Anatomy of an Epidemic (14 page)

As many speakers noted, this tool wasn’t particularly well suited for assessing outcomes of a psychiatric drug. How could a study of a neuroleptic possibly be “double-blind”? The psychiatrist would quickly see who was on the drug and who was not, and any patient given Thorazine would know he was on a medication as well. Then there was the problem of diagnosis: How would a researcher know if the patients randomized into a trial really had “schizophrenia”? The diagnostic boundaries of mental disorders were forever changing. Equally problematic, what defined a “good outcome”? Psychiatrists and hospital staff might want to see drug-induced behavioral changes that made the patient “more socially acceptable” but weren’t to the “ultimate benefit of the patient,” said one conference speaker.
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And how could outcomes be measured? In a study of a drug for a known disease, mortality rates or laboratory results could serve as objective measures of whether a treatment worked. For instance, to test whether a drug for tuberculosis was effective, an X-ray of the lung could show whether the bacillus that caused the disease was gone. What would be the measurable endpoint in a
trial of a drug for schizophrenia? The problem, said NIMH physician Edward Evarts at the conference, was that “the goals of therapy in schizophrenia, short of getting the patient ‘well,’ have not been clearly defined.”
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All of these questions bedeviled psychiatry, and yet the NIMH, in the wake of that conference, made plans to mount a trial of the neuroleptics. The push of history was simply too great. This was the scientific method now used in internal medicine to assess the merits of a therapy, and Congress had created the NIMH with the thought that it would transform psychiatry into a more modern, scientific discipline. Psychiatry’s adoption of this tool would prove that it was moving toward that goal. The NIMH established a Psychopharmacology Service Center to head up this effort, and Jonathan Cole, a psychiatrist from the National Research Council, was named its director.

Over the next couple of years, Cole and the rest of psychiatry settled on a trial design for testing psychotropic drugs. Psychiatrists and nurses would use “rating scales” to measure numerically the characteristic symptoms of the disease that was to be studied. Did a drug for schizophrenia reduce the patient’s “anxiety”? His or her “grandiosity”? “Hostility”? “Suspiciousness”? “Unusual thought content”? “Uncooperativeness”? The severity of all of those symptoms would be measured on a numerical scale and a total “symptom” score tabulated, and a drug would be deemed effective if it reduced the total score significantly more than a placebo did within a six-week period.

At least in theory, psychiatry now had a way to conduct trials of psychiatric drugs that would produce an “objective” result. Yet the adoption of this assessment put psychiatry on a very particular path: The field would now see short-term reduction of symptoms as evidence of a drug’s efficacy. Much as a physician in internal medicine would prescribe an antibiotic for a bacterial infection, a psychiatrist would prescribe a pill that knocked down a “target symptom” of a “discrete disease.” The six-week “clinical trial” would prove that this was the right thing to do. However, this tool wouldn’t provide any insight into how patients were faring over the long term.
Were they able to work? Were they enjoying life? Did they have friends? Were they getting married? None of those questions would be answered.

This was the moment that magic-bullet medicine shaped psychiatry’s future. The use of the clinical trial would cause psychiatrists to see their therapies through a very particular prism, and even at the 1956 conference, New York State Psychiatric Institute researcher Joseph Zubin warned that when it came to evaluating a therapy for a psychiatric disorder, a six-week study induced a kind of scientific myopia. “It would be foolhardy to claim a definite advantage for a specified therapy without a two- to five-year follow-up,” he said. “A two-year follow-up would seem to be the very minimum for the long-term effects.”
¹³

The Psychopharmacology Service Center launched its nine-hospital trial of neuroleptics in 1961, and this is the study that marks the beginning of the scientific record that serves today as the “evidence base” for these drugs. In the six-week trial, 270 patients were given Thorazine or another neuroleptic (which were also known as “phenothiazines,”) while the remaining 74 were put on a placebo. The neuroleptics did help reduce some target symptoms—unrealistic thinking, anxiety, suspiciousness, auditory hallucinations, etc.—better than the placebo, and thus, according to the rating’s scales cumulative score, they were effective. Furthermore, the psychiatrists in the study judged 75 percent of the drug-treated patients to be “much improved” or “very much improved,” versus 23 percent of the placebo patients.

After that, hundreds of smaller trials produced similar results, and thus the evidence that these drugs reduce symptoms over the short term better than placebo is fairly robust.
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In 1977, Ross Baldessarini at Harvard Medical School reviewed 149 such trials and found that the antipsychotic drug proved superior to a placebo in 83 percent of them.
¹⁴
The “Brief Psychiatric Rating Scale” (BPRS) was regularly employed in such trials, and the American Psychiatric Association eventually decided that a 20 percent reduction in total BPRS score represented a clinically significant response to a drug.
¹⁵
Based on this measurement, an estimated 70 percent of all schizophrenia patients suffering from an acute episode of psychosis “respond,” over a six-week period, to an antipsychotic medication.

Once the NIMH investigators determined that the antipsychotics were efficacious over the short term, they naturally wanted to know how long schizophrenia patients should stay on the medication. To investigate this question, they ran studies that, for the most part, had this design: Patients who were good responders to the medication were either maintained on the drug or abruptly withdrawn from it. In 1995, Patricia Gilbert at the University of California at San Diego reviewed sixty-six relapse studies, involving 4,365 patients, and she found that 53 percent of the drug-withdrawn patients relapsed within ten months versus 16 percent of those maintained on the medications. “The efficacy of these medications in reducing the risk of psychotic relapse has been well documented,” she concluded.
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This is the scientific evidence that supports the use of antipsychotic medications for schizophrenia, both in the hospital and long-term. As John Geddes, a prominent British researcher, wrote in a 2002 article in the
New England Journal of Medicine
, “Antipsychotic drugs are effective in treating acute psychotic symptoms and preventing relapse.”
¹⁷
Still, as many investigators have noted, there is a hole in this evidence base, and it’s the very hole that Zubin predicted would arise. “Little can be said about the efficacy and effectiveness of conventional antipsychotics on nonclinical outcomes,” confessed Lisa Dixon and other psychiatrists at the University of Maryland School of Medicine in 1995. “Well-designed long-term studies are virtually nonexistent, so the longitudinal impact of treatment with conventional antipsychotics is unclear.”
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This doubt prompted an extraordinary 2002 editorial in
European Psychiatry
, penned by Emmanuel Stip, a professor of psychiatry at the Université de Montréal. “After fifty years of neuroleptics, are we able to answer the following simple question: Are neuroleptics effective in treating schizophrenia?” There was, he said, “no compelling evidence on the matter, when ‘long-term’ is considered.”
¹⁹

Although Dixon’s and Stip’s comments suggest that there is no long-term data to be reviewed, it is in fact possible to piece together a story of how antipsychotics alter the course of schizophrenia, and this story begins, quite appropriately, with the NIMH’s follow-up study of the 344 patients in its initial nine-hospital trial. In some ways, the patients—regardless of what treatment they had received in the hospital—were not faring so badly. At the end of one year,
254 were living in the community, and 58 percent of those who—according to their age and gender—could be expected to work were in fact employed. Two-thirds of the “housewives” were functioning OK in that domestic role. Although the researchers didn’t report on the medication use of patients during the one-year follow-up, they were startled to discover that “patients who received placebo treatment [in the six-week trial] were
less
likely to be rehospitalized than those who received any of the three active phenothiazines.”
²⁰

Here, at this very first moment in the scientific literature, there is the hint of a paradox: While the drugs were effective over the short term, perhaps they made people more vulnerable to psychosis over the long term, and thus the higher rehospitalization rates for drug-treated patients at the end of one year. Soon, NIMH investigators were back with another surprising result. In two drug withdrawal trials, both of which included patients who weren’t on any drug at the start of the study, relapse rates
rose
in correlation with drug dosage. Only 7 percent of those who had been on a placebo at the start of the study replapsed, compared to 65 percent of those taking more than five hundred milligrams of chlorpromazine before the drug was withdrawn. “Relapse was found to be significantly related to the dose of the tranquilizing medication the patient was receiving before he was put on placebo—the higher the dose, the greater the probability of relapse,” the researchers wrote.
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Something was amiss, and clinical observations deepened the suspicion. Schizophrenia patients discharged on medications were returning to psychiatric emergency rooms in such droves that hospital staff dubbed it the “revolving door syndrome.” Even when patients reliably took their medications, relapse was common, and researchers observed that “relapse is greater in severity during drug administration than when no drugs are given.”
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At the same time, if patients relapsed after quitting the medications, Cole noted, their psychotic symptoms tended to “persist and intensify,” and, at least for a time, they suffered from a host of new symptoms as well: nausea, vomiting, diarrhea, agitation, insomnia, headaches, and weird motor tics.
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Initial exposure to a neuroleptic seemed to be setting patients up for a future of severe psychotic episodes, and that was true regardless of whether they stayed on the medications.

These poor results prompted two psychiatrists at Boston Psychopathic Hospital, J. Sanbourne Bockoven and Harry Solomon, to revisit the past. They had been at the hospital for decades, and in the period after World War II ended, when they treated psychotic patients with a progressive form of psychological care, they had seen the majority regularly improve. That led them to believe that “the majority of mental illnesses, especially the most severe, are largely self-limiting in nature if the patient is not subjected to a demeaning experience or loss of rights and liberties.” The antipsychotics, they reasoned, should speed up this natural healing process. But were the drugs improving long-term outcomes? In a retrospective study, they found that 45 percent of the patients treated in 1947 at their hospital hadn’t relapsed in the next five years and that 76 percent were successfully living in the community at the end of that follow-up period. In contrast, only 31 percent of the patients treated at the hospital in 1967 with neuroleptics remained relapse-free for five years, and as a group they were much more “socially dependent”—on welfare and needing other forms of support. “Rather unexpectedly, these data suggest that psychotropic drugs may not be indispensable,” Bockoven and Solomon wrote. “Their extended use in aftercare may prolong the social dependency of many discharged patients.”
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With debate over the merits of neuroleptics rising, the NIMH funded three studies during the 1970s that reexamined whether schizophrenia patients—and in particular those suffering a first episode of schizophrenia—could be successfully treated without medications. In the first study, which was conducted by William Carpenter and Thomas McGlashan at the NIMH’s clinical research facility in Bethesda, Maryland, those treated without drugs were discharged
sooner
than the drug-treated patients, and only 35 percent of the nonmedicated group relapsed within a year after discharge, compared to 45 percent of the medicated group. The off-drug patients also suffered less from depression, blunted emotions, and retarded movements. Indeed, they told Carpenter and McGlashan that they had found it “gratifying and informative” to have gone through their psychotic episodes without having their feelings numbed by the drugs. Medicated patients didn’t have that
same learning experience, and as a result, Carpenter and McGlashan concluded, over the long term they “are less able to cope with subsequent life stresses.”
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A year later, Maurice Rappaport at the University of California in San Francisco announced results that told the same story, only more strongly so. He had randomized eighty young newly diagnosed male schizophrenics admitted to Agnews State Hospital into drug and non-drug groups, and although symptoms abated more quickly in those treated with antipsychotics, both groups, on average, stayed only six weeks in the hospital. Rappaport followed the patients for three years, and it was those who weren’t treated with antipsychotics in the hospital and who stayed off the drugs after discharge that had—by far—the best outcomes. Only two of the twenty-four patients in this never-exposed-to-antipsychotics group relapsed during the three-year follow-up. Meanwhile, the patients that arguably fared the worst were those on drugs throughout the study. The very standard of care that, according to psychiatry’s “evidence base,” was supposed to produce the best outcomes had instead produced the worst.