Read Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century Online
Authors: Morton A. Meyers
Tags: #Health & Fitness, #Reference, #Technology & Engineering, #Biomedical
The use of MAO inhibitors in the treatment of depression became severely restricted in the face of unexpected consequences. Complex, sometimes severe, and often unpredictable interactions with other food-derived amines (particularly those in cheese) chemically related to adrenaline and thus liable to raise blood pressure, sometimes sufficient to precipitate strokes or heart failure, made their medical use difficult and potentially hazardous.
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Fortunately, only a few years later, the next important, and now dominant, class of antidepressant compounds—the tricyclics—was introduced.
T
RICYCLIC
A
NTIDEPRESSANTS
Roland Kuhn at the Cantonal Psychiatric Clinic in Münsterlingen, Switzerland, was a distinguished and cultivated thirty-eight-year-old psychiatrist who had been trained in psychoanalysis. Despite this training, his clinical experiences had led him to seriously consider the
possibility that mental illnesses were caused by biological factors. At the request of the Geigy pharmaceutical company in Basel, he began testing a drug called imipramine, one of the tricyclics (so named for their chemical structure, characterized by three interlinked carbon rings) that had originally been synthesized with antihistaminic activity in mind. Kuhn set out in 1950 to investigate it for use in treatment of schizophrenic patients. Over the next several years, Kuhn made an astute observation of an apparent paradoxical effect. Rather than exerting a sedative effect, imipramine did exactly the opposite—it served as a stimulant.
A few quiet, withdrawn schizophrenics became less withdrawn and began reacting to their hallucinations, hence harder to handle. Rather than concluding that the drug had made them “worse,” Kuhn took the view that the drug had eased the depressed component in these patients, resulting in what might be considered a “normal” reaction to hallucinations. He therefore decided to reevaluate the drug by trying it in patients who were primarily depressed and not necessarily schizophrenic.
The results were dramatic and breathtaking. Deeply depressed patients were resurrected to activity, socialization, contentment, and accessibility. The patients themselves spoke of a “miracle cure.” Kuhn was candid in acknowledging that “chance admittedly had something to do with the discovery of imipramine…. Good fortune, too, played a part.” But in also declaring that “a discovery does not arise of its own accord out of a particular scientific solution,”
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this experienced psychiatrist paid tribute as well to Pasteur's dictum: “Chance favors the prepared mind.”
Thus was born a class of drugs that would have a profound effect on millions of patients suffering from depression, thanks to both chance and sagacity. Kuhn's sagacity, in this case, was in his ability to see the drug's potential for use as an antidepressant, even though that potential good use was masked by its failure as a sedative.
P
ROZAC
N
ATION
Depression was recognized as having biological causes, and the search was on for even more effective drugs to treat it. It is remarkable that,
over the next thirty years, so little progress was made. The most notable advance was the introduction of agents that have, in essence, the same mechanism of action as the original tricyclic antidepressants, but with fewer side effects. These are called selective serotonin reuptake inhibitors, or SSRIs, and they include the well-known brand-name drugs Prozac, Paxil, and Zoloft. (Prozac's generic name is fluoxetine; Paxil's is paroxetine; and Zoloft's is sertraline.) SSRIs prolong serotonin's neurotransmission by inhibiting its reuptake by the nerves that release it, which is the normal way that serotonin signaling is terminated.
Prozac was the first SSRI approved by the FDA, in December 1987, and the others soon followed. Prozac in particular became a buzzword for the new zeitgeist, built on society's acceptance of the chemical regulation of mood. By 1994, according to
Newsweek,
the drug had “attained the familiarity of Kleenex and the social status of spring water.”
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Organizations like the National Alliance for the Mentally Ill and the National Depression and Manic-Depressive Association assert that these disorders are illnesses like diabetes or heart disease, not weaknesses or failures of character. Americans are coming to think of depression as an illness like any other, a topic discussed on dates and at dinner parties.
As of 2006, about 40 million people had taken Prozac since it was introduced in 1988. In 2001 it had retail sales of $2.7 billion in the United States, with similar figures posted by Zoloft and other agents. In 2004 antidepressants became the best-selling category of prescription medicines in the United States. Global sales totaled $20 billion dollars that year. In 2006, at least 7 million Americans were on antidepressants.
The search continues for even better drugs that are more effective and have fewer side effects. Despite a better understanding of drug effects on neurotransmission, a trial-and-error approach endures in the development of new drugs. What physically initiates and sustains depression remains poorly understood, largely because an animal model for human depression does not exist. Animal tests do not mimic anything like human depression. Not only do antidepressants affect different parts of the brain in animals and humans, but in people depression has a strong emotional and cognitive component.
Yet even with more sophisticated laboratory investigations, additional serendipitous discoveries will be needed for real progress to take place. Eric Nestler of the Division of Molecular Psychiatry at the Yale University School of Medicine acknowledged that reality when he wrote in 1998: “It is likely that truly novel antidepressants will be developed either by luck once again or by revealing more about the basic mechanisms that underlie depressive syndromes.”
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© The New Yorker Collection 1997 Mike Twohy from
cartoonbank.com
. All Rights Reserved.
37
Librium and Valium
Following the early reports of the medical usefulness of the initial psychotropics, much interest was generated to develop further new drugs. In the mid-1950s the pharmaceutical company Hoffman–La Roche in New Jersey, eager to enter this exploding market, launched a program to synthesize novel compounds in order to discover a new “psychosedative” drug.
Leo H. Sternbach, a Polish immigrant, was Roche's director of medicinal chemistry. He decided to take a “from the shelf” approach that might prove therapeutic. It led Sternbach to a self-described “chain of events that started with the haphazard synthesis of new chemical compounds”
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and led to what was later acknowledged at Hoffman–La Roche as an “accidental discovery”
2
of new blockbuster drugs.
Sternbach decided to reinvestigate some tricyclic compounds he had synthesized eighteen years earlier at the University of Cracow, just before the Nazis invaded Poland, while doing studies on dyestuffs.
3
Nobody else had paid any attention to these compounds—which had turned out to be useless as dyes—in the long interval since he had first prepared them. Having in mind the tricyclic nature of the newly discovered tranquilizer Thorazine, Sternbach's idea was to modify the molecular structure of his compounds by introducing a basic side chain, known to be important for the biological activity of many drugs.
T
IDYING
U
P THE
L
AB
B
ENCH
: “E
UREKA
!”
Sternbach prepared around forty new compounds, which he screened for muscle relaxant, sedative, and anticonvulsant properties, but all proved biologically inactive. Then the program was virtually suspended for almost two years. In April 1957 Sternbach, tidying up a lab bench that had become littered with dishes, flasks, and beakers, was about to discard a crystalline compound when a colleague pointed out that it had been overlooked during the testing process. He suggested it be sent for animal testing. Agreeing, Sternbach promised management that this compound would be his last product of the series. “We thought that the expected negative pharmacological result would complete our work with this series of compounds and yield at least some publishable material.”
4
A few days later, he got a call from Roche's director of pharmacology. This compound, later called Librium, had extraordinary qualities. It tamed a colony of vicious monkeys, without affecting their alertness. A mouse would hang limply when held by one ear, but unlike those given Miltown, it was able to walk when prodded. In headlining his description of the results of the animal tests, Sternbach was justified in using the term “Eureka!”
5
The compound was superior to Miltown for allaying anxiety and muscle tension. All this with a very low level of acute toxicity and no significant side effects.
The unexpected finding of a pharmacologically active compound after what had been a fruitless search generated considerable interest and enthusiasm. However, the question loomed: Why was only this compound active of the forty he had synthesized?
M
OTHER'S
L
ITTLE
H
ELPER
Sternbach reinvestigated its chemistry and found that a key intermediate was not truly of the class of compound that he originally thought but was rather an entirely different one. This last compound had followed a different synthetic pathway and had undergone an “unusual transformation” to an unexpected molecular rearrangement that was
not then well known. The product thus formed was now shown to be a benzodiazepine.
Sternbach was granted a U.S. patent for this new tranquilizer in July 1959. The drug was quickly found to calm patients’ tension and anxiety with a minimum of side effects. Most important, the calming action was accomplished without clouding consciousness or interfering with intellectual activity. The interest of clinicians grew enormously and, within what today appears an incredibly short time, initial clinical studies were conducted on around 16,000 patients. The drug received FDA approval in February 1960 and was marketed as Librium. It was highly successful as a tranquilizer that was stronger than Miltown. A brief clinical note in the March 12, 1960, issue of the
Journal of the American Medical Association
was the first published announcement that the drug was therapeutically effective.
As certain features of Librium's chemical structure were not necessary in order to achieve the desired effects, Sternbach did additional work to find simpler analogs. The one he came up with, diazepam, was five to ten times more powerful than Librium and did not have its bitter taste. Marketed as Valium in December 1963, it became the country's best-selling drug, as well as an American cultural icon.
By 1970, one woman in five and one man in thirteen were using “minor tranquilizers and sedatives,” meaning mainly the benzodiazepines.
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Valium reached the height of its popularity in 1978, a year when Americans consumed 2.3 billion of the little yellow pills. In 1980 Roche was making 30 million Valium tablets a day. By the mid-1980s, the benzodiazepines accounted for up to 100 million prescriptions per year in the United States alone.
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Today about thirty benzodiazepines, of thousands synthesized since 1960 by many pharmaceutical companies, are in regular use throughout the world, principally as antianxiety agents but also as muscle relaxants, anesthetics, and epilepsy medication. They are among the most commercially successful drugs of all time.
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Although they have been proven valuable in patients whose anxiety interferes with their work, leisure, and personal relationships, they are considered by some to be widely misused in the management of the most trivial symptoms of stress.
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38
“That's Funny, I Have the Same Bug!”
During World War II, Erik Jacobsen, the forty-four-year-old director of the biological laboratory at the Danish pharmaceutical firm Medicinalco in Copenhagen, thought he was coming down with the flu. After eating a sandwich at lunchtime, accompanied by a customary bottle of beer, he felt nauseated and his head throbbed. But strangely, no flu developed.
A few weeks later, he and the managing director went out to lunch and celebrated the company's good fortunes with a few glasses of aquavit. Shortly thereafter, Jacobsen had a reoccurrence of his symptoms. Colleagues told him he was strikingly red-faced.