Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (37 page)

The result took him aback.

Far from increasing the toxic effect of urea, the lithium urate exerted some kind of protection. Moreover, and what was equally unexpected, the normally jittery guinea pigs lost their natural timidity and became instead placid, tranquilized, and generally lacking in responsiveness to stimulation. Cade turned them on their backs, and instead of frantically trying to right themselves and scurry away, they lay still and gazed serenely back at him. Further experiments confirmed that this calming action was due not to the urate component but to the lithium ion itself.
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Lithium is a metallic element that is abundant. It is found in most rocks of volcanic origin. In 1817 it was discovered in a Swedish iron mine and quickly became the object of health claims. The British physician Sir A. B. Garrod advocated rubbing lithium and rosewater onto gouty joints to dissolve the crystal deposits of uric acid. Others promoted lithium preparations as nostrums for indigestion and gallstones. A St. Louis merchant, C. L. Grigg, marketed a fruity drink he named Bib-Label Lithiated Lemon-Lime Soda. A doctor's testimonial promised “an abundance of energy, enthusiasm, a clear complexion, lustrous hair, and shining eyes.” Grigg later devised a punchier slogan—“You Like It, It Likes You”—and a new name, 7UP. Later, lithium was taken out of the soft drink, at about the time of reports of cardiac toxicity from its use as a salt substitute.

Bottled Lithium

In Lithia Springs, Georgia, Lithia Springs Mineral Water is still sold to devoted self-healers, one of whom is quoted as drinking a gallon a day because “it keeps my nerves steady.” Other bottled curative waters, many of which are still on the market—Vichy, Apollinaire, Perrier, Lithée—were all promoted at one time for their high lithium content.

In the wake of the surprising results he saw in his becalmed guinea pigs, Cade then tested lithium salts on himself in the clinical doses contemplated. Aware that lithium salts had been used clinically during the nineteenth century to treat such diverse conditions as epilepsy, gout, cancer, and diabetes, Cade considered self-administration safe.

Finding no harmful effects, he then gave the lithium salt to a fiftyone-year-old male patient who had been in a state of manic excitement for five years. After five days, there was a clear improvement in the patient's condition, and within three weeks he was considered well enough to be transferred to a convalescence ward for the first time. In his fourth month of continuous treatment, he was sent home with instructions to take lithium carbonate daily. The man was even able to
return to his former occupation. Unfortunately, neglecting to take his medication over several weeks led to irritability and erratic behavior and necessitated his readmission. Back on lithium, the patient strikingly improved and was discharged once again.

Cade achieved similar dramatic success with nine other manic cases. He watched, thunderstruck, as their raging moods subsided. All showed rapid and marked improvement.
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The serendipitous nature of the discovery of the therapeutic effect of lithium is stunning. Cade openly acknowledged: “My discovery of the specific anti-manic effect of the lithium ion was an unexpected… by-product of experimental work I was doing to test a hypothesis regarding the etiology of manic-depressive illness.”
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The decision to use lithium in the experiments rested solely upon its known solubility.

Doctors were slow to begin using lithium for manic patients. Cade's 1949 report appeared in an obscure regional publication, the
Medical Journal of Australia,
not usually read by the major international scientific and clinical centers.
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Furthermore, Cade did not take an active role in proselytizing, with his next report not appearing until more than twenty years later, in 1970, at which time he was president of the Australian–New Zealand Psychiatric Association. His breakthrough discovery would have languished if not for the persistent efforts of a clinical researcher named Mogens Schou, professor of biological psychiatry at Århus University in Denmark, who undertook intense investigations of the biology and clinical actions of lithium salts, confirming Cade's claims.
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Schou was drawn to the investigation because manic-depressive illness ran in his family. He and a number of his relatives benefited from lithium treatment.

It was not until the mid-1960s that anything like general awareness of lithium's dramatic effect on mania dawned on the psychiatric profession. By 1972 there were more than seventy reports on the treatment of mania with lithium, with improvement rates between 60 and 100 percent. It became accepted in European and English psychiatric practice as a highly effective and safe treatment for manic-depressive illness, both for the treatment of acute mania and for reducing the frequency and severity of recurrent mania and depression.

For a variety of reasons, lithium salts were not readily accepted into American medical practice. One reason was the notoriety attached to lithium salts following several cases of severe intoxication and even death during the 1940s among patients using large, uncontrolled amounts of lithium chloride as a salt substitute while on a sodium-restricted regimen for congestive heart failure or renal failure. (Such use was discontinued in 1950.) It is now known that lithium salts are contraindicated in these conditions. Another factor contributing to slow development of lithium therapy was the lack of commercial interest by pharmaceutical companies in this inexpensive, unpatentable mineral. However, evidence accumulated to support the usefulness and safety of lithium, and it finally appeared “as a public service” on the American market in 1970, more than twenty years after Cade's report.

An estimated 1 to 3 percent of Americans, or between 3 and 9 million people, have manic-depressive illness, now more commonly known as bipolar affective disorder. “Mania is sickness for one's friends,” the poet Robert Lowell, a longtime sufferer declared, “depression for one's self.” The affliction is unusually prevalent among poets: Lowell, Theodore Roethke, John Berryman, Anne Sexton, and Sylvia Plath. In this group, suicide claimed an unusually high number.

An Unquiet Mind

Kay Redfield Jamison, long afflicted with bipolar disorder and a professor of psychiatry at the Johns Hopkins University School of Medicine, brilliantly recorded the fluctuating pains and pleasures of the intense dichotomy in her 1995 memoir
An Unquiet Mind:
“I have often asked myself whether, given the choice, I would choose to have manic-depressive illness. If lithium were not available to me, the answer would be a simple no—and it would be an answer laced with terror. But lithium does work for me, and therefore I suppose I can afford to pose the question. Strangely enough, I think I would choose it…. Because I honestly believe that as a result of it I have felt things, more deeply; had more
experiences, more intensely…. And I think much of this is related to my illness—the intensity it gives to things and the perspective it forces on me.”

The simple lithium ion remains the first-line treatment for mania and the prevention of recurrent attacks of manic-depressive illness. Its dramatic surprise discovery marked the dawn of the modern era of psychotropic medicine.
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34

Thorazine

In the middle of the twentieth century, people believed that shock occurred through the release of histamine by the autonomic, or involuntary, nervous system. (Today, we know that this is not the case.) Military surgeons operating on soldiers in shock faced many problems. In 1949 Henri Laborit, a thirty-five-year-old French naval surgeon stationed at the Maritime Hospital in Bizerte, Tunisia, undertook a clinical investigation to see if an antihistamine could reduce the symptoms of shock. He obtained a synthetic antihistamine, promethazine, from the Rhône-Poulenc drug company and introduced it into surgery.

The origin of this drug dated back as far as 1883, when phenothiazine was first synthesized in the course of chemical analyses on a dye called methylene blue that was derived from coal tar, a by-product of coal gas production. Thereafter, a remarkable succession of fortunate happenings occurred. Paul Ehrlich, the eminent researcher, found uses for dyes in the staining of biological tissues, which prompted his idea that they might also be of value in selectively destroying microorganisms. Methylene blue was noted to have antimalarial activity. By the time of World War II, this led to Rhône-Poulenc's pursuit of synthesizing phenothiazine amines in the hope of uncovering a new antimalarial agent. (Fortunately, the French researchers did not see a scientific paper that appeared in the American literature around this time, showing that these products did not work against malaria, or they
would have abandoned their research project.) In the fall of 1944, the investigators noted the antihistamine activity of some of these products and marketed one of these, promethazine, as Phenergan. Like many antihistamines, it had a strong sedative effect.

Laborit was immediately impressed by promethazine's tendency to promote what he termed a “euphoric quietude” in his patients. “Our patients are calm, relaxed, and euphoric even after major operations; they appear to really suffer less.”
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Promethazine and similar compounds replaced barbiturates preoperatively and morphine postoperatively. Surgeons found that it put patients into such a state of diminished arousal that they needed less anesthesia during surgery. This latter finding caused Rhône-Poulenc to shift its focus from anti-histamines to drugs that affect the central nervous system, with the goal of developing even better drugs to enhance the effects of anesthesia. The potential market was enormous. The company's researchers synthesized chlorpromazine (CPZ), a phenothiazine derivative, in December 1950.

Laborit was transferred to Val-de-Grâce, the famed military hospital in Paris, in early 1951, where he studied the effects of CPZ upon his surgical patients. His results were groundbreaking. In a 1952 report summarizing his experience with CPZ in sixty patients, he made the first published suggestion that the drug could be used in psychiatry.
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Extensive clinical tests of CPZ were begun by Jean Delay, a highly respected and influential psychiatrist, and his associate, Pierre Deniker, at the Ste. Anne mental hospital in Paris, and the positive results of these trials were promptly embraced by other psychiatrists in France.
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“By May 1953,” writes one historian, “the atmosphere in the disturbed wards of mental hospitals in Paris was transformed: strait-jackets, psychohydraulic packs and noise were things of the past! Once more, Paris psychiatrists who long ago unchained the chained, became pioneers in liberating their patients, this time from inner torments, and with a drug: chlorpromazine. It accomplished the pharmacologic revolution of psychiatry.”
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A S
ERENDIPITOUS
O
VERSIGHT

An accidental discovery over the next two years, as further clinical trials in England, Europe, and Canada were promoted by RhônePoulenc, provided another astonishing breakthrough. Dr. Heinz E. Lehmann in Montreal published the first North American report on CPZ in psychiatry in 1954, having found it most useful in manic patients. But he soon uncovered an inadvertent occurrence:

About three months after the trial had ended, we discovered that some of the chronic, back-ward schizophrenics had been accidentally left on large doses of CPZ. And incredibly, to us, four or five of these back-ward patients were getting better. No one believed that a pill could cause remission in schizophrenia, and we seemed to be getting the best results with chronic paranoids, the group most refractory to treatment.
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Large clinical studies in Europe and the United States then confirmed Lehmann's observations: CPZ was effective in palliating and, in almost 75 percent, “socially” curing acute schizophrenia. In chronic schizophrenia, the drug improved 40 percent and “socially” cured 18 percent of patients.
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Institutionalized patients with aggressive, violent, and destructive behavior, kept in restraints, in locked wards, receiving repeated electroshock treatment to control explosive behavior, became calm, cooperative, and communicative. The improvement was so dramatic that most of them were able to go home as long as they received continuous outpatient management.

In May 1954, following a licensing agreement with RhônePoulenc, Smith Kline & French Laboratories of Philadelphia began to market CPZ in the United States under the trade name Thorazine. Like other antipsychotic agents, Thorazine acts by blocking dopamine receptors and inactivating certain sites of dopamine transmission in the forebrain. This strongly suggests that the underlying chemical defect in the brains of schizophrenics is either an excess of dopamine formation
or a supersensitivity to dopamine receptors. Thorazine is easy to use and quick-acting, and its acute toxicity is practically zero, a useful feature in the treatment of acute schizophrenia and mania. Side effects are often extensions of the many pharmacological actions of these drugs. The major liability of Thorazine and similar drugs is a pernicious side effect of excessive dosage: tardive dyskinesia, a disorder that causes repetitive movements: chewing motions, lip smacking, and contortions of the arms and legs.

A revolution in psychiatry had occurred. Over the next eight months, Thorazine was given to an estimated 2 million patients. The impact on mental hospitals was astounding, particularly involving patients with schizophrenia, the most prevalent and severe of the major psychoses. Patients on antipsychotic drugs tend to show drowsiness and reduced initiative but retain intact intellectual functions. Typically, psychotic patients become less agitated, and withdrawn patients may become more responsive. Hallucinations, delusions, and disorganized thinking tend to gradually disappear.