Anatomy of an Epidemic (24 page)

Once again, psychiatry had reached a moment of crisis. The specter of supersensitivity psychosis had stirred up a hornets’ nest in the early 1980s, and now, in the mid-1990s, a concern very similar in kind had appeared. This time, the stakes were perhaps even higher. Fava was raising this issue even as U.S. sales of SSRIs were soaring. Prominent psychiatrists at the best medical schools in the United States had told newspaper and magazine reporters of their wonders. These drugs were now being prescribed to an ever-larger group of people, including to more than a million American children. Could
the field now confess that these medications might be making people chronically depressed? That they led to a “malignant” long-term course? That they caused biological changes in the brain that “sensitized” a person to depression? And if that were so, how could they possibly be prescribed to young children and teenagers? Why would doctors do that to children? This concern of Fava’s needed to be hushed up, and hushed up fast. Early in 1994, after Fava first broached the subject, Donald Klein from Columbia University told
Psychiatric News
that this subject was not going to be investigated.

“The industry is not interested [in this question], the NIMH is not interested, and the FDA is not interested,” he said. “Nobody is interested.”
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Indeed, by this time, leaders of American psychiatry were already coming up with an alternative explanation for the “bleak” long-term outcomes, one that spared their drugs any blame. The old epidemiological studies from the pre-antidepressant era, which had shown that people regularly recovered from a severe depressive episode and that a majority then stayed well, were “flawed.” A panel of experts convened by the NIMH put it this way: “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.”
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Depression was at last being understood, that was the story that psychiatry embraced, and textbooks were rewritten to tell of this advance in knowledge. Not long ago, noted the 1999 edition of the American Psychiatric Association’s
Textbook of Psychiatry
, it was believed that “most patients would eventually recover from a major depressive episode. However, more extensive studies have disproved this assumption.”
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It was now known, the APA said, that “depression is a highly recurrent and pernicious disorder.”

Depression, it seemed, had never been the relatively benign illness described by Silverman and others at the NIMH in the late 1960s and early 1970s. And with depression reconceived in this way, as a chronic illness, psychiatry now had a rationale for long-term use of antidepressants. The problem wasn’t that exposure to an antidepressant caused a biological change that made people more
vulnerable to depression; the problem was that once the drug was withdrawn, the disease returned. Moreover, psychiatry did have studies proving the merits of keeping people on antidepressants. After all, relapse rates were higher for patients withdrawn from the medications than for those maintained on the drugs. “Antidepressants reduce the risk of relapse in depressive disorder, and continued treatment with antidepressants would benefit many patients with recurrent depressive disorder,” explained a group of psychiatrists who reviewed this literature.
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During the 1990s, psychiatrists in the United States and elsewhere fleshed out the spectrum of outcomes achieved with this new paradigm of care, which emphasized “maintaining” people on the medications. One-third of all unipolar patients, researchers concluded, are “non-responders” to antidepressants. Their symptoms do not abate over the short term, and this group is said to have a poor long-term outcome. Another third of unipolar patients are “partial responders” to antidepressants, and in short-term trials, they show up as being helped by the drugs. The problem, NIMH investigators discovered, in a long-term study called the Collaborative Program on the Psychobiology of Depression, was that these drug-maintained patients fared poorly over the long term. “Resolution of major depressive episode with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course,” explained Lewis Judd, a former director of the NIMH, in a 2000 report.
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The final third of patients see their symptoms remit over the short term, but only about half of this group, when maintained on an antidepressant, stay well for long periods of time.
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In short, two-thirds of patients initially treated with an antidepressant can expect to have recurrent bouts of depression, and only a small percentage of people can be expected to recover and stay well. “Only 15% of people with unipolar depression experience a single bout of the illness,” the APA’s 1999 textbook noted, and for the remaining 85 percent, with each new episode, remissions become “less complete and new recurrences develop with less provocation.”
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This outcomes data definitely told of a pernicious disorder, but then John Rush, a prominent psychiatrist at Texas
Southwestern Medical Center in Dallas, suggested that “real-world outcomes” were even worse. Those outcome statistics arose from clinical trials that had cherry-picked patients most likely to respond
well
to an antidepressant, he said. “Longer-term clinical outcomes of representative outpatients with nonpsychotic major depressive disorder treated in daily practice in either the private or public sectors are yet to be well defined.”
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In 2004, Rush and his colleagues filled in this gap in the medical literature. They treated 118 “real world” patients with antidepressants and provided them with a wealth of emotional and clinical support “specifically designed to maximize clinical outcomes.” This was the best care that modern psychiatry could provide, and here were their real-world results: Only 26 percent of the patients even responded to the antidepressant (meaning that their symptoms decreased at least 50 percent on a rating scale), and only about half of those who responded stayed better for any length of time. Most startling of all, only 6 percent of the patients saw their depression fully remit and stay away during the yearlong trial. These “findings reveal remarkably low response and remission rates,” Rush said.
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This dismal picture of real-world outcomes was soon confirmed by a large NIMH study known as the STAR*D trial, which Rush helped direct. Most of the 4,041 real-world outpatients enrolled in the trial were only moderately ill, and yet fewer than 20 percent remitted and stayed well for a year. “Most individuals with major depressive disorders have a chronic course, often with considerable symptomatology and disability even between episodes,” the investigators concluded.
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In the short span of forty years, depression had been utterly transformed. Prior to the arrival of the drugs, it had been a fairly rare disorder, and outcomes generally were good. Patients and their families could be reassured that it was unlikely that the emotional problem would turn chronic. It just took time—six to twelve months or so—for the patient to recover. Today, the NIMH informs the public that depressive disorders afflict one in ten Americans every year, that depression is “appearing earlier in life” than it did in the past, and that the long-term outlook for those it strikes is glum. “An episode of major depression may occur only once in a
person’s lifetime, but more often, it recurs throughout a person’s life,” the NIMH warns.
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We’ve now arrived at an intellectual place similar to what we experienced with the antipsychotics: Can it really be that antidepressants, which are so popular with the public, worsen long-term outcomes? All of the data we’ve reviewed so far indicates that the drugs do just that, but there is one piece of evidence that we are still missing: What does unmedicated depression look like today? Does it run a better long-term course? Unfortunately, as researchers from the University of Ottawa discovered in 2008, there aren’t good-quality randomized trials comparing long-term outcomes in antidepressant-treated and never-medicated patients. As such, they concluded, randomized trials “provide no guidance for longer treatment.”
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However, we can search for “naturalistic” studies that might help us answer this question.
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Researchers in the UK, the Netherlands, and Canada investigated this question by looking back at case histories of depressed patients whose medication use had been tracked. In a 1997 study of outcomes at a large inner-city facility, British scientists reported that ninety-five never-medicated patients saw their symptoms decrease by 62 percent in six months, whereas the fifty-three drug-treated patients experienced only a 33 percent reduction in symptoms. The medicated patients, they concluded, “continued to have depressive symptoms throughout the six months.”
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Dutch investigators, in a retrospective study of the ten-year outcomes of 222 people who had suffered a first episode of depression, found that 76 percent of those not treated with an antidepressant recovered and never relapsed, compared to 50 percent of those prescribed an antidepressant.
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Finally, Scott Patten, from the University of Calgary, plumbed a large Canadian health database to assess the five-year outcomes of 9,508 depressed patients, and he determined that the medicated patients were depressed on average nineteen weeks each year, versus eleven weeks for those not taking the drugs. These findings, Patten wrote, were consistent with Giovanni Fava’s hypothesis that “anti-depressant treatment may lead to a deterioration in the long-term course of mood disorders.”
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A study conducted by the World Health Organization in fifteen cities around the world to assess the value of screening for depression led to similar results. The researchers looked for depression in patients who showed up at health clinics for other complaints, and then, in a fly-on-the-wall manner, followed those they had identified as depressed for the next twelve months. They reasoned that the general practitioners in the clinics would detect depression in some of the patients but not all, and hypothesized that outcomes would fall into four groups: those diagnosed and treated with antidepressants would fare the best, those diagnosed and treated with benzodiazepines would fare the second best, those diagnosed and treated without psychotropics the third best, and those undetected and untreated the worst. Alas, the results were the opposite. Altogether, the WHO investigators identified 740 people as depressed, and it was the 484 who weren’t exposed to psychotropic medications (whether diagnosed or not) that had the best outcomes. They enjoyed much better “general health” at the end of one year, their depressive symptoms were much milder, and a lower percentage were judged to still be “mentally ill.” The group that suffered most from “continued depression” were the patients treated with an antidepressant. The “study does not support the view that failure to recognize depression has serious adverse consequences,” the investigators wrote.
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Next, researchers in Canada and the United States studied whether antidepressant use affected disability rates. In Canada, Carolyn Dewa and her colleagues at the Centre for Addiction and Mental Health in Ontario identified 1,281 people who went on short-term disability between 1996 and 1998 because they missed ten consecutive days of work due to depression. The 564 people who subsequently didn’t fill a prescription for an antidepressant returned to work, on average, in 77 days, while the medicated group took 105 days to get back on the job. More important, only 9 percent of the unmedicated group went on to long-term disability, compared to 19 percent of those who took an antidepressant.
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“Does the lack of antidepressant use reflect a resistance to adopting a sick role and consequently a more rapid return to work?” Dewa wondered.
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In a similar vein, University of Iowa psychiatrist William Coryell and his NIMH-funded colleagues studied the six-year “naturalistic” outcomes of 547 people who suffered a bout of depression, and they found those who were treated for the illness were three times more likely than the untreated group to suffer a “cessation” of their “principal social role” and nearly seven times more likely to become “incapacitated.” Moreover, while many of the treated patients saw their economic status markedly decline during the six years, only 17 percent of the unmedicated group saw their incomes drop, and 59 percent saw their incomes
rise
. “The untreated individuals described here had milder and shorter-lived illnesses [than those who were treated], and, despite the absence of treatment, did not show significant changes in socioeconomic status in the long term,” Coryell wrote.
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One-Year Outcomes in WHO Screening Study for Depression