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A History of Antidepressants: The Tricyclics

Part II: The search for a new anti-psychotic leads to imipramine.

After my previous post on the discovery of MAO inhibitors, the first type of antidepressant developed, I had several queries about tricyclic antidepressants, another type that was released at about the same time. Their saga isn’t as colorful, in that it didn’t start with rocket fuel, but it’s interesting in its own way, as tricyclics were stumbled upon while looking for a new anti-psychotic; in turn, a later search for new antidepressants led to the truly accidental discovery of the anti-psychotic clozapine, bringing the story full circle.

In the early 1950s, when there was a great deal of interest in antihistamines and chlorpromazine, scientists at the Swiss pharmaceutical house Geigy were exploring chemical variations on the chlorpromazine molecule for possible use as a sedative or anesthetic. One of them, named G22150, was given for testing to doctors including Roland Kuhn (1912-2005), a psychodynamically trained psychiatrist working at a facility in Münsterlingen, an obscure village in Switzerland near the border with southern Germany. The drug appeared to have little sedative properties, and the matter was not pursued further. In the next few years, with the new recognition of chlorpromazine’s utility in schizophrenia, the hospital used it enthusiastically but was limited by its expense. As an alternative, Kuhn approached Geigy for more G22150 or for any new medicines they might have for psychoses. As it happened, due to the success of chlorpromazine, Geigy had renewed interest in the area and sent a related compound, G22355 (later named imipramine), to Kuhn and other psychiatrists. It was their compound closest in chemical design to chlorpromazine, with both having variations on three ring-like structures with a side chain.

Psychiatrische Dienste Thurgau/Wikimedia Commons, Public doman
Münsterlingen Psychiatric Clinic, 2016
Source: Psychiatrische Dienste Thurgau/Wikimedia Commons, Public doman

Imipramine turned out to be largely unsuccessful in schizophrenics. Kuhn may have been more sensitive to the need for treating depression, perhaps because of the population he was seeing. It had also been noted that some patients had become euphoric, and there had been improvement in some psychotic patients who also had depressive features. Whether for these reasons or desiring a sense of completeness, Kuhn—who had been tasked with testing it in psychoses—tried it in depression. In 1956, he described a severely depressed woman who, after six days of treatment, seemed remarkably better. Encouraged, he repeated this experience in two more patients, all of whom became depressed again when the medicine was stopped and improved when it was re-started.

In 1957, he published a report on a larger group in a Swiss medical journal and presented his findings at an international psychiatry meeting, both of which were met with little interest. It was a challenge in that there wasn't even a generally accepted name for this type of medicine. The word "antidepressant" wasn't in general use yet, and Kuhn called it a "thymoleptic." Undaunted, a year later he gave a lecture at Galesburg State Hospital in Illinois and published it in the American Journal of Psychiatry. Some have likened it to the Gettysburg Address, not fully appreciated at the time, but later understood to be a landmark event.

Ultimately, interest grew, and the drug, named imipramine (Tofranil), which had been released in Switzerland in 1957, was marketed as an antidepressant in the U.S. in 1959. Soon, related compounds were developed as well. Since the mechanism by which they worked was unknown at the time, they were named after their chemical, three ring-like structures with a side chain. It wasn’t until the 1960s that it was recognized that, among their actions, they raise brain norepinephrine and serotonin levels by blocking their re-uptake, leading to the biogenic amine hypothesis of depression.

The tricyclics became the most popular medicines for depression, with the perceived advantage of fewer side effects than the MAO inhibitors, as well as not needing a specialized diet required when taking MAOIs. As years went by, there was growing recognition of concerns in their use, including anticholinergic effects (blurred vision, dry mouth, rapid heartbeat, difficulty urinating), as well as very significant toxicity in overdose. Ultimately, tricyclic overdose became one of the most common reasons for admissions to medical intensive care units. They remain in use today, though at a much lower amount, since the development of the SSRIs and subsequent antidepressants in the 1980s.

In looking back, Kuhn’s finding was all the more remarkable, in that his background was very different, and had focused primarily on Rorschach inkblot tests and Daseinanalysis, an existentialist-oriented form of psychoanalysis. There was skepticism in those years that even in principle depression could be cured by a drug. Depression was thought to have its genesis in a loss, and how, it was asked, could a drug replace a loss? Some have speculated that one reason Kuhn tried G22355 in depression was that the population in Münsterlingen differed from that of most hospitals in its day, which were oriented to the psychoses; in contrast, Münsterlingen had a busy outpatient clinic as well, and hence large numbers of persons with depression, for whom he was responsible. At that time, the major forms of therapy were opiates and various forms of shock therapy. It is striking that his background and theoretical orientation did not blind him to being open to a new medicine.

This brings us to the story of clozapine. Spurred by the success of imipramine, in the late 1950s, pharmaceutical houses began looking for new tricyclic antidepressants. While making modifications to the imipramine molecule in 1958, the Swiss company Wander AG (also the maker of Ovaltine) discovered a group of compounds called "neuroleptic tricyclics." One of them, clozapine, stood out in that, in addition to having properties similar to chlorpromazine, it caused less decrease in motor activity, as well as more resistance to pain in animal studies. These two qualities heavily influenced the decision to pursue clozapine as a possible treatment for schizophrenia.

Later, though, it turned out that the pain data were incorrect, a consequence of electrodes short-circuited by saliva. Although its ultimate acceptance was hampered by a side effect involving alterations in white blood cells, it was ultimately approved with a set of safety precautions by the FDA in 1989, and it remains one of the most effective medicines for patients who have not responded to other antipsychotics. But the original decision to pursue studying it came about partly as a result of a peculiar malfunction in the testing equipment. So the search for an antipsychotic led to an antidepressant, and the search for an antidepressant led—by accident—to an anti-psychotic.

This blog was excerpted and adapted from The Curious History of Medicines in Psychiatry.


Mendelson, W.B.: The Curious History of Medicines in Psychiatry. Pythagoras Press, 2020.

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