aware that his book may have the sameeffect on patients as dropping the magic feather did for Dumbo: without it, the littleelephant began crashing to earth. Friends and colleagues who believe Kirsch is right ask why he doesn't just shut up, since publicizing the finding that the effectiveness of antidepressants is almost entirely due to people's hopes and expectations will underminethat effectiveness.It's all well and good to point out that psychotherapy is more effective than either pills or placebos, with dramatically lower relapse rates. But there's the little matter of reality. Inthe U.S., most patients with depression are treated by primary-care doctors, not psychiatrists. The latter are in short supply, especially outside cities and especially for children and adolescents. Some insurance plans discourage such care, and some psychiatrists do not accept insurance. Maybe keeping patients in the dark about theineffectiveness of antidepressants, which for many are their only hope, is a kindness.Or maybe not. As shown by the explicit criticism of drug companies by the authors of therecent
JAMA
paper, more and more scientists believe it is time to abandon the "don't ask,don't tell" policy of not digging too deeply into the reasons for the effectiveness of antidepressants. Maybe it is time to pull back the curtain and see the wizard for what heis. As for Kirsch, he insists that it is important to know that much of the benefit of antidepressants is a placebo effect.If placebos can make people better, then depression can be treated without drugs thatcome with serious side effects, not to mention costs. Wider recognition thatantidepressants are a pharmaceutical version of the emperor's new clothes, he says, mightspur patients to try other treatments. "Isn't it more important to know the truth?" he asks.Based on the impact of his work so far, it's hard to avoid answering, "Not to many people."
With Sarah Kliff
Find this article athttp://www.newsweek.com/id/232781
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