Just Plain Luck?

In previous blogs I’ve described the stories of how many psychiatric medicines were discovered, often seemingly by accident. Chlorpromazine (Thorazine), for instance, was developed in the early 1950s after Henri Laborit, a French surgeon looking for drugs to reduce surgical shock, noticed that patients became quiet and seemingly indifferent, and wondered if this might be useful in psychiatry (1).

Monoamine oxidase inhibitors became antidepressants after doctors giving iproniazid (Marsilid) as a treatment for tuberculosis noticed that patients had improved energy and mood (2). Chlordiazepoxide (Librium), the first benzodiazepine tranquilizer, came about because Leo Sternbach, a chemist at Hoffman LaRoche, decided to test behavioral effects of a chemical derived from failed fabric dyes, which was about to be discarded (3). Imipramine (Tofranil), the first tricyclic antidepressant, was developed after psychiatrist Roland Kuhn, who was tasked with giving a new possible antipsychotic to schizophrenics, decided to include some depressed patients as well, and clozapine (Clozaril) was discovered largely because of an instrumentation error when testing new tricyclics in animals (4).

These seemingly accidental events are often referred to as ‘serendipitous’. In this blog we will give another example in order to set the stage, and then explore more carefully the relative roles of luck and other factors, notably the personalities and previous experiences of the discoverers.

Frank Berger and the discovery of the first modern tranquilizer: In the 1940s, one of the limitations of the newly discovered penicillin was that it was rapidly broken down by bacteria which secreted an enzyme known as penicillinase. In 1945, Frank Berger, a Czechoslovakian-born physician, was working on penicillin preservatives for a British firm when he noticed that one of them caused rats and mice to become very quiescent, though easily aroused. He had a longstanding interest in why some people are ‘overexcitable and irritable, and create crisis situations over things that are not important’, and wondered if this compound might be a possible treatment.

After moving to the U.S., he and a colleague developed a related compound, meprobamate. His employers at Wallace Laboratories, however, were not convinced that there was a market for a drug to reduce anxiety, and shelved the project. Undeterred, Berger made a film of meprobamate’s effect on monkeys, and showed it at a medical meeting in San Francisco. There was such enthusiasm that his bosses relented, and meprobamate came on the market as Miltown in 1955. It became one of the first ‘blockbuster’ drugs, and by the end of the decade it was the most widely prescribed drug in the U.S. It also changed the direction of psychiatric practice; the recent marketing of chlorpromazine had been oriented to inpatient treatment, while meprobamate was appropriate for outpatient clinical care.

Horace Walpole (1717-1797), who coined the word 'serendipity'.

Source: Louis Le Coeur in Wikimedia Commons/Public Domain

Horace Walpole and serendipity: Though meprobamate ultimately proved to have a number of side effects, and one could appropriately view with concern its remarkably widespread use, it serves as a good example of how drugs are often discovered seemingly by accident. The notion of serendipity goes back to Horace Walpole, an eighteenth century art critic and publisher who is best known for his several decades of correspondence with a friend, Horace Mann, vividly describing the age in which they lived. In 1754 he coined the word serendipity to describe his experience of unexpectedly making a connection between two noble families based on their coat of arms. He derived the term from the Persian legend of the three princes of Serendip (an old word for Ceylon, or Sri Lanka), who wandered the world, and often discovered useful things which they had not been looking for. Presciently, Walpole commented that in science this was often the case, saying that though the transmutation of lead to gold or the secret to immortality had not been found, the process was producing many ‘noble discoveries’.

Having an open mind: Clearly many psychiatric drugs came about through seemingly chance events, but I would argue that there were other factors at work, notably the presence of discoverers who were open to seeing the implications of unexpected observations. Henri Laborit, the surgeon who noticed that chlorpromazine made his patients calm, made the jump to thinking of psychiatric applications. As we just described, Frank Berger made a similar leap when observing that animals receiving a penicillin preservative became quiescent. This is a particularly good example, since it was the discovery of penicillin, seemingly by accident, that in turn led to the development of meprobamate, again with a strong element of chance. In fact, the example of penicillin is also more complex than the story as it is usually told, of Alexander Fleming noticing that some mold growing in glassware appeared to be toxic to bacterial growth. In reality, Fleming had a history of working with infected war wounds, and was very interested in natural substances which inhibit bacteria; he had previously discovered lysozyme, an enzyme in saliva with antibacterial properties. Thus he was quite prepared to see the implications of an accidental mold growth affecting his staphylococcus culture.

The courage of one's convictions: Other qualities of many of these drug discoverers included a strong belief in their new ideas, and a certain rebellious streak. Leo Sternbach had been told by his supervisor to stop work on new tranquilizers and move on to antibiotics, but when presented with an old unused bottle from previous work, which seemed destined for the trash bin, he chose to have it tested for behavioral effects, and discovered chlordiazepoxide (3). Frank Berger, when told by his superiors that there was no market for drugs for anxiety, made a movie of the drug effects on monkeys and generated enough enthusiasm to lead them to reverse this decision, leading to the marketing of meprobamate. Henri Laborit, who discovered the psychiatric implications of chlorpromazine, never fit into the accepted academic mold, and had a career in an independent laboratory funded by his many later drug discoveries.

Indeed, this was another quality of most of the discoverers—the findings we describe here were not isolated events. They were not ‘one trick ponies’, but rather went on to startlingly successful careers. Henri Laborit found other drugs including the MAO inhibitor minaprine and the sedative chlormethiazole. Leo Sternbach went on to discover other drugs as varied as anticholinergics and antibiotics, and ultimately received 241 drug patents.

In short, chance played a role in many of the discoveries of psychiatric medicines, but it’s important to remember they were often made by people who drew on previous experiences, demonstrated creativity in other areas, were open to seeing the implications of unexpected observations, and showed a strong—often rebellious—belief in their convictions.

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This article is adapted from The Curious History of Medicines in Psychiatry.