Anatomy of an Epidemic (8 page)

In the spring of 1952, two prominent French psychiatrists, Jean
Delay and Pierre Deniker, began administering chlorpromazine to psychotic patients at St. Anne’s Hospital in Paris, and soon use of the drug spread to asylums throughout Europe. Everywhere the reports were the same: Hospital wards were quieter, the patients easier to manage. Delay and Deniker, in a series of articles they published in 1952, described the “psychic syndrome” induced by chlorpromazine:

U.S. psychiatrists dubbed chlorpromazine, which was marketed in the United States as Thorazine, as a “major tranquilizer.” Back in France, Delay and Deniker coined a more precise scientific term: This new drug was a “neuroleptic,” meaning it took hold of the nervous system. Chlorpromazine, they concluded, induced deficits similar to those seen in patients ill with encephalitis lethargica. “In fact,” Deniker wrote, “it would be possible to cause true encephalitis epidemics with the new drugs. Symptoms progressed from reversible somnolence to all types of dyskinesia and hyperkinesia, and finally to parkinsonism.”
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Physicians in the United States similarly understood that this new drug was not fixing any known pathology. “We have to remember that we are not treating diseases with this
drug,” said psychiatrist E. H. Parsons, at a 1955 meeting in Philadelphia on chlorpromazine. “We are using a neuropharmacologic agent to produce a specific effect.”
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At the same time that Rhône-Poulenc was testing phenothiazines for their possible magic-bullet properties against malaria, Frank Berger, a Czech-born chemist, was doing research of a somewhat similar kind in London, and his work led, in 1955, to the introduction of “minor tranquilizers” to the market.

During the war, Berger had been one of the scientists in Britain who had helped develop methods to produce medically useful quantities of penicillin. But penicillin was effective only against grampositive bacteria (microbes that took up a stain developed by Danish scientist Hans Christian Gram), and after the war ended, Berger sought to find a magic bullet that could kill gram-negative microbes, the ones that caused a host of troubling respiratory, urinary, and gastrointestinal illnesses. At that time, there was a commercial disinfectant sold in Britain, called Phenoxetol, that was advertised as effective against gram-negative bacteria in the environment, and Berger, who worked for British Drug Houses, Ltd., tinkered with the active ingredient in that product, a phenylglycerol ether, in an effort to produce a product with superior antibacterial effects. When a compound called mephenesin proved promising, he gave it to mice to test its toxicity. “The compound, much to my surprise, produced reversible flaccid paralysis of the voluntary skeletal muscles unlike that I had ever seen before,” Berger wrote.
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Berger had stumbled on a potent muscle-relaxing agent. That was curious enough, but what was even more surprising, the drug-paralyzed mice didn’t show any signs of being stressed by their new predicament. He would put the animals on their backs and they would be unable to right themselves, and yet their “heart beat was regular, and there were no signs suggesting an involvement of the autonomic nervous system.” The mice remained quiet and tranquil, and Berger found that even when he administered low doses of this amazing new compound to mice—the doses too small to cause muscle paralysis—they displayed this odd tranquility.

Berger realized that a drug of this sort might have commercial possibilities as an agent that allayed anxiety in people. However, mephenesin was a very short-acting drug, providing only a few minutes of peace. In 1947, Berger moved to the United States and went to work for Wallace Laboratories in New Jersey, where he synthesized a compound, meprobamate, that lasted eight times as long in the body as mephenesin. When Berger gave it to animals, he discovered that it also had powerful “taming” effects. “Monkeys after being given meprobamate lost their viciousness and could be more easily handled,” he wrote.
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Wallace Laboratories brought meprobamate to market in 1955, selling it as Miltown. Other pharmaceutical companies scrambled to develop competitor drugs, and as they did so, they looked for compounds that would make animals less aggressive and numb to pain. At Hoffmann-La Roche, chemist Leo Sternbach identified chlordiazepoxide as having a “powerful and unique” tranquilizing effect after he gave it to mice that ordinarily could be prompted to fight by the application of electric shocks to their feet.
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Even with a low dose of the drug, the mice remained noncombative when shocked. This compound also proved to have potent taming effects in larger animals—it turned tigers and lions into pussycats. The final proof of chlordiazepoxide’s merits involved another electric-shock exam. Hungry rats were trained to press a lever for food, and then they were taught that if they did so while a light in the cage blinked on, they would be shocked. Although the rats quickly learned not to press the lever while the light was on, they nevertheless exhibited signs of extreme stress—defecating, etc.—whenever it lit up their cage. But if they were given a dose of chlordiazepoxide? The light would flash and they wouldn’t be the least bit bothered. Their “anxiety” had vanished, and they would even press the lever to get something to eat, unworried about the shock to come. Hoffmann-La Roche brought chlordiazepoxide to market in 1960, selling it as Librium.

For obvious reasons, the public heard little about the animal tests that had given rise to the minor tranquilizers. However, an article published in the
Science News Letter
was the exception to the rule, as its reporter put the animal experiments into a human frame of
reference. If you took a minor tranquilizer, he explained, “this would mean that you might still feel scared when you see a car speeding toward you, but the fear would not make you run.”
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Psychiatry now had a new drug for quieting hospitalized patients and a second one for easing anxiety, the latter a drug that could be marketed to the general population, and by the spring of 1957, it gained a medicine for depressed patients, iproniazid, which was marketed as Marsilid. This drug, which was dubbed a “psychic energizer,” could trace its roots back to a poetically apt source: rocket fuel.

Toward the end of World War II, when Germany ran low on the liquid oxygen and ethanol it used to propel its V-2 rockets, its scientists developed a novel compound, hydrazine, to serve as a substitute fuel. After the war ended, chemical companies from the Allied countries swooped in to grab samples of it, their pharmaceutical divisions eager to see if its toxic properties could be harnessed for magic-bullet purposes. In 1951, chemists at Hoffmann-La Roche created two hydrazine compounds, isoniazid and iproniazid, that proved effective against the bacillus that caused tuberculosis. The novel medicines were rushed into use in several TB hospitals, and soon there were reports that the drug seemed to “energize” patients. At Staten Island’s Sea View Hospital,
Time
magazine reported, “patients who had taken the drugs danced in the wards, to the delight of news photographers.”
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The sight of TB patients doing a jig suggested that these drugs might have a use in psychiatry as a treatment for depression. For various reasons, iproniazid was seen as having the greater potential, but initial tests did not find it to be particularly effective in lifting spirits, and there were reports that it could provoke mania. Tuberculosis patients treated with iproniazid were also developing so many nasty side effects—dizziness, constipation, difficulty urinating, neuritis, perverse skin sensations, confusion, and psychosis—that its use had to be curtailed in sanitariums. However, in the spring of 1957, Nathan Kline, a psychiatrist at Rockland State Hospital in Orangeburg, New York, rescued iproniazid with a report that if depressed patients were kept on the drug long enough, for at
least five weeks, it worked. Fourteen of the sixteen patients he’d treated with iproniazid had improved, and some had a “complete remission of all symptoms.”
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On April 7, 1957, the
New York Times
summed up iproniazid’s strange journey: “A side effect of an anti-tuberculosis drug may have led the way to chemical therapy for the unreachable, severely depressed mental patient. Its developers call it an energizer as opposed to a tranquilizer.”
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Such were the drugs that launched the psychopharmacology revolution. In the short span of three years (1954–1957), psychiatry gained new medicines for quieting agitated and manic patients in asylums, for anxiety, and for depression. But none of these drugs had been developed after scientists had identified any disease process or brain abnormality that might have been causing these symptoms. They arrived out of the post–World War II search for magic bullets against infectious diseases, with researchers, during that process, stumbling on compounds that affected the central nervous system in novel ways. The animal tests of chlorpromazine, meprobamate, and chlordiazepoxide revealed that these agents sharply curbed normal physical and emotional responses, but did so without causing a loss of consciousness. That was what was so novel about the major and minor tranquilizers. They curbed brain function in a selective manner. It was unclear how iproniazid worked—it seemed to rev up the brain in some way—but, as the
New York Times
had noted, its mood-lifting properties were properly seen as a “side effect” of an anti-tuberculosis agent.

The drugs were best described as “tonics.” But in the media, a story of a much different sort was being told.

The storytelling forces in American medicine underwent a profound shift in the 1950s, and to see how that is so, we need to briefly
recount the history of the American Medical Association prior to that time. At the turn of the century, the AMA set itself up as the organization that would help the American public distinguish the good from the bad. At that time, there were fifty thousand or so medicinal products sold in the United States, and they were of two basic types. There were thousands of small companies that sold syrups, elixirs, and herbal remedies directly to the public (or as packaged goods in stores), with these “patent” medicines typically made from “secret” ingredients. Meanwhile, Merck and other “drug houses” sold their chemical preparations, which were known as “ethical” drugs, to pharmacists, who then acted as the retail vendors of these products. Neither group needed to prove to a government regulatory agency that its products were safe or effective, and the AMA, eager to establish a place for doctors in this freewheeling marketplace, set itself up as the organization that would do this assessment. It established a “propaganda department” to investigate the patent medicines and thus protect Americans from “quackery,” and it established a Council on Pharmacy and Chemistry to conduct chemical tests of the ethical drugs. The AMA published the results of these tests in its journals and provided the best ethical drugs with its “seal of approval.” The AMA also published each year a “useful drugs” book, and its medical journals would not allow advertisements for any drug that had not passed its vetting process.

With this work, the AMA turned itself into a watchdog of the pharmaceutical industry and its products. By doing so, the organization was both providing a valuable service to the public and furthering its members’ financial interests, for its drug evaluations provided patients with a good reason to visit a doctor. A physician, armed with his book of useful drugs, could prescribe an appropriate one. And it was this
knowledge
, as opposed to any government-authorized prescribing power, that provided physicians with their value in the marketplace (in terms of providing access to medicines).

The selling of drugs in the United States began to change with the passage of the 1938 Food and Drug Cosmetics Act. The law required drug firms to prove to the Food and Drug Administration that their products were safe (they still did not have to prove that their drugs were helpful), and in its wake, the FDA began decreeing
that certain medicines could be purchased only with a doctor’s prescription.
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In 1951, Congress passed the Durham-Humphrey Amendment to the act, which decreed that most new drugs would be available by prescription only, and that prescriptions would be needed for refills, too.

Physicians now enjoyed a very privileged place in American society. They controlled the public’s access to antibiotics and other new medicines. In essence, they had become the retail vendors of these products, with pharmacists simply fulfilling their orders, and as vendors, they now had financial reason to tout the wonders of their products. The better the new drugs were perceived to be, the more inclined the public would be to come to their offices to obtain a prescription. “It would appear that a physician’s own market position is strongly influenced by his reputation for using the latest drug,” explained
Fortune
magazine.
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The financial interests of the drug industry and physicians were lined up in a way they never had been before, and the AMA quickly adapted to this new reality. In 1952, it stopped publishing its yearly book on “useful drugs.” Next, it began allowing advertisements in its journals for drugs that had not been approved by its Council on Pharmacy and Chemistry. In 1955, the AMA abandoned its famed “seal of acceptance” program. By 1957, it had cut the budget for its Council on Drugs to a paltry $75,000, which was understandable, given that the AMA was no longer in the business of assessing the merits of these products. Three years later, the AMA even lobbied against a proposal by Tennessee senator Estes Kefauver that drug companies prove to the FDA that their new drugs were effective. The AMA, in its relationship to the pharmaceutical industry, had “become what I would call sissy,” confessed Harvard Medical School professor Maxwell Finland, in testimony to Congress.
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