Imipramine and the Tricyclic Antidepressants

   (from 1957)

   By the mid-1950s, a number of drugs had become available with some effectiveness in nonhospital depression, such as meprobamate (Carter-Wallace’s Miltown, launched in 1955) or the amphetamines (see ANTIDEPRESSANT: first-generation) and the amphetamine–barbiturate combinations. Yet, hospital depression remained untreatable except with electroconvulsive therapy. With the "tricyclic" antidepressants—so named because of their chemical structure—for the first time in history, serious depression acquired a pharmacotherapy of its own.

   The story begins: In 1899, chemist Johannes Thiele (1856–1918), at the time director of the organic division of the chemistry laboratory of the Bavarian Academy of Sciences in Munich, together with his associate Otto Holzinger, synthesized an iminodibenzyl nucleus: two benzene rings attached to each other by a nitrogen atom and an ethylene bridge; this was unlike the phenothiazine nucleus [see CHLORPROMAZINE], which had a sulfur bridge instead of ethylene. Their article appeared in 1899 in Justus Liebigs Annalen der Chemie. In the late 1940s, chemists from the Geigy pharmaceutical company in Basel synthesized a number of derivatives from this base in their search for new antihistamines. Roland Kuhn (1912–), a staff psychiatrist at the Münsterlingen asylum in Switzerland, had a long-standing arrangement with Geigy to undertake drug trials for them.

   In 1951, at a time of great interest in the potential of antihistamines as hypnotics, Kuhn had tested a Geigy compound (G 22150) that turned out to be a poor hypnotic but had some effect on schizophrenic psychoses. In 1954, he called this to the attention of the head of pharmacology at Geigy, Robert Domenjoz (1908–1998), asking Geigy in light of the recent success of chlorpromazine if the firm wished him to undertake a larger trial. He also asked what else they might have on the shelf. Later in 1954, Kuhn met Domenjoz in a hotel in Zurich, where Domenjoz spread out a chart with about 40 chemical formulas and asked Kuhn to choose one for testing. Kuhn chose G 22355.

   In the late autumn of 1954, Kuhn undertook trials of G 22355 at Münsterlingen. The drug turned out to be unimpressive in schizophrenia, but as Kuhn continued the trial, he started giving it to patients with "vital," or endogenous, depression. On the morning of January 18, 1956, one such patient, Paula I., who had been on G 22355 for 6 days, woke up cured of her depression. Said Kuhn later, "She reported this to Anna Keller, the nurse on her unit, who recognized the complete remission of her depression from the patient’s facial expression, her behavior and her total being" (Ban, Psychopharmacology, III, p. 303). Kuhn reported this to Geigy shortly thereafter: "It is possible that . . . G 22355 [has] better effects on depression than Largactil [chlorpromazine] and Serpasil [reserpine]. So far, this cannot be said for certain, however. Should this impression be confirmed, it would be of importance." Yet, the firm was largely uninterested and continued to press for trials in other clinics of G 22355 as a "neuroleptic" (antipsychotic) or possibly as a hypnotic.

   By April 1956, Kuhn was continuing the trials of G 22355 in depression and now was waving large signal flags at Geigy: "Since depression is not only one of the most frequently occurring mental illnesses, but one of the most frequently occurring illnesses in general, I see an immense potential here," he wrote to them. By April 1957, Geigy was sending G 22355 out to a wide network of trialists, but for trials in schizophrenia. Meanwhile, the Second World Congress of Psychiatry in Zurich was looming for the coming September 1957. Kuhn was asked to prepare a paper for it, to be published simultaneously in the August 31 issue of the Swiss Medical Weekly (Schweizer Medizinische Wochenschrift), and did so on his experiences with G 22355 in vital depression. On September 6, Kuhn read his paper to a half-empty room. (Kuhn said later it was probably a mistake not to have explained "vital depression," a concept of Kurt Schneider’s and not widely familiar outside of German-speaking Europe.) (See Depression: Emergence: vital . . . [1920].) Later that year, Geigy launched G 22355 in Switzerland as imipramine; brand name Tofranil.

   But nobody at Geigy really woke up to the fact that the company had a drug on its hands with the potential impact of penicillin until a year later, in September 1958 at the first International Congress of Neuropharmacology in Rome (the company had organized a symposium to which Kuhn was not invited), Kuhn ran into Robert Boehringer, one of the owners of Geigy. Said Kuhn later, "After I told him that on 16 February [1958] in Basel I had pointed out the significance of G 22355 for the treatment of depression, Robert Boehringer, who had a case of depression in his family, took some tablets of the drug to Geneva, where he resided. After he returned home a week later he found the patient recovered. He notified the direction of the firm, whereupon it was agreed to continue the cooperation with me."

   Geigy brought imipramine out in the American market in 1959. (They had patented it in 1951.) Heinz Lehmann at Verdun Protestant Hospital in Montreal did the first North American trials together with staff psychiatrists Charles Cahn (1921–) and Roger Louis De Verteuil (1919–ca. 1971), publishing the results in the October 1958 issue of the Canadian Psychiatric Association Journal. In 1965, in Pharmacological Reviews, Gerald L. Klerman and Jonathan O. Cole (1925–), under the auspices of the Psychophamacology Service Center of the National Institute of Mental Health, conducted a large review of the safety and effectiveness of imipramine, considering various head-to-head studies of the tricyclic antidepressants vs. electroconvulsive therapy vs. the MAOIs (see Iproniazid) and vs. chlorpromazine and other phenothiazines.

   The great success of imipramine prompted a host of other tricyclic antidepressants, some of which, together with their launch date in the American market, follow by year of patent:

   ♦ 1960: amitriptyline (Merck launched Elavil in 1961).

   ♦ 1962: desipramine (Geigy launched Pertofrane in 1965); this is one of the main active metabolites of imipramine.

   ♦ 1963: clomipramine (Ciba-Geigy* launched as Anafranil in the United States in 1990—earlier in other markets, with Switzerland and West Germany in 1968 being the first).

   ♦ 1965: doxepin (Pfizer launched as Sinequan in 1969).

   ♦ 1965: nortriptyline (Lilly launched as Aventyl in 1965); this is a major metabolite of amitriptyline.

   Although the many tricyclic antidepressants had varying side-effects, none was ever demonstrated superior in efficacy to imipramine, which remains today, despite the proliferation of many different drug classes of "antidepressants," the gold standard of antidepressant therapy.

   In his pioneering work, Kuhn scorned rating scales such as those of Max Hamilton and believed that only close clinical observation of patients, informed by a knowledge of psychopathology, would identify homogeneous groups of drug responders.