The problem with treating depression isn’t that antidepressants don’t work.

Such bad food and so little of it. This week, we heard claims that antidepressants work only for the severest forms of mood disorder and that few depressed people receive even the most minimal care. To my mind, the undertreatment problem is the real news. As for drugs not working—that’s a complicated story.

The idea that antidepressants offer scant benefit for mild or moderate disorders comes from research published in this week’s JAMA. The study in question is scrupulous but odd. The researchers, from the University of Pennsylvania and elsewhere, wanted to reexamine the much-debated claim that antidepressants are little more than glorified placebos. To this end, they sought out trials in which they could examine data in detail and in particular in which they could determine whether patients were gravely afflicted.

To focus on major depression, the Penn group narrowed the field in a series of ways. They started with more than 2,000 treatment studies. Almost half were discarded because they used either no FDA-approved antidepressant or no placebo. Reasoning that it is well-established that antidepressants work for dysthymia—chronic or frequently recurring minor depression—the researchers next eliminated trials in which that sort of mood disorder played a role. The exclusion is important. Of the 1,000 or so studies of depression treated with an FDA-approved drug, the Penn researchers threw out almost 600 for this reason.

Then the researchers introduced a third, quite stringent filter. They would not consider any trials that contained a “placebo washout period.” Many serious studies of psychiatric treatment begin with an interval, often two weeks, in which patients are offered a placebo. Some subjects recover, and others improve at a fast pace. These patients then do not enter the trial. The delay eliminates people who did not have much of an illness in the first place or who respond readily to investigators’ attentions or the sugar pill. Reasoning that this set-up may hide placebo effects that arise in ordinary practice, the Penn group scratched off a couple of hundred more studies.

In the end, the researchers were able to apply their analysis to only six of the original 2,000-plus trials. These lucky few constitute an idiosyncratic mix: on the one hand, a multi-center NIMH trial, on the other, a study of St. John’s wort and imipramine as used in general medical practice in Germany. By chance, the trials tested only two antidepressants, Paxil and imipramine. (Parenthetically, some overviews have found Paxil to be among the least effective of the antidepressants.) It is this summary of six studies of two medications that has led the press to report more or less conclusively that antidepressants do little for minor mood disorders.

In critiquing their own study, the researchers highlight two problems. First, few subjects included in their analysis had very mild depression, so the conclusion about drug effects at the healthy end of the spectrum is based on minimal data. Second, studies of depression are plagued by “rater inflation,” a problem I have discussed before. In order to fill up a study quickly, researchers overstate prospective subjects’ symptom levels. That means that subjects enrolled with apparently mild symptoms may not have depression at all—and they will “recover” over time, whatever the treatment. If you look at the graph in the Penn study, you see just what you’d imagine given rater inflation and the lack of a washout: In the treatment of mild cases, placebo effects are large, swamping even apparently substantial drug effects.

Tags: anti-depressants, depression, peter kramer, prozac

Peter D. Kramer is the author of Listening to Prozac and is working on a book about psychiatric diagnosis.

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The Real Depression Story