Are Antidepressants Placebos?

60 Minutes' antidepressant report in 2012 may have been 'explosive,' but it's not conclusive. Studies linking the placebo effect to antidepressants have been around for more than a decade. There have, however, been far more studies showing antidepressants to be significantly more effective than placebos. The good in the program is that it will stimulate scientific inquiry into this question. If Dr. Kirsch is right, we want to know. If he has an agenda and/or is wrong, he and the media, which uncritically jump on sensational stories, are doing a disservice with potentially great harm.

Furthermore, if he is wrong, suicide - now the 10th leading cause of death, according to statistics from the Centers for Disease Control published in 2011 – may increase. So let’s try to get the story as measured and reasoned as possible.

CBS’s 60 Minutes aired its explosive story on February 19, 2012, the gist of which was that antidepressants are no more effective than placebos in treating depression. Leslie Stahl conducted the report, which prominently featured Harvard psychologist, Dr. Irving Kirsch. Dr. Kirsch stated that his research shows that antidepressants are generally no more effective than placebos.

Seemingly stunned, Leslie Stahl said “If a sugar pill is just as good, how can we keep prescribing these [antidepressant] pills?” Afterwards, she said “I walked away really confused.” What’s an ordinary person supposed to gain from watching this segment?

The report was received by some with enthusiasm. Prior to CBS’s airing of the report, I received an email from a psychologist gleefully advising me to watch the program that night. Within a day or two of the show’s airing, I Googled the term, “60 Minutes antidepressants and placebos” which brought up a raft of links, many of which expressed a very positive reaction to the 60 Minutes report., e.g., “…how your antidepressant may not be what you think.”

Actually, Dr. Kirsch did not conclude that antidepressants are no more effective than placebos in treating severe depression. He concluded that they are no more effective than placebos in treating mild to moderate depression.

Unfortunately, 60 Minutes could only tell part of the story in less than 20 minutes. It did not tell us that Dr. Kirsch may have an agenda, i.e., that placebos are as potent as established psychiatric treatments. In 2010, he published his book, The Emperor’s New Drugs: Exploding the Antidepressant Myth, which essentially attacked all placebo-controlled studies. In fact, later in the 60 Minutes interview, he backtracked and even included antidepressants’ effectiveness in severe depression as a result of a flawed methodology of blinded drug trials.

The placebo effect is undeniably real. However, it is another thing to conclude that, as Dr. Kirsch did on 60 Minutes,"The difference between the effect of a placebo and the effect of an antidepressant is minimal for most people. They'd have almost as large an effect, and whatever difference there would be would be clinically insignificant." … [T]he reason [people] get better is not because of the chemicals in the drug.”

What 60 Minutes also did not say is that Kirsch’s research is selective. Kirsch did not include every antidepressant study ever done (decades worth of antidepressant research and thousands of studies). Not only were the thousands of studies not addressed, but even with studies designed to seek FDA approval, he looked at the clinical trials performed to gain FDA approval for 6 antidepressant drugs while there are over a dozen antidepressants on the market. Using studies designed to seek FDA approval might seem like the best studies to look at, but these studies have problems.

As I see it, the major problem with equating antidepressants with placebos is the misdiagnosis of depression – the failure to distinguish depression as a normal reaction to unfortunate circumstances from depression as an illness. You can't solve a problem if you don’t know what it is. If you think depression is an illness when it is normal, what do you expect will happen if you compare an antidepressant to a placebo in treating normal depression?

So, what is depression?

First, it is a word in our language that essentially means the emotion of sadness.

I have often explained emotions, including depression, to my patients as follows: We generally think of our rational nature as the epitome of being human. In contrast, we often think of emotions as a troublesome bother. However, I don’t think Mother Nature gave us emotions just to trouble us or so that psychiatrists could charge people money. Emotions, even unpleasant emotions – when they are normal – are a gift, a kind of miniature instinct. Unpleasant emotions let us know something is amiss.

I like to use a stove analogy. When you place your hand on a hot stove, it hurts. That’s a good thing. Unpleasant as it is, it saves us from burning the flesh off our hand. It’s Mother Nature’s way of helping us. And so it is with normal depression. We’re supposed to feel bad when we are in unhappy circumstances, such as the loss of a loved one. As members of a social species, we bond with others. When those bonds are broken, it hurts. If it didn’t hurt, we wouldn’t care. It wouldn’t mean anything if others left us. So the bonding and then the mourning that follows the loss of a loved one serve the bonding process and makes us the social species we are.

It’s also advantageous to feel depressed if we are in an unhappy marriage or in some other destructive relationship. If we didn’t feel bad, we might stay in that relationship indefinitely at the possible ruination of our lives.Some psychiatrists, myself included, distinguish demoralization (depression as a reaction to miserable circumstances) from depression that is truly an illness. We might assume that investigators in drug trials to gain FDA approval would define “depression” in a consistent manner. They should, but they often do not. A problem is in the recruitment of participants in drug trials. These subjects have minimal psychiatric and medical coexisting conditions. They are not chronically depressed, and they are willing to accept placebo treatment. Often subjects who feel depressed but don’t have the illness of depression are included — and spontaneously in a few weeks are not depressed. People also may exaggerate their symptoms to get free care or incentive payments offered in trials. Other subjects participate when they are at their worst and then spontaneously improve.

F.D.A. data reveal that placebo responses have been steadily rising over the past two decades. Peter Kramer, author of Listening to Prozac, points out in an Opinion Piece in The New York Times published July 9, 2011, that “In some studies, 40 percent of subjects not receiving medication get better.”

The clinical trial recruitment process has increasingly emphasized recruitment of subjects rather than the quality of depression for drug trials.

According to Peter Kramer: The problem is so big that entrepreneurs have founded businesses promising to identify genuinely ill research subjects. The companies use video links to screen patients at central locations where (contrary to the practice at centers where trials are run) reviewers have no incentives for enrolling subjects. In early comparisons, off-site raters rejected about 40 percent of subjects who had been accepted locally — on the ground that those subjects did not have severe enough symptoms to qualify.

Rajnish Mago, MD, director of the mood disorders program at Thomas Jefferson University in Philadelphia, wrote in an email to ABC News and MedPage Today. "We expanded the concept of depression to include less severe cases (so-called 'minor depression') and cases where the depression occurred after a significant life problem." He compares antidepressant drug trials to diluting the chances of finding a benefit of antibiotics by including both viral and bacterial illness in a treatment trial. The viral infections will tend to remit with placebo or with antibiotic.

Antibiotics are effective against bacterial illness. I also suspect that antidepressants actually are effective in true depressive illness. There have been decades and thousands of drug trials testing antidepressant effectiveness. Peter Kramer, additionally, makes an excellent point about the placebo issue: The F.D.A encourages companies to submit “maintenance studies.” In these trials, researchers take patients who are doing well on medication and switch some to dummy pills. If the drugs are acting as placebos, switching should do nothing. In an analysis that looked at maintenance studies for 4,410 patients with a range of severity levels, antidepressants cut the odds of relapse by 70 percent. These results, rarely referenced in the antidepressant-as-placebo literature, hardly suggest that the usefulness of the drugs is all in the patients’ heads.

Mild and moderately depressed people do well with psychotherapy. They also often respond to placebos. However, the media, some scientists, and some ordinary people have proclaimed that antidepressants are equivalent to placebos.

For the true illness of depression, antidepressants are not equivalent to placebos. To give the impression that they are is likely to cause significant harm.