Anatomy of an Epidemic (44 page)

Gushed neuropsychiatrist Richard Restak: “For the first time in human history, we will be in a position to design our own brains.”
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As the Prozac story unfolded in the media, surely the ghost of John Brinkley was smiling somewhere. He had transfixed listeners to his radio show with tales of the wonders of transplanted goat gonads, and now here was a storytelling process that had transformed a drug “totally unsuited” for treating depression into a miracle compound, with psychiatrists publicly wringing their hands over their new godlike powers to shape the human mind. Should they worry about making people “better than well”? Would our society lose something precious if everybody were happy all the time? The widespread medicating of the American mind was now under way, and—as a very quick review will reveal—it was this same storytelling process that supported the launch of Xanax as a drug for panic disorder and the atypical antipsychotics for schizophrenia. Once those “second-generation” drugs became blockbusters, the drug companies and academic psychiatrists began touting psychiatric drugs of all kinds for use in children, this storytelling sweeping millions of American youth into the “mental illness” bin.

Xanax (alprazolam) was approved by the FDA as an anti-anxiety agent in 1981, and then Upjohn set out to get it approved for panic disorder, which had been newly identified as a discrete condition for the first time in DSM-III (1980). As a first step, it hired former NIMH director Gerald Klerman to co-chair its “steering committee” for the testing process, and it paid Daniel Freedman, editor of the
Archives of General Psychiatry
, to be an assistant to its “division of medical affairs.”
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This was just part of the company’s efforts to co-opt academic psychiatry: “The most senior psychiatrists in the world were flooded with offers of consultancies” from
Upjohn, said Isaac Marks, an expert in anxiety disorders at the Institute of Psychiatry in London.
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Klerman and Upjohn designed Upjohn’s Cross National Collaborative Panic Study in a manner that could be expected to produce a poor placebo response. Patients who had been on benzodiazepines were allowed into the study, which meant that many in the placebo group would in fact be going through the horrors of benzodiazepine withdrawal, and thus could be expected to be extremely anxious during the first weeks of the trial. Nearly one-fourth of the placebo patients had traces of benzodiazepines in their blood when the treatment period began.
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Benzodiazepines are known to work quickly, and that proved true in this study. At the end of four weeks, 82 percent of the alprazolam patients were “moderately improved” or “better,” versus 43 percent of the placebo group. However, during the next four weeks, the placebo patients continued to improve, while the alprazolam patients did not, and by the end of the eighth week, there “was no significant difference between the groups” on most of the rating scales, at least among the patients who remained in the study. The alprazolam group also experienced a variety of troubling side effects: sedation, fatigue, slurred speech, amnesia, and poor coordination. One of every twenty-six alprazolam patients suffered a “serious” reaction to the drug, such as mania or aggressive behavior.
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At the end of eight weeks, the patients were tapered from their medication for four weeks and then followed while medication-free for another two weeks. The results were predictable. Thirty-nine percent of those withdrawn from alprazolam “deteriorated significantly,” their panic and anxiety skyrocketing to such an extent they had to start taking the medication again. Thirty-five percent of the alprazolam patients suffered “rebound” panic and anxiety symptoms more severe than when the study began, and an equal percentage suffered a host of debilitating new symptoms, including confusion, heightened sensory perceptions, depression, a feeling that insects were crawling over them, muscle cramps, blurred vision, diarrhea, decreased appetite, and weight loss.
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In sum, at the end of fourteen weeks, the drug-exposed patients were worse off than the placebo group: They were more phobic, more anxious, more panic stricken, and doing worse on a “global scale” that assessed overall well-being. Forty-four percent had been unable to get off the drug, on their way to a lifetime of addiction. In every way, the results painted a powerful portrait of the benzo trap: This was a drug that worked for a short time, then its efficacy over a placebo petered out, and yet when patients tried to go off the drug, they became quite sick and many couldn’t kick the habit. The first few weeks of relief came at a very high long-term cost, with those stuck on the drug—as previous benzodiazepine studies had shown—likely to end up physically, emotionally, and cognitively impaired.

The Xanax Study

In Upjohn’s study of Xanax, patients were treated with the drug or placebo for eight weeks. Then this treatment was slowly withdrawn (weeks 9 through 12), and during the last two weeks patients didn’t receive any treatment. The Xanax patients fared better during the first four weeks, which is the result that the Upjohn investigators focused on in their journal articles. However, once the Xanax patients began withdrawing from the the drug, they suffered many more panic attacks than the placebo patients, and at the end of the study were much more symptomatic. Source: Ballenger, C “Alprazolam in panic disorder and
agoraphobia
.”
Archives of General Psychiatry
45 (1988): 413–22. Pecknold, C “Alprazolam in panic disorder and agoraphobia.”
Archives of General Psychiatry
45 (1988): 429–36.

The Upjohn investigators published three articles in the
Archives of General Psychiatry
in May 1988, and anyone who carefully reviewed the data could see the harm caused by alprazolam. But in order for Xanax to be successfully marketed, Upjohn needed its investigators to draw a different sort of conclusion, and so they did,
particularly in the abstracts of the three articles. First, they focused their attention on the four-week results (rather than the eight-week outcomes at the end of the treatment period), announcing that “alprazolam was found to be effective and well-tolerated.”
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Next, they noted that 84 percent of the alprazolam patients had finished the eight-week study, which was evidence that “patient acceptance of alprazolam was high.” Although their alprazolam patients regularly exhibited such problems as “slurred speech, amnesia” and other signs of “impaired mentation,” they still concluded that the drug had “few side effects and is well tolerated.”
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Finally, while they acknowledged that some alprazolam patients fared poorly when the drug was withdrawn, they reasoned that it had been used for
too short
a period and the withdrawal done too abruptly. “We recommend that patients with panic disorder be treated for a longer period, at least six months,” they said.
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In London, Isaac Marks and several of his colleagues at the Institute of Psychiatry subsequently pointed out how transparently ridiculous this all was. In a letter to the
Archives of General Psychiatry
, they observed that since the alprazolam patients “were in a worse state than patients receiving placebo” at the end of the study, the finding by the Upjohn investigators that the drug was effective and well tolerated could only be seen as “biased and arguable.”
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The entire affair, Marks subsequently wrote, “is a classic demonstration of the hazards of research funded by industry.”
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Yet the fact that the alprazolam patients came to such a bad end, with many on a path to a lifelong addiction, did not deter Upjohn, Klerman, the APA, and the NIMH from touting Xanax’s benefits to the American public. The same marketing machinery that had made Prozac a bestseller was rolled out again. Upjohn sponsored a symposium at the APA’s 1988 meeting where the “expert panel” highlighted the four-week results. Robert Pasnau, who had been head of the APA in 1987, sent a glossy booklet on the
Consequences of Anxiety
to APA members, an “educational” effort paid for by Upjohn. Both Shervert Frazier and Gerald Klerman penned a “Dear Doctor” letter that Upjohn included in the promotional literature it sent to doctors about Xanax as a treatment for panic disorder. Upjohn also gave $1.5 million to the APA so that it could mount a
DART-like campaign to “educate” psychiatrists, health-care workers, and the public about panic disorder, which was said to be “under-recognized and undertreated.”
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Finally, the NIMH chipped in too, identifying panic disorder as a priority concern and sponsoring a conference in 1991 on it, with its panel of experts designating “high potency benzodiazepines”—this would be Xanax—as one of the two “treatments of choice.”
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The FDA approved Xanax as a treatment for panic disorder in November 1990, and many newspapers and magazines ran the usual features.
IN A PANIC
?
HELP IS ON THE WAY
, a
St. Louis Post-Dispatch
headline announced. Treatment, the paper said, helped 70 to 90 percent of those with the debilitating condition, which afflicted “4 million adults in this country.”
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The Associated Press explained that “a biochemical malfunctioning in the brain is believed to be one of the causes of panic attacks. Xanax can block the attacks by interacting with several different systems in the brain.”
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In the
Chicago Sun-Times
, Dr. John Zajecka at Rush Medical College in Chicago announced that “Xanax is the fastest acting and least toxic” of medications for the disorder.
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Once again, a very effective, safe drug had arrived on the market, and in 1992, Xanax became the fifth most frequently prescribed medication in the United States.
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Even as Xanax was on the way to market as a treatment for panic disorder, Janssen was conducting tests of risperidone, a new drug for schizophrenia. By this time, the methods that pharmaceutical firms were employing to create new “blockbuster” psychotropics were becoming quite well practiced, with nearly everyone employing the Prozac model of drug development, and so Janssen, like Eli Lilly and Upjohn, designed trials that were biased in favor of its drug. In particular, Janssen compared multiple doses of risperidone to a high dose of haloperidol (Haldol), as it could then be relatively certain that one of the risperidone doses would have a good safety profile in comparison to the old “standard” neuroleptic. As FDA reviewers noted, these studies were “incapable” of providing any
meaningful comparison of the two drugs.
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In the FDA’s letter of approval to Janssen, Robert Temple, director of the Office of Drug Evaluation, made this clear:

However, while the FDA could prohibit Janssen from placing advertisements touting its drug as superior to haloperidol, it did not have authority over what the academic psychiatrists hired by Janssen could say. This was the commercial beauty of the “partnership” that had emerged between psychiatry and the pharmaceutical industry during the 1980s—the academic doctors could make claims, both in their medical journals and to the public, that the FDA considered false in kind. In this case, they published more than twenty articles in psychiatric journals touting risperidone as equal or superior to haloperidol in reducing positive symptoms of schizophrenia (psychosis) and superior to haloperidol in improving negative symptoms (lack of emotion). The academic doctors reported that risperidone reduced hospital stays, improved the patient’s ability to function socially, and reduced hostility. “Risperidone has important advantages compared with haloperidol,” they wrote in the
Journal of Clinical Psychiatry
. “When administered in an effective dose range, risperidone produced greater improvements on all five dimensions of schizophrenia.”
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Once again, this was a scientific story of a new and improved treatment, and in their interviews with the media, Janssen’s investigators told of a wonder drug. This new agent, the
Washington Post
reported, “represents a glimmer of hope for a disease that until recently had been considered hopeless.” Risperidone, it explained, did not “cause sedation, blurred vision, impaired memory or muscle stiffness, side effects commonly associated with an earlier generation of antipsychotic drugs.”
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The
New York Times
, quoting
Richard Meibach, Janssen’s clinical research director, reported that “no major side effects” had appeared in the two-thousand-plus patients treated with risperidone in the clinical trials.
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The drug was thought to “relieve schizophrenia symptoms by blocking excessive flows of serotonin or dopamine, or both,” the paper said.
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