Weaving the story of modern psychopharmacology’s birth leads us to a most surprising origin.
Many modern psychiatric medicines share a single, and surprising, origin story. They stem from a 19th-century attempt to deal with the problem of malaria, and its unexpected consequence, the development of the synthetic fabric dye industry. To see how medicines as seemingly diverse as chlorpromazine, imipramine, clozapine, and diazepam evolved from this unlikely source, let us step back in time to the 1850s.
At that point in time, malaria was taking a tremendous toll on the British effort to build and maintain an empire, and its devastation among the troops in the Crimean War was widely publicized. The only effective treatment was quinine, derived from the bark of the Cinchona tree in South America and Polynesia. There was an impetus to find a way to synthesize it at home, and a professor at the Royal College of Chemistry, August Wilhelm von Hofmann, believed that this could be done using the raw material of coal tar, in effect industrial waste from the manufacture of coke and illuminating gas. He challenged his students to do it, and one of them, 18-year-old William Henry Perkin, took the challenge to heart.
During Easter vacation in 1856, Perkin attempted the synthesis in the attic of his home in east London. This was a risky project; not too long before, another student had burned to death while trying to obtain benzene from coal tar. Perkin tried to combine the coal tar derivative aniline, an oily, fishy-smelling liquid, with orange-red potassium dichromate powder. The result was a dark-colored sludge lodged in the bottom of his glassware, which is not usually considered a desirable outcome. When trying to dislodge the mess, he added alcohol, and found that it turned a vivid purple. When it imparted this color to his cleaning cloth, Perkin, who had a longstanding interest in painting and photography, wondered if it might be useful as a fabric dye. At the time, purple dye was obtained laboriously from the mucous secretions of mollusks and, hence, it was very expensive. A synthetic product from coal could in principle be made very cheaply.
Perkin took his idea to professor Hofmann, who at first scoffed at it as trivial and recommended that he turn his attention back to quinine. Undeterred, Perkin, along with his brother and a friend, built a laboratory in his backyard garden. After testing its ability to color silk, they applied for a patent and founded a company. Although he had not synthesized quinine (this would not happen for another 90 years), he had inadvertently opened the new field of synthetic organic chemistry.
Initially there was little interest in aniline purple, or mauveine, but after the Spanish-born Empress Eugenie de Montijo favored the new color and Queen Elizabeth wore a mauveine dress to the Great Exhibition of 1862, there was great public enthusiasm. Soon a variety of other dye companies, including Bayer, Ciba, Geigy, and Sandoz were using these newfound techniques to make fabric dyes, and later expanded into paints, food colorings, agricultural chemicals, explosives, and medicines. And here our story of synthetic dyes evolving into psychiatric drugs begins. (The depiction of these discoveries is presented in summary form; more detailed accounts can be found elsewhere.1,2)
A cascade of discoveries began with methylene blue
In 1876, Heinrich Caro, a German calico printer and chemist who would later co-discover indigo, synthesized the azo dye methylene blue, subsequently determined to be a tricyclic phenothiazine. It might have remained a footnote to the history of fabric production, but for 2 events. Fifteen years later, the pharmacologist Dr Paul Ehrlich was using methylene blue to stain microscopic organisms when he noticed that it seemed to immobilize the Plasmodium parasites that cause malaria when transmitted by Anopheles mosquitos. He wondered whether it might become a clinical treatment and gave it to patients. Their condition improved.
Methylene blue went on to be widely used, notably for treating malaria in Allied troops in the Pacific during World War II. Although subsequently replaced by synthetic drugs such as quinacrine, chloroquine, and hydroxychloroquine (much in the news in this past year in another context), methylene blue was important because it was the first fully synthetic drug in medical practice. As an aside, Ehrlich also noted that it might have antidepressant or sedative effects, although that was not actively pursued at the time.
The second development based on methylene blue came some 70 years later. With the success of antihistamines such as diphenhydramine in 1945, pharmaceutical houses looked for other similar agents. Paul Charpentier, a chemist at Rhône-Poulenc, developed chlorpromazine, a derivative of methylene blue. Charpentier had been making antihistamines for Dr Henri Laborit, a French surgeon who believed that histamine release contributed to surgical shock. He recalled that chlorpromazine, which had been unsuccessfully tested as an antimalarial, had significant antihistaminic properties, and sent it on to Laborit. It was soon noticed that chlorpromazine quieted surgical patients, who seemed to develop a state of indifference, and Laborit wondered if it might be useful in psychiatry. He and colleagues at Val de Grâce hospital in Paris gave it to a 24-year-old patient with bipolar disorder, who improved and was ultimately discharged. The encouraging results were reported at a medical meeting, but they were met with indifference.
Things might have remained had not an anesthetist colleague of Laborit’s mentioned that his brother-in-law was Dr Pierre Deniker, a psychiatrist at the prestigious St. Anne’s Hospital in Paris. They contacted Deniker, who, along with his director Jean Delay, tested chlorpromazine, and soon publicized its success in improving the conditions of patients with psychosis. As more and more reports of efficacy came in from around the world, chlorpromazine was first marketed in Europe as Largactil (“large in action”) in 1953. The result was a transformation in the treatment of psychoses. Many patients no longer requiring inpatient care and were transferred to communities that were not always equipped to receive them.
The effect of chlorpromazine on the medical community was so great that soon other companies began modifying the molecule in the hopes of developing a related drug. Among them was Geigy, which provided compounds for testing to various psychiatrists, including Dr Roland Kuhn in Münsterlingen, a lakeside community in northern Switzerland. One compound, G22355, was similar to chlorpromazine, with 3 ring-like structures attached to a side chain. When it offered little benefit to patients with schizophrenia, Kuhn decided to try it on patients with depression. Why he did this is not completely clear. One possibility is that the experiment came from a desire for completeness; alternatively, the Münsterlingen facility was unusual in that it had a large outpatient clinic with patients with depression, and Kuhn may have been particularly sensitive to depression because of his work there. He gave it to a woman who seemed improved after 6 days, and went on to study additional patients. He reported his findings in a Swiss journal and at an international meeting, but he too met with little interest. Undeterred, he later gave a lecture at Galesburg State Hospital in the United States and published his findings in the American Journal of Psychiatry. This time he found a more enthusiastic audience, and imipramine, the first of the tricyclic antidepressants, was released in Switzerland in 1957 and in the United States in 1959.
Just as the success of chlorpromazine ultimately resulted in imipramine, the enthusiasm for imipramine led other companies to seek similar agents. In the process, the Swiss firm Wander AG (which also made Ovaltine) came across what were known as “neuroleptic tricyclics.” During animal screening, an agent seemed of particular interest. It caused less sedation, and unexpectedly seemed to reduce sensitivity to pain. They selected this one for further study, and although it turned out that the analgesia finding had been an error due to deteriorated electrodes, it was a potent antipsychotic. After developing elaborate protocols to monitor its hematologic effects, clozapine came on the market in the United States in 1989, and it remains the gold standard for treatment resistant schizophrenia.
How failed fabric dyes evolved into tranquilizers
The benzodiazepines also have a background in fabric dyes. The rising popularity of meprobamate in 1955 inspired other companies to find antianxiety agents. Leo Sternbach, PhD, a chemist at Hoffman LaRoche, was asked to do so, but because other companies were already looking at variants on the meprobamate molecule, his task was to look for something with a completely different molecular structure. When thinking about possible chemical building blocks, he chose some azo dyes and derivatives that he had worked with at the University of Krakow in the 1930s. At the time, they had not been effective for coloring fabrics, so he had published a paper and moved on to other things. This time, he made about 40 variants of these molecules and gave them to colleagues for behavioral testing. Most of them were not successful, and Sternbach was told to let the project go and begin work on antibiotics.
A few years later, while cleaning out the laboratory, an assistant came across an old bottle from that previous work. He showed it to Sternbach; although he had moved on to other projects, Sternbach chose to test it. This last compound, chlordiazepoxide, came onto the market in 1960 as Librium (from “equilibrium”), the first of the benzodiazepine tranquilizers. It was followed 3 years later by diazepam and later others, and they rapidly became very popular, largely because of perceived advantages over barbiturates. They were less toxic in overdose when taken alone by healthy individuals (although indeed very toxic when combined with a number of other substances), had less respiratory depression, and did not stimulate hepatic enzymes to increase metabolism of other drugs. Their potential for misuse and abuse was not well recognized in those early years, but became more evident by 1975 when they were scheduled as Drug Enforcement Agency Class IV controlled substances, and again more recently with FDA Black Box warnings in 2016 and 2020.
Dye-derived drugs in other fields
The history of dyes leading to drug development is not confined to psychiatry. In 1931, a yellow acridine dye derived from methylene blue became quinacrine, a treatment for malaria. Another dye, prontosil red, became the first sulfonamide antibacterial agent. Sometime later its developer, Dr Gerhard Domagk, went on to modify related sulfa compounds and laid the groundwork for 1 of the routes to the antituberculosis drug isoniazid. In the early 1950s, iproniazid, closely related to isoniazid (which in this case came from a different source), was noted to elevate the mood of patients with tuberculosis, and ultimately came to market in 1958 as Marsilid, the first monoamine oxidase inhibitor (MAO) antidepressant.
In the modern world, dyes continue to be explored as drugs. Derivatives of indigo (as in blue jeans), known as indigoid dyes, are being developed to act as photo switches that could turn antibacterial or anticancer drugs on and off when exposed to light.3 Methylene blue is still used as a treatment for the blood disease methemoglobinemia. Its effects on tau proteins have led to current studies of its possible utility in mild cognitive impairment4, and a derivative, hydromethylthionine, is under investigation for Alzheimer disease and frontotemporal dementia.5
In summary, psychopharmacology as a field continues to grow rapidly and fruitfully, but it is good to remember its curious beginnings. Who could have guessed 150 years ago that a fabric printer, building on the lessons from a student’s failed chemistry project, would stumble upon a new coloring agent for calico and inadvertently set the stage for psychiatric pharmacology?
Dr Mendelson is a professor of psychiatry and clinical pharmacology (ret) at the University of Chicago. His recent books include Molecules, Madness, and Malaria: How Victorian Fabric Dyes Evolved into Modern Medicines for Mental Illnessand Infectious Disease and Nepenthe’s Children: The History of the Discoveries of Medicines for Sleep and Anesthesia.
1. Mendelson WB. The Curious History of Medicines in Psychiatry. Pythagoras Press; 2020.
2. Mendelson WB. Molecules, Madness, and Malaria: How Victorian Fabric Dyes Evolved into Modern Medicines for Mental Illness and Infectious Disease. Pythagoras Press; 2020.
3. Petermayer C, Dube H. Indigoid Photoswitches: Visible Light Responsive Molecular Tools. Acc Chem Res. 2018;51(5):1153-1163.
4. Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer Disease (MB2). Clinical Trials.gov. Accessed October 2, 2020. https://clinicaltrials.gov/ct2/show/NCT02380573
5. Shiells H, Schelter BO, Bentham P. Concentration-dependent activity of hydromethylthionine on clinical decline and brain atrophy in a randomized controlled trial in behavioral variant frontotemporal dementia. J Alzheimers Dis. 2020;75(2):501-519.
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