Anatomy of an Epidemic (15 page)

“Our findings suggest that antipsychotic medication is not the treatment of choice, at least for certain patients, if one is interested in long-term clinical improvement,” Rappaport wrote. “Many unmedicated-while-in-hospital patients showed greater long-term improvement, less pathology at follow-up, fewer rehospitalizations, and better overall functioning in the community than patients who were given chlorpromazine while in the hospital.”
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Rappaport’s Study: Three-Year Schizophrenia Outcomes

In this study, patients were grouped according to both their in-hospital care (placebo or drug) and whether they used antipsychotics after they were discharged. Thus, 24 of the 41 patients treated with placebo in the hospital remained off the drugs during the follow-up period. This never-exposed group had the best outcomes by far. Rappaport, M. “Are there schizophrenics for whom drugs may be unnecessary or contraindicated.”
International Pharmacopsychiatry
13 (1978): 100–11.

The third study was led by Loren Mosher, head of schizophrenia studies at the NIMH. Although he may have been the nation’s top schizophrenia doctor at the time, his vision of the illness was at odds with many of his peers, who had come to think that schizophrenics suffered from a “broken brain.” He believed that psychosis could arise in response to emotional and inner trauma and, in its own way, could be a coping mechanism. As such, he believed there was the possibility that people could grapple with their hallucinations and delusions, struggle through a schizophrenic break, and regain their sanity. And if that was so, he reasoned that if he provided newly psychotic patients with a safe house, one staffed by people who had an evident empathy for others and who wouldn’t be frightened by strange behavior, many would get well, even though they weren’t treated with antipsychotics. “I thought that sincere human involvement and understanding were critical to healing interactions,” he said. “The idea was to treat people as people, as human beings, with dignity and respect.”

The twelve-room Victorian house he opened in Santa Clara, California, in 1971 could shelter six patients at a time. He called it Soteria House, and eventually he started a second home as well, Emanon. All told, the Soteria Project ran for twelve years, with eighty-two patients treated at the two homes. As early as 1974, Mosher began reporting that his Soteria patients were faring better than a matched cohort of patients being treated conventionally with drugs in a hospital, and in 1979, he announced his two-year results. At the end of six weeks, psychotic symptoms had abated as much in his Soteria patients as in the hospitalized patients, and at the end of two years, the Soteria patients had “lower psychopathology scores, fewer [hospital] readmissions, and better global adjustment.”
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Later, he and John Bola, an assistant professor at the University of Southern California, reported on their medication use: Forty-two percent of the Soteria patients had never been exposed to drugs, 39 percent had used them on a temporary basis, and only 19 percent had needed them throughout the two-year follow-up.

“Contrary to popular views, minimal use of antipsychotic medications combined with specially designed psychosocial intervention for patients newly identified with schizophrenia spectrum disorder is not harmful but appears to be advantageous,” Mosher and Bola wrote. “We think that the balance of risks and benefits associated with the common practice of medicating nearly all early episodes of psychosis should be re-examined.”
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Three NIMH-funded studies, and all pointed to the same conclusion.
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Perhaps 50 percent of newly diagnosed schizophrenia patients, if treated without antipsychotics, would recover and stay well through lengthy follow-up periods. Only a minority of patients seemed to need to take the drugs continuously. The “revolving door” syndrome that had become so familiar was due in large part to the drugs, even though, in clinical trials, the drugs had proven to be effective in knocking down psychotic symptoms. Carpenter and McGlashan neatly summarized the scientific conundrum that psychiatry now faced:

And if that was so, these drugs were increasing the likelihood that a person who suffered a psychotic break would become chronically ill.

All drugs have a risk-benefit profile, and the usual thought within medicine is that a drug should provide a benefit that outweighs the risks. A drug that curbs psychotic symptoms clearly provides a marked benefit, and that was why antipsychotics could be viewed as helpful even though the list of negatives with these drugs was a long one. Thorazine and other first-generation neuroleptics caused Parkinsonian symptoms and extraordinarily painful muscle spasms. Patients regularly complained that the drugs turned them into emotional “zombies.” In 1972, researchers concluded that neuroleptics “impaired learning.”
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Others reported that even if medicated patients stayed out of the hospital, they seemed totally unmotivated and socially disengaged. Many lived in “virtual solitude” in group homes, spending most of the time “staring vacantly at television,” wrote one investigator.
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None of this told of medicated schizophrenia patients faring well, and here was the quandary that psychiatry now faced: If the drugs
increased
relapse rates over the long term, then where was the benefit? This question was made all the more pressing by the fact that many patients maintained on the drugs were developing tardive dyskinesia (TD), a gross motor dysfunction that remained even after the drugs were withdrawn, evidence of permanent brain damage.

All of this required psychiatry to recalculate the risks and benefits of antipsychotics, and in 1977 Jonathan Cole did so in an article provocatively titled “Is the Cure Worse Than the Disease?” He reviewed all of the long-term harm the drugs could cause and
observed that studies had shown that at least 50 percent of all schizophrenia patients could fare well without the drugs. There was only one moral thing for psychiatry to do: “Every schizophrenic outpatient maintained on antipsychotic medication should have the benefit of an adequate trial without drugs.” This, he explained, would save many “from the dangers of tardive dyskinesia as well as the financial and social burdens of prolonged drug therapy.”
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The evidence base for maintaining schizophrenia patients on antipsychotics had collapsed. “Are the antipsychotics to be withdrawn?” asked Pierre Deniker, the French psychiatrist who, in the early 1950s, had first promoted their use.
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In the late 1970s, two physicians at McGill University, Guy Chouinard and Barry Jones, stepped forward with a biological explanation for why the drugs made schizophrenia patients more biologically vulnerable to psychosis. Their understanding arose, in large part, from the investigations into the dopamine hypothesis of schizophrenia, which had detailed how the drugs perturbed this neurotransmitter system.

Thorazine and other standard antipsychotics block 70 to 90 percent of all D
₂
receptors in the brain. In an effort to compensate for this blockade, the postsynaptic neurons increase the density of their D
₂
receptors by 30 percent or more. The brain is now “supersensitive” to dopamine, Chouinard and Jones explained, and this neurotransmitter is thought to be a mediator of psychosis. “Neuroleptics can produce a dopamine supersensitivity that leads to both dyskinetic and psychotic symptoms,” they wrote. “An implication is that the tendency toward psychotic relapse in a patient who has developed such a supersensitivity is determined by more than just the normal course of the illness.”
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A simple metaphor can help us better understand this drug-induced biological vulnerability to psychosis and why it flares up when the drug is withdrawn. Neuroleptics put a brake on dopamine transmission,
and in response the brain puts down the dopamine accelerator (the extra D
₂
receptors). If the drug is abruptly withdrawn, the brake on dopamine is suddenly released while the accelerator is still pressed to the floor. The system is now wildly out of balance, and just as a car might careen out of control, so too the dopaminergic pathways in the brain. The dopaminergic neurons in the basal ganglia may fire so rapidly that the patient withdrawing from the drugs suffers weird tics, agitation, and other motor abnormalities. The same out-of-control firing is happening with the dopaminergic pathway to the limbic region, and that may lead to “psychotic relapse or deterioration,” Chouinard and Jones wrote.
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This was an extraordinary piece of scientific detective work by the two Canadian investigators. They had—at least in theory—identified the reason that relapse rates were so high in the medication-withdrawal trials, which psychiatry had mistakenly interpreted as proving that the drugs prevented relapse. The severe relapse suffered by many patients withdrawn from antipsychotics was not necessarily the result of the “disease” returning, but rather was drug-related. Chouinard and Jones’s work also revealed that both psychiatrists and their patients would regularly suffer from a clinical delusion: They would see the return of psychotic symptoms upon drug withdrawal as proof that the antipsychotic was necessary and that it “worked.” The relapsed patient would then go back on the drug and often the psychosis would abate, which would be further proof that it worked. Both doctor and patient would experience this to be “true,” and yet, in fact, the reason that the psychosis abated with the return of the drug was that the brake on dopamine transmission was being reapplied, which countered the stuck dopamine accelerator. As Chouinard and Jones explained: “The need for continued neuroleptic treatment may itself be drug-induced.”

In short, initial exposure to neuroleptics put patients onto a path where they would likely need the drugs for life. Yet—and this was the second haunting aspect to this story of medicine—staying on the drugs regularly led to a bad end. Over time, Chouinard and Jones noted, the dopaminergic pathways tended to become permanently dysfunctional. They became
irreversibly
stuck in a hyperactive state,
and soon the patient’s tongue was slipping rhythmically in and out of his mouth (tardive dyskinesia) and psychotic symptoms were worsening (tardive psychosis). Doctors would then need to prescribe higher doses of antipsychotics to tamp down those tardive symptoms. “The most efficacious treatment is the causative agent itself, the neuroleptic,” Chouinard and Jones said.

Over the next few years, Chouinard and Jones continued to flesh out and test their hypothesis. In 1982, they reported that 30 percent of 216 schizophrenia outpatients they studied showed signs of tardive psychosis.
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They also observed that it tended to afflict those patients who, at initial diagnosis, had a “good prognosis,” and thus would have had a chance to fare well over the long term if they had never been exposed to neuroleptics. These were the “placebo responders” who had fared best in the studies conducted by Rappaport and Mosher, and now Chouinard and Jones were reporting that they were becoming chronically psychotic after years of taking antipsychotics. Finally, Chouinard quantified the risk, reporting that tardive psychosis seemed to develop at a slightly slower rate than tardive dyskinesia. It afflicted 3 percent of patients a year, with the result that after fifteen years on the drugs, perhaps 45 percent suffered from it. When tardive psychosis sets in, Chouinard added, “the illness appears worse” than ever before. “New schizophrenic or original symptoms of greater severity will appear.”
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Animal studies confirmed this picture too. Philip Seeman reported that antipsychotics caused an increase in D
₂
receptors in rats, and while the density of these receptors could revert to normal if the drug was withdrawn (he reported that for every month of exposure, it took two months for renormalization to occur), at some point the increase in receptors became irreversible.
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In 1984, Swedish physician Lars Martensson, in a presentation at the World Federation of Mental Health Conference in Copenhagen, summed up the devastating bottom line. “The use of neuroleptics is a trap,” he said. “It is like having a psychosis-inducing agent built into the brain.”
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This was the view of neuroleptics that came together in the early 1980s, and it was a story of science at its best. Psychiatrists saw that the drugs “worked.” They saw that antipsychotics knocked down psychotic symptoms, and they observed that patients who stopped taking their medications regularly became psychotic again. Scientific tests reinforced their clinical perceptions. Six-week trials proved the drugs were effective. Relapse studies proved that patients should be maintained on the drugs. Yet once researchers came to understand how the drugs acted on the brain, and once they began investigating why patients were developing tardive dyskinesia and why they were becoming so chronically ill, then this
counterintuitive
picture of the drugs—that they were increasing the likelihood that patients would become chronically ill—emerged. It was Chouinard and Jones who explicitly connected all the dots, and for a time, their work did stir up a hornet’s nest within psychiatry. One physician, at a meeting where the two McGill University doctors spoke, asked in astonishment: “I put my patients on neuroleptics because they’re psychotic. Now you’re saying that the same drug that controls their schizophrenia also causes a psychosis?”
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