The Incredible History of Where Antidepressants Come From

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Have you ever wondered where antidepressants came from? The story of how these medicines were first developed begins with the applied use of organic chemistry—and a bit of luck– in the 1950s. To give this a bit of context, it might be worthwhile to see how this came to be, in the intertwined commercial efforts to manufacture dyes and drugs. Modern organic chemistry began in 1856 with a British professor’s assignment to an 18-year-old chemist named William Henry Perkin to synthesize quinine, a drug for malaria which at the time was obtained from the bark of the cinchona tree. While trying to do so Perkin, working on a holiday in his home laboratory, added chemicals to coal tar, and unhappily ended up with a black sludge in the bottom of his flask—usually not a good outcome in organic chemistry. He attempted to remove this sludge from his flask using alcohol and noted that the resulting solution had a rich purple-blue color, and adhered to fabrics. He had inadvertently created the first synthetic dye, aniline (from a Sanskrit word for dark blue), and opened the doors to the development over the years of a wide range of compounds ranging from polyurethanes to medicines. In the 1860s, the German chemist Adolph von Bayer synthesized indigo dyes, the color of blue jeans, as well as the barbituric acid from which barbiturate sedatives were later developed. The uses of organic chemical synthesis were quickly adapted by companies devoted to making dyes, with names such as Ciba, Geigy, Sandoz, and of course Bayer. Not surprisingly, many of these companies began to use their same skills for developing drugs. One result of these endeavors, combining skills both in chemistry and clinical observation, was a flowering of psychopharmacology in the mid-20th century, with the discovery of the first modern antipsychotics and antidepressants.

In 1951, chemists at Roche laboratories in New Jersey synthesized the medicine iproniazid, which they hoped would be useful in the treatment of tuberculosis. Unfortunately, it was not effective, but the doctors noticed that some of the TB patients receiving it had improvements in their mood or became euphoric. This observation led to trying it in depressed patients, and it ultimately became the first of a new class of antidepressants known as MAO inhibitors.

In a theme which may be becoming familiar, in the mid-1950s, Roland Kuhn, a Swiss psychiatrist, was working with the Swiss Geigy company to develop a drug for schizophrenia, based on the recent success of the first modern antipsychotic, chlorpromazine. When he administered a new compound related to chlorpromazine to his schizophrenic patients, it was without benefit. Before throwing in the towel, something led Kuhn to try one more thing, giving to a very depressed patient. She and two subsequent patients got better, relapsed when the medicine was stopped, and got better again when it was re-started. Ultimately this compound was named imipramine and was the first of the tricyclic antidepressants.

There may be a tendency to think of drugs as being developed by white-coated scientists rationally combining molecules in the isolation of their laboratories. As we’ve seen here, in the early years, the story was often more complicated, involving mixtures of chemistry, careful observation of patients, perseverance, and a bit of luck. By the 1980s, the development of the selective serotonin reuptake inhibitors reflected the advent of ‘rational psychopharmacology’. For the first time, antidepressants were created by a systematic method which, while less prone to colorful stories, produced drugs based on an understanding of their molecular actions at biological targets such as receptors and reuptake pumps. In ‘Understanding Antidepressants’ we will see how these newer drugs came about, and look at their benefits, limitations, and alternatives.

About the Author:

Wallace B. Mendelson is a Professor of Psychiatry and Clinical Pharmacology, Distinguished Fellow of the American Psychiatric Association, and author of Understanding Antidepressants.

In Understanding Antidepressants, Dr. Mendelson makes sense of the many treatments for depression and shows that understanding how antidepressants work can help in making better decisions. Written with both scientific rigor and compassion, Understanding Antidepressants is a useful guide for anyone suffering from depression, as well as their families.

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