Guest Editorial Half a Century of Antidepressant Drugs On the Clinical Introduction of Monoamine Oxidase Inhibitors, Tricyclics, and Tetracyclics. Part II: Tricyclics and Tetracyclics Peter Fangmann, MD,* Hans-Jo¨rg Assion, MD, PhD,* Georg Juckel, MD, PhD,* Cecilio A´lamo Gonza´lez, MD, PhD,y and Francisco Lo´pez-Mun˜oz, MD, PhDy FIVE DECADES OF ANTIDEPRESSANTS The 50th anniversary of antidepressive pharmacotherapy is worth commemorating.1 In 2 parts, we review the onset of drug treatment with convincing antidepressive efficacy, and in this second part, we recap the development and clinical introduction of tricyclics and tetracyclics. In speaking with Gerhart Harrer, who reviewed his own experience, he said, BThe introduction of antidepressants meant an enrichment for doctor’s therapeutic possibilities which matched a Quantum leap.[ A whole generation of psychiatrists felt the same way, remembering the improvements after the introduction of imipramine and iproniazid.2 These compounds, together with other tricyclic antidepressants, revolutionized the approach to the treatment of depression. Until the clinical introduction of selective serotonin reuptake inhibitor at the beginning of the 1990s, tricyclic antidepressants were the Bgold standard[ in drug treatment of depression.3 Progress has been achieved during the last 2 decades, with new reuptake inhibitors on the market, new methodologies for data analysis, and new principles of action. This second part focuses on the historical background of tricyclics and tetracyclics. FROM BENZYLCYANID TO G 22355 The history of tricyclic and tetracyclic antidepressants began in 1883, with the synthesis of a first phenothiazine. Professor Heinrich August Bernthsen, a Bsumma cum laude[ doctor of philosophy who graduated with his works BAbout Some Derivatives of Benzylcyanid[ and BAbout Urea and Derivatives of the Same,[ was then a 28-year-old laboratory director of BBadische Anilin und Sodafabriken[ in Mannheim, Germany. He was given the assignment of experimenting with chemical dyes, particularly methylenblue elements.4,5 In 1883, Professor Bernthsen synthesized the first phenothiazine. In 1898, J. Thiele and O. Holzinger manufactured iminodibenzyle, for which no significant use was found in the cloth-dying industry at that time. Thus, it ended up in a warehouse in Basel and, to some extent, went Binto oblivion,[ hidden away in the 240-year-old JR Geigy company.4 Fifty years later, the director of the pharmacological section at Geigy, Robert Domenjoz, who later became head of the pharmacological institute of the University of Bonn, was impressed by the success of Parisian company Rhone-Poulenc. Rhone-Poulenc developed some antihistaminics in close cooperation with the Pasteur Institute, which promised to become a commercial success as sleep or sedative remedies. Domenjoz encouraged his staff members to explore the effects of phenothiazines, for which no application had been found. He hoped that they could be used as suitable sedatives. In 1948, Geigy chemists F. Ha¨fliger and W. Schindler used iminodibenzyle as a basis for the synthesis of altogether 42 derivatives.4,6 After some animal and human self-experimentation, interested hospitals were then contacted to do clinical research; at that time, there were almost no bureaucratic restraints for such studies. *LWL-Klinik Bochum, Department of Psychiatry, Psychotherapy, Psychosomatic and Preventive Medicine, Ruhr-University Bochum, Bochum, Germany and yNeuropsychopharmacology Unit, Department of Pharmacology, Faculty of Medicine, University of Alcala´, Madrid, Spain. Address correspondence and reprint requests to Hans-Jo¨rg Assion, MD, PhD, LWL-Klinik Bochum, Department of Psychiatry, Psychotherapy, Psychosomatic and Preventive Medicine, Ruhr-University Bochum, Alexandrinenstr. 1, 44791 Bochum, Germany. E-mail: [email protected]. Copyright * 2008 by Lippincott Williams & Wilkins ISSN: 0271-0749/08/2801-0001 DOI: 10.1097/jcp.0b013e3181627b60 Journal of Clinical Psychopharmacology Volume 28, Number 1, February 2008 1 Copyright @ Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Guest Editorial Journal of Clinical Psychopharmacology Volume 28, Number 1, February 2008 One of these substances—internally known as G 22150—was achieving more than simply reducing symptoms of depression. given to Dr Roland Kuhn, a 38-year-old assistant medical The widespread hypothesis stated that depression itself director at the BThurgauische Heil- und Pflegeanstalt[ in emerged from intrapsychological conditions and conflicts Mu¨nsterlingen, with the purpose of answering the question as (eg, object loss). How could a single pill do more than cover to whether it would be suitable as a hypnotic. The preparation up symptoms? Despite this conviction of experts, Geigy was Bdismissed as a sleeping pill,[ but had Ba somewhat introduced the new compound onto the domestic market under peculiar positive effect.[7 However, further scientific research the brand name Tofranil at the end of 1957. It was brought and interest for this substance was put to rest. onto the European market at the beginning of 1958.4 Then, in 1952, the word spread that Pierre Deniker and Jean Delay had made a breakthrough while exploring a IMIPRAMINE phenothiazine named chlorpromazine (thioridazine) at the It was in Rome in September 1958 at the newly founded University Hospital of Saint-Anne, Paris. Thirty-eight psy- Collegium Internationale Neuro-Psychopharmacologicum chotic patients had shown spectacular improvements. At the (CINP) that a broader psychiatric public was made aware of same time in Switzerland, the Brauwolfia alkaloid[ reserpine the astonishing pharmacological effects and achievements, obviously also attained good results in the treatment of curiously enough not through Kuhn himself. More was to psychotic patients. This intensified the search for similar come in that same year when 2 publications appeared in the substances. Of course, one motive was simply not to leave the American Journal of Psychiatry. One of them followed a market open to Rhone-Poulenc. As mentioned above, some lecture by Roland Kuhn at the Galesburg State Hospital in hitherto useless antihistaminics were found in the reserves of May 1958. This lecture was published in the November Geigy company. New hope emerged that they could perhaps edition of the American Journal of Psychiatry.11 It did not be given to psychiatric patients.4,7,8 contain anything new, but it provoked a magnitude of In those years, it was a generally accepted doctrine that international excitement. Kuhn comprehensively described depression had its main source in psychodynamic processes, the effects and side effects of imipramine gave recommen- despite the fact that the therapeutic effects of electrocon- dations for indication, dosage, and duration of treatment. His vulsive therapy were obvious. The thesis consequentially observations were later confirmed in larger studies, which evolved that drugs might have effects on mood symptoms mostly supported his estimates.7 After the publication data but, ultimately, could not change the course of illness itself. base from the year 1959, more than 60 publications were Roland Kuhn was scientifically engaged predominantly with brought out concerning trials on the efficacy and side effects philosophical and psychoanalytical questions.9 However, he of imipramine on various groups of patients.12 Particularly, also must be counted as one of the pioneers of the new psychiatrists from Italy, France, and Canada were very open generation of Bbiological psychiatrists,[ especially due to the to use new types of treatment. Positive results were also fact that in 1954, he contacted Geigy (or Geigy contacted him reported from Russia, Poland, Sweden, and South Africa. according to other reports) with the request to explore the It was once again Heinz Lehmann who propagated the possible antipsychotic effects of substance G 22150. tremendous efficacy of imipramine on the North American Although the following clinical studies had to be interrupted market on the basis of a study on 48 patients with because of intolerable side effects,6,7 he asked Geigy for depression.13 At the Zurich congress in 1957, he heard of another phenothiazine in the hope of coming up with a potent Kuhn’s observations and immediately began treating Cana- antipsychotic for his patients without burdening the small dian patient groups.4 The fact that the internationally cash reserves of Mu¨nsterlingen Hospital. At the beginning of acknowledged expert Lehmann favored imipramine was 1956, a preparation called G 22355 was made available to tremendously important for its worldwide acceptance. Kuhn, a substance with the same side chain as chlorproma- zine. It had been manufactured by Ha¨fliger and Schindler in 1948 from promethazine by replacing the sulfate bridge of TRICYCLIC ANTIDEPRESSANTS phenothiazine with an ethylene bridge.2 Broad clinical Despite the remarkable success, it took until the year research at BKantonsspital Mu¨nsterlingen[ near Basel soon 1961 before a second tricyclic antidepressant was introduced. revealed that this substance had no considerable neuroleptic Three years earlier, staff members of the pharmaceutical potency. However, 3 patients diagnosed with depressive company Merck had developed amitriptyline by modifying psychosis showed marked improvement in their general the chemical structure of imipramine,7 of course with the aim condition within just a few weeks. Consequently,