Anatomy of an Epidemic (23 page)

Four years later, the NIMH conducted a review of all anti-depressant studies, and it found that the “more stringently controlled the study, the lower the improvement rate reported for a drug.” In well-controlled studies, 61 percent of the drug-treated patients improved versus 46 percent of the placebo patients, a net benefit of only 15 percent. “The differences between the effectiveness of antidepressant drugs and placebo are not impressive,” it said.
¹⁹
The NIMH then conducted its own trial of imipramine, and it was only in
psychotically
depressed patients that this tricyclic showed any significant benefit over a placebo. Only 40 percent of the drug-treated patients completed the seven-week study, and the reason so many dropped out was that their condition “deteriorated.” For many depressed patients, the NIMH concluded in 1970, “drugs play a minor role in influencing the clinical course of their illness.”
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The minimal efficacy of imipramine and other antidepressants led some investigators to wonder whether the placebo response was the mechanism that was helping people feel better. What the drugs did, several speculated, was amplify the placebo response, and they did so because they produced physical side effects, which helped convince patients that they were getting a “magic pill” for depression. To test this hypothesis, investigators conducted at least seven studies in which they compared a tricyclic to an “active” placebo, rather than an inert one. (An active placebo is a chemical that produces an unpleasant side effect of some kind, like dry mouth.) In six of the seven, there was no difference in outcomes.
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That was the efficacy record racked up by tricyclics in the 1970s: slightly better than inactive placebo, but no better than an active placebo. The NIMH visited this question of imipramine’s efficacy one more time in the 1980s, comparing it to two forms of psychotherapy and placebo, and found that nothing had changed. At the end of sixteen weeks, “there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.” Only the severely depressed patients fared better on imipramine than on a placebo.
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Societal belief in the efficacy of antidepressants was reborn with the arrival of Prozac in 1988. Eli Lilly, it seemed, had come up
with a very good pill for the blues. This selective serotonin reuptake inhibitor (SSRI) was said to make people feel “better than well.” Unfortunately, once researchers began poking through the clinical trial data submitted to the FDA for Prozac and the other SSRIs that were subsequently brought to market, the “wonder drug” story fell apart.

The first blow to the SSRIs’ image came from Arif Khan at the Northwest Clinical Research Center in Washington. He reviewed the study data submitted to the FDA for seven SSRIs and concluded that symptoms were reduced 42 percent in patients treated with tricyclics, 41 percent in the SSRI group, and 31 percent in those given a placebo.
²³
The new drugs, it turned out, were no more effective than the old ones. Next, Erick Turner from Oregon Health and Science University, in a review of FDA data for twelve antidepressants approved between 1987 and 2004, determined that thirty-six of the seventy-four trials had failed to show any statistical benefit for the antidepressants. There were just as many trials that had produced negative or “questionable” results as positive ones.
²⁴
Finally, in 2008, Irving Kirsch, a psychologist at the University of Hull in the United Kingdom, found that in the trials of Prozac, Effexor, Serzone, and Paxil, symptoms in the medicated patients dropped 9.6 points on the Hamilton Rating Scale of Depression, versus 7.8 points for the placebo group. This was a difference of only 1.8 points, and the National Institute for Clinical Excellence in Britain had previously determined that a three-point drug-placebo difference was needed on the Hamilton scale to demonstrate a “clinically significant benefit.” It was only in a small subgroup of patients—those most severely depressed—that the drugs had been shown to be of real use. “Given these data, there seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit,” Kirsch and his collaborators concluded.
²⁵

All of this provoked some soul-searching by psychiatrists in their journals. Randomized clinical trials, admitted a 2009 editorial in the
British Journal of Psychiatry
, had generated “limited valid evidence” for use of the drugs.
²⁶
A group of European psychiatrists
affiliated with the World Health Organization conducted their own review of Paxil’s clinical data and concluded that “among adults with moderate to severe major depression,” this popular SSRI “was not superior to placebo in terms of overall treatment effectiveness and acceptability.”
²⁷
Belief in these medications’ effectiveness, wrote Greek psychiatrist John Ioannidis, who has an appointment at Tufts University School of Medicine in Massachusetts, was a “living myth.” A review of the SSRI clinical data had led to a depressing end for psychiatry, and, as Ioannidis quipped, he and his colleagues couldn’t even now turn to Prozac and the other SSRIs for relief from this dispiriting news because, alas, “they probably won’t work.”
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There is one other interesting addendum to this research history. In the late 1980s, many Germans who were depressed turned to
Hypericum perforatum
, the plant known as Saint-John’s-wort, for relief. German investigators began conducting double-blind trials of this herbal remedy, and in 1996, the
British Medical Journal
summarized the evidence: In thirteen placebo-controlled trials, 55 percent of the patients treated with Saint-John’s-wort significantly improved, compared with 22 percent of those given a placebo. The herbal remedy also bested antidepressants in head-to-head competition: In those trials, 66 percent given the herb improved compared to 55 percent of the drug-treated patients. In Germany, Saint-John’s-wort was effective. But would it work similar magic in Americans? In 2001, psychiatrists at eleven medical centers in the United States reported that it wasn’t effective at all. Only 15 percent of the depressed outpatients treated with the herb improved in their eight-week trial. Yet—and this was the curious part—only 5 percent of the placebo patients got better in this study, far below the usual placebo response. American psychiatrists, it seemed, were not eager to see anyone as having gotten better, lest the herb prove effective. But then the NIH funded a second trial of Saint-John’s-wort that had a design that complicated matters for any researcher who wanted to play favorites. It compared Saint-John’s-wort to both Zoloft and a placebo. Since the herb causes side effects, such as dry mouth, it would act at the very least as an active placebo. As such, this truly was a blinded trial, the psychiatrists unable to rely on side effects as a clue to which patients were getting what, and here were
the results: Twenty-four percent of the patients treated with Saint-John’s-wort had a “full response,” 25 percent of the Zoloft patients, and 32 percent of the placebo group. “This study fails to support the efficacy of
H perforatum
in moderately severe depression,” the investigators concluded, glossing over the fact that their drug had failed this test too.
²⁹

The antidepressants’ relative lack of short-term efficacy was not, by itself, a reason to think that the drugs were causing harm. After all, most of those treated with antidepressants were seeing their symptoms abate. Medicated patients in the short-term trials were getting better. The problem was that they were not improving significantly more than those treated with a placebo. However, during the 1960s, several European psychiatrists reported that the long-term course of depression in their drug-treated patients seemed to be worsening.

Exposure to antidepressants, wrote German physician H. P. Hoheisel in 1966, appeared to be “shortening the intervals” between depressive episodes in his patients. These drugs, wrote a Yugoslavian doctor four years later, were causing a “chronification” of the disease. The tricyclics, agreed Bulgarian psychiatrist Nikola Schipkowensky in 1970, were inducing a “change to a more chronic course.” The problem, it seemed, was that many people treated with antidepressants were only “partially cured.”
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Their symptoms didn’t entirely remit, and then, when they stopped taking the anti-depressant, their depression regularly got much worse again.

With this concern having surfaced in a few European journals, a Dutch physician, J. D. Van Scheyen, examined the case histories of ninety-four depressed patients. Some had taken an antidepressant and some had not, and when Van Scheyen looked at how the two groups had fared over a five-year period, the difference was startling: “It was evident, particularly in the female patients, that more systematic long-term antidepressant medication, with or without ECT [electroconvulsive therapy], 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…. Should [this increase] be regarded as an untoward long-term side effect of treatment with tricyclic antidepressants?”
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Over the next twenty years, investigators reported again and again that people treated with an antidepressant were very likely to relapse once they stopped taking the drug. In 1973, investigators in Britain wrote that 50 percent of drug-withdrawn patients relapsed within six months;
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a few years later, investigators at the University of Pennsylvania announced that 69 percent of patients withdrawn from antidepressants relapsed within this time period. There was, they confessed, “rapid clinical deterioration in most of the patients.”
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In 1984, Robert Prien at the NIMH reported that 71 percent of depressed patients relapsed within eighteen months of drug withdrawal.
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Finally, in 1990, the NIMH added to this gloomy picture when it reported the long-term results from its study that had compared imipramine to two forms of psychotherapy and to a placebo. At the end of eighteen months, the stay-well rate was best for the cognitive therapy group (30 percent) and lowest for the imipramine-exposed group (19 percent).
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Everywhere, the message was the same: Depressed people who were treated with an antidepressant and then stopped taking it regularly got sick again. In 1997, Ross Baldessarini from Harvard Medical School, in a meta-analysis of the literature, quantified the relapse risk: Fifty percent of drug-withdrawn patients relapsed within fourteen months.
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Baldessarini also found that the longer a person was on an antidepressant, the greater the relapse rate following drug withdrawal. It was as though a person treated with the drug gradually became less and less able, in a physiological sense, to do without it. Investigators in Britain came to the same sobering realization: “After stopping an antidepressant, symptoms tend to build up gradually and become chronic.”
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Although a handful of European physicians may have sounded the alarm about the changing course of depression in the late 1960s and early 1970s, it wasn’t until 1994 that an Italian psychiatrist, Giovanni Fava, from the University of Bologna, pointedly announced that it was time for psychiatry to confront this issue. Neuroleptics had been found to be quite problematic over the long term, the benzodiazepines had, too, and now it looked like the antidepressants were producing a similar long-term record. In a 1994 editorial in
Psychotherapy and Psychosomatics
, Fava wrote:

In this editorial and several more articles that followed, Fava offered a biological explanation for what was going on with the anti-depressants. Like antipsychotics and benzodiazepines, these drugs perturb neurotransmitter systems in the brain. This leads to compensatory “processes that oppose the initial acute effects of a drug…. When drug treatment ends, these processes may operate unopposed, resulting in appearance of withdrawal symptoms and increased vulnerability to relapse,” he wrote.
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Moreover, Fava noted, pointing to Baldessarini’s findings, it was evident that the longer one stayed on antidepressants, the worse the problem. “Whether one treats a depressed patient for three months, or three years, it does not matter when one stops the drugs. A statistical trend suggested that the longer the drug treatment, the higher the likelihood of relapse.”
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But, Fava also wondered, what was the outcome for people who stayed on antidepressants indefinitely? Weren’t they also relapsing
with great frequency? Perhaps the drugs cause “irreversible receptor modifications,” Fava said, and, as such, “sensitize” the brain to depression. This could explain the “bleak long term outcome of depression.” He summed up the problem in this way:

This possibility was now front and center in psychiatry. “His question and the several related matters … are not pleasant to contemplate and may seem paradoxical, but they now require open-minded and serious clinical and research consideration,” Baldessarini said.
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Three physicians from the University of Louisville School of Medicine echoed the sentiment. “Long-term antidepressant use may be depressogenic,” they wrote, in a 1998 letter to the
Journal of Clinical Psychiatry
. “It is possible that antidepressant agents modify the hardwiring of neuronal synapses [which] not only render anti-depressants ineffective but also induce a resident, refractory depressive state.”
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