In his March 1 article in the New Yorker, Louis Menand wrote that the NIMH's STAR*D trial showed that antidepressants produced a 67% recovery rate, which was "far better than the rate for placebo." As I noted in a previous post, the notion that antidepressants produced a "67% recovery rate" was highly exaggerated. But my focus in this post is on the second part of that statement: What do we really know about the long-term recovery rate for unmedicated depression?

Now answering this question thoroughly involves telling a complicated history of science that has unfolded over the past forty years. It's a history that I relate in Anatomy of an Epidemic, a book that will be published in April. But here's a thumbnail version of that history.

In 1921, the great German psychiatrist Emil Kraepelin reported that patients hospitalized with manic-depressive psychosis had fairly good long-term outcomes. "Usually all morbid manifestations completely disappear; but where that is exceptionally not the case, only a rather slight, peculiar psychic weakness develops." In a long-term follow-up study, sixty percent of Kraepelin's 450 "depressed-only" patients experienced but a single episode of depression, and only 13 percent had three or more episodes.

Other investigators in the first half of the 20th century, both in Europe and the United States, reported similar outcomes. In 1972, Samuel Guze at Washington University Medical School reviewed the outcomes literature for depression, and he determined that in follow-up studies that lasted ten years, 50% of people hospitalized for depression had no recurrence of their illness. Only a small minority -- one-in-ten -- became chronically ill.

With this evidence in mind, the NIMH regularly advised the public during the 1960s and early 1970s that the long-term course of depression was fairly benign. "Depression is, on the whole, one of the psychiatric conditions with the best prognosis for eventual recovery with or without treatment. Most depressions are self-limited," explained the NIMH's Jonathan Cole in 1964. In 1969, Washington University psychiatrist George Winokur wrote that "assurances can be given to a patient and to his family that subsequent episodes of illness after a first mania or even a first depression will not tend toward a more chronic course." Five years later, the NIMH's Dean Schuyler concluded that most depressive episodes "will run their course and terminate with virtually complete recovery without specific intervention."

Given this understanding of the natural course of depression, Schuyler and others reasoned that antidepressants, while they might not significantly boost the recovery rate (which was so naturally high,) they could help quicken the recovery process. Early trials suggested that might be the case, but then a handful of psychiatrists noticed something odd happening to their drug-treated patients. While they might be recovering more quickly, they were now relapsing more frequently. Were the drugs, one psychiatrist wondered, inducing a "change to a more chronic course?"

In 1973, Dutch psychiatrist J.D. Van Scheyen studied this possibility, and concluded that antidepressant medication "exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrent rate and a decrease in cycle duration."

During the next decade, outcome studies regularly found that drug-treated patients were indeed relapsing frequently. This change in the long-term course of depression was so noticeable that, in 1985, a panel of experts convened by the NIMH felt compelled to investigate what was going on. Here's what they wrote:

"Improved approaches to the description and classification of [mood] disorders and new epidemiologic studies [have] demonstrated the recurrent and chronic nature of these illnesses, and the extent to which they represent a continual source of distress and dysfunction for affected individuals."

This explanation -- that the old studies must have been flawed -- became the accepted wisdom in psychiatry. Not too long ago, the 1999 edition of the American Psychiatric Association's Textbook of Psychiatry explained, it was believed that "most patients would eventually recover from a major depression episode. However, more extensive studies have disproved this assumption." Indeed, the NIMH now informs the public that "most individuals with major depressive disorders have a chronic course, often with considerable symptomatology and disability even between episodes."

Now perhaps that explanation is true. Perhaps the old epidemiological studies were flawed. But another possibility is that antidepressants -- for some paradoxical reason -- have turned an episodic illness into a chronic one.

So now we need to ask a second question: What does unmedicated depression look like today? Does it run a better long-term course? There are a number of studies conducted during the past 15 years that shed light on that question, and thus too many to be reviewed in the post. But here are the findings from one such study, led by Michael Posternak at Brown University.

To assess the untreated course of major depression, Posternak identified 84 patients enrolled in the NIMH's Psychobiology of Depression program who, after recovering from an initial bout of depression, subsequently relapsed but did not then go back on medication. He then tracked their "untreated" recovery from this second episode of depression. In 2006, he reported that twenty-three percent recovered in one month, 67 percent in six months, and 85 percent within a year.

Kraepelin, Posternak observed, had said that untreated depressive episodes usually cleared up within six to eight months. This study provided "perhaps the most methodologically rigorous confirmation of this estimate."

As I noted above, the information presented here is just a thumbnail sketch of a larger history of science that can be dug out from the outcomes literature. But even this thumbnail sketch suggests that our society, as it debates the merits of antidepressants, needs to address this fundamental question: Why does depression run a much more chronic course than it used to?

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