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The Washington Post
Placebo Effects

New! Improved! And Still 100 Percent Fake

By Jay Dixit
Sunday, May 19, 2002; Page B01

On the windowsill of his Columbia University office, psychiatrist B. Timothy Walsh has a little golden bottle labeled “placebo.” The container is filled with sugar pills — breath mints, to be exact — and purports to treat everything from “bad hair” to “can’t take a joke” to “no rhythm” to “the blahs.” About 50 conditions are listed with a box next to each. The label directs patients: “Select symptom. Check box. Take 2 mints. Bingo. . . all better!”

Walsh’s “cure” is reminiscent of the snake oil, tonics and magical elixirs that used to be popular in this country — the kind of carnival quackery that no one falls for anymore. Right?

Well, not quite. According to a recent report by Seattle psychiatrist Arif Khan, who conducted analyses of the placebo effect in 96 clinical trials submitted to the FDA between 1979 and 1996, sugar pills were often as effective as antidepressants. And judging by the media’s reaction to the publication of Khan’s findings, you might think that people are getting ready to throw away their little green-and-white Prozac pills. It all leaves our collective faith in modern medicine a little shaken.

But it shouldn’t. Studies like Khan’s, which was first reported in The Post, are confusing, and and some people have assumed that his findings mean that sugar pills work just as well as Prozac, Paxil and Zoloft. But in fact, as the original article pointed out, these studies don’t mean that antidepressants don’t work, or that sugar pills work just as well or even that antidepressants don’t work as well as we previously thought. Quite the opposite. We’re seeing these results because antidepressants do work — and because of our increased faith in the power of modern medicine. What has happened is that our confidence in antidepressants has grown — partly because of modern pharmaceutical marketing techniques. Our belief in their power causes placebos to work better. When people volunteer to take part in clinical trials, they expect the medication they are given to work — and it does work, even if it is just sugar.

Confusion abounds about the “placebo effect” — the term that doctors use to describe the phenomenon where patients get better because they expect the treatment to work, even though they’re actually ingesting a pharmacologically inert substance. And that confusion has been compounded by a variety of recent studies that seem to contradict each other. Last year, an article in the New England Journal of Medicine declared the placebo effect to be a statistical chimera, arguing that sick people tend to get better over time, regardless of whether they take sugar pills, and that belief plays no part in that process. Khan’s study seemed to refute that: Prozac had five clinical trials, and in only two of them did it work significantly better than sugar pills. For Zoloft and Paxil, it took even more trials to obtain a positive result.

There is an answer to these apparent contradictions — and it’s not to stop taking antidepressants. The first step is to ask why the placebo effect is so strong relative to the actual effect of the drug.

A major reason for the placebo’s efficacy stems from the care and concern shown to patients during clinical trials, which has a big impact on their well-being — especially in the case of depression. “Care, concern, and general attention are crucial factors in our patients’ recoveries from illness — not only from depression, but from all medical illnesses,” says Andrew Leuchter, a professor of psychiatry at UCLA.

Another factor is the time scale. Clinical trials are fairly short (usually eight weeks) and often that’s not enough time to observe the long-term effects of a depression treatment. A placebo group might show equal improvement to a medication group at first. But if a placebo study were done over a period of several years, the placebo group would almost certainly fall behind.

But the main factor that explains why antidepressants often fare no better than sugar pills is more mysterious, and it was suggested by a separate study: The placebo effect is growing more powerful.

In a survey of antidepressant trials from 1981 to 2000, Walsh found that the placebo effect grew more pronounced over the years. (As Walsh jokes, “They’re making placebos better and better.”) But why? The answer to that question is cultural, not medical. After all, those trials were conducted in basically the same way 20 years ago as they are today. The thing that’s changed is us.

It’s well established that confidence in a treatment can have a mind-over-body effect on how well the treatment works. And our culture’s faith in technology generally, and in medicine in particular, has grown in that time period.

In 1981, the first year examined in Walsh’s study, AIDS was just appearing on our radar screens.Doctors were diagnosing a mysterious and frightening new disease and no one knew how to fight it. Now, people expect to live long and productive lives with HIV. That’s just one of the examples of the ways the medical and technological breakthroughs of the past 20 years have changed our expectations of medicine and science. We are mapping the genome, can explore the brain using magnetic resonance imaging, transplant organs and build artificial hearts.

Today, we also have a better understanding of mental illness. We know that many people experience depression, we view depression as an illness, and the stigma about seeking treatment for it is fading. A study published in January in the Journal of the American Medical Association found that the number of Americans being treated for depression had tripled between 1987 and 1997, and the number taking antidepressants had doubled. In fact, according to an ABC News poll, one in every eight Americans has been treated with antidepressants at some stage in their lives.

Pharmaceutical marketing also has bolstered our feelings of faith in drugs. With a million antidepressant prescriptions a week in this country, drug giants can afford to spend billions on advertising to convince us their products work. Commercials feature animations of sad neurons weeping, presumably because they don’t have enough serotonin to go around. Once they get Zoloft, they become smiling, flying, animated neurons.

That marketing has an effect on our psyche. We have become more willing to believe that depression can be caused by a chemical imbalance in the brain — and that it can be treated chemically. “It has to do with the profoundly cognitive nature of depression,” says Jack Glaser, a social psychologist and professor of public policy at the University of California at Berkeley. Since depression can be treated without medication, using cognitive therapy, taking a pill you think will make you better can break the cycle and help you cope. “The most likely reason placebo effects are getting bigger is the increasingly prevailing belief that pills work for treating depression — thus the placebo has more credibility.”

Walsh’s study found that, for the most part, the effectiveness of a drug increased along with the effectiveness of the placebo. But he found that the placebo effect is not only stronger today, but more variable. This variability accounts for why placebos sometimes score better than real drugs. “The drugs are more effective, but there’s so much noise in the system, and people are getting better for so many different reasons, that it can be hard to show every time that the drug is better than placebo,” says Walsh. “But it is.”

Doctors have long known that the power of suggestion can have real medical effects. And expectation of harm — the so-called nocebo effect — can be as powerful as the placebo effect. In one nocebo study, patients were given sugar water and told it was an emetic. Eighty percent vomited. In another, asthmatic patients inhaled saline spray thinking it was an irritant. Many had breathing problems and asthma attacks. Many recovered when researchers gave them the same spray again, this time telling them it was a bronchiodilator.

Other studies have demonstrated that placebos improve blood pressure, cholesterol levels, heart rate and allergies, and can make warts vanish. For some reason, red sugar pills kill pain better than green, blue, or yellow ones; blue sugar pills work better as sedatives than pink ones. Patients don’t just think they get better on placebos: They really do get better, and the changes are reflected in brain scans and blood tests.

Because people are suggestible, doctors know that the hype (often, true hype) surrounding a medication can make it more effective. One old doctors’ cynical joke goes, “Use new drugs quickly, while they still work.”

What does all of this research imply for pharmaceutical companies and for the public? The first conclusion is that if the kind of care and attention patients received in the clinical trials can have such a strong impact on an individual’s recovery, health insurance companies should realize that encouraging longer doctor’s visits will save money in the long run, and we should make sure that depressed people receive therapy or counseling. The ABC News poll that found one in eight Americans had taken antidepressants also showed that 59 percent had not received therapy in conjunction with the medication. The Journal of the American Medical Association, which reported that antidepressant use has gone up, also reported that face-to-face therapy has gone down: From 1987 to 1997, the percentage of patients in counseling dropped from 71 percent to 60 percent.

The key to understanding the placebo effect is to disentangle the effect of the drug from the effect of the care. But in the real world, we don’t have to worry about which is helping more. The message we should take from Khan’s new research is not that antidepressants don’t work, but that they work best in conjunction with increased care and concern — in the form of therapy. That’s the combination of treatment that the medical profession should aim to provide.

Jay Dixit is a writer living in New York City.

© 2002 The Washington Post Company

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