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Overstating the Placebo Effect

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Psychotropic medications are no stranger to controversy, but lately there has been a surge in attacks on their efficacy. The latest comes from Irving Kirsch, Ph.D., of the Placebo Studies Program at Harvard Medical School, who shared his highly-debatable theory that antidepressant medications are no more effective than placebos on 60 Minutes.

Dr. Kirsch says he got involved in evaluating antidepressant medications by accident during a study researching the placebo effect. To his surprise, he could find no appreciable difference between treating depression with antidepressants and treating it with entirely different drugs, including tranquilizers and barbiturates. Dr. Kirsch then went on to study data from published and unpublished antidepressant drug trials and found that antidepressants performed about as well as placebo in many of the unpublished trials. He concedes that some people did get better while taking antidepressants, but insists the medication wasn't responsible for the change -- the placebo effect was.

The conclusions look damning, but in this case appearances are deceiving. To understand why, we need to talk about placebos -- and depression.

A placebo is by definition pharmacologically inert, but the effect it can have is remarkable, through heightened expectations, suggestion and other less understood effects. This is not limited to depression; placebo can help with pain, digestion, Parkinson's disease and much more. Neuroscientists have taken brain scans of people experiencing the placebo effect and watched as patients' brains mimicked the effects of anti-Parkinson medication. The therapeutic effect is real, although it doesn't last as long as actual medication or surgery.

Two things make depression hard to study: First, people diagnosed with the disorder may get better on their own, making it difficult to determine if a patient is improving because of treatment or for other reasons. Second, not all depressions are alike: People with mild depression and people with severe depression respond differently to medications. There's a subtype called "atypical depression" that teenagers are especially prone to. Those who have it respond best to medications that aren't often used.

To evaluate efficacy as well as safety, the FDA started testing new medications in the 1960s. Unfortunately, there are many problems with how these clinical trials are conducted. Pharmaceutical companies rush to get their product on the market as soon as possible because the patent clock (and their opportunity to profit by marketing exclusivity) starts ticking well before their drug becomes eligible for FDA testing. A primary concern in clinical trials is minimizing potential side effects that could keep the drug off the market. This means giving patient volunteers the smallest dose that could still yield statistically significant benefits -- and when the dosage is kept low to minimize side effects, it will also be less likely to have any real clinical success on someone with a disorder. Rather than taking the time to determine a correct clinical dose, it's cheaper to do lots of studies and throw out the ones that don't get results.

There's also a problem with trial volunteers, who may have varying degrees of depression, ranging from severe to mild to no disorder at all. Doctors running FDA trials are pressured to recruit volunteers as quickly as possible, so they often do a poor job screening volunteers. The doctors may be less discriminating or even outright biased towards volunteers who will be more susceptible to treatment -- both the antidepressant and the placebo form. Some of the recruited patients may be feeling down because of a recent divorce or unemployment or some other life event. These patients are likely to get better on their own, regardless of any medication. Taking a placebo could simply be a morale-booster for them.

What we know from clinical experience -- that antidepressants work best with people who have severe depression -- was actually borne out by the unpublished trials Dr. Kirsch studied. People with more severe depression were helped by antidepressants; it is the people with much milder cases of depression who were less likely to benefit.

The 60 Minutes report seems scandalous, and it is, although not in the way that Dr. Kirsch intended. The argument put forth by Dr. Kirsch and others like him is an ideological one, with no basis in science. Some people are simply opposed to treating psychiatric disorders with medication. Unfortunately, the science behind psychotropic medications is very complicated and what they have to say sounds very simple, so the ideologues can make a big splash.

My colleague Dr. Donald Klein has spent his psychiatric career evaluating medications for their clinical application and helped refine how doctors prescribe medication today. Dr. Klein began studying medicine in the 1950s, a time when psychotropic drugs and indeed diagnoses were still poorly understood. People with severe depression and schizophrenia were contained in massive institutions, and treatment was dominated by psychoanalysis. Dr. Klein tells a powerful story from his residency, when he was in charge of a unit for veterans with psychosis. Dr. Klein began prescribing the vets medication and after six weeks of treatment, one veteran who hadn't spoken in 30 years asked him, "Hey Doc, when am I getting out of here?"

The man's question helped convince Dr. Klein that drugs were not the "chemical straightjacket" that many had assumed them to be. He saw that psychotropic drugs had the power to change lives, and the same is true today. As a child and adolescent psychiatrist, I have also seen the lives of many children turned around by psychotropic medication. I have seen it help kids who were so acutely anxious they were afraid to speak, and I have seen it help teenagers who were so depressed they were ready to take their own lives.

Unfortunately, there are still people who are afraid of medication and choose to ignore the science that supports it. It's true that not everyone should be prescribed a psychotropic medication -- or be included in an FDA trial of one -- but that doesn't mean they don't work for others. Hopefully those who could really benefit from medications won't be scared off by the headlines.

Harold S. Koplewicz, M.D., is a leading child and adolescent psychiatrist and the president of the Child Mind Institute. For more on psychopharmacology, go to childmind.org, which also offers a wealth of information on childhood psychiatric and learning disorders.

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