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Guest Editorial

Half a Century of Drugs On the Clinical Introduction of Monoamine Oxidase Inhibitors, , and . 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 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 and .2 These compounds, together with other antidepressants, revolutionized the approach to the treatment of depression. Until the clinical introduction of selective 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 antidepressants began in 1883, with the synthesis of a first . 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 remedies. Domenjoz encouraged his staff members to explore the effects of , for which no application had been found. He hoped that they could be used as suitable . 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 , 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

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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 . 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 had made a breakthrough while exploring a IMIPRAMINE phenothiazine named () 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[ 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 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 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 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 by modifying showed marked improvement in their general the chemical structure of imipramine,7 of course with the aim condition within just a few weeks. Consequently, 37 other of creating an antipsychotic. The diamine side chain became depressive patients were put on this substance. It became a monoamine structure. Merck assigned Frank Ayd Jr. to clear that it was especially effective in vital depressive mood carry out clinical research. He had become famous as one disorder.7,10 Within 1 year, the results were published in the of the US pioneers in thorazine testing in 1952 and Swiss Journal Schweizerische Medizinische Wochenschrift on later—in 1962 to 1965—curiously figured as host of the the occasion of the second world congress of psychiatry in series BReligion and Science[ on radio Vatican. He was Zurich in September 1957.2 honored as one of the most profiled biological psychiatrists The reports were received with skepticism. One con- of his time. At Baltimore Square Hospital, he treated 130 clusion drawn from the numerous pharmaceutical conventions patients with the new substance amitriptyline and reported between 1953 and 1958 claimed that there could presumably an effect comparable to imipramine. On April 7, 1961, never be a genuinely effective antidepressant substance amitriptyline—brand name BElavil[—was approved by the

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Food and Drug Administration (FDA) to enter the US market conducted a pilot study with 10 schizophrenic patients as an antidepressant. Pharmaceutical companies Roche and receiving . It quickly became evident that somewhat later had also manufactured amitriptyline clomipramine worked mainly as an antidepressant.4 Never- by imipramine modification. Due to the higher priority of their theless, Geigy decided that it made little sense to have an request, Roche received the European marketing rights for additional tricyclic antidepressant on the market in an oral BSaroten.[14 application form. Moreover, during the 1960s, the important Further tricyclic antidepressants were rapidly developed US American market was barred. After the 1962 thalidomide because many acknowledged scientists were involved in the disaster, the FDA implemented higher standards for clinical process. For example, a broad basic research program was studies with regard to efficacy and tolerability. In the face of coordinated by Professor Bernard Brodie, who was born in the FDA’s restrictive approval standards, Geigy remained Liverpool in 1907 and had become head of the Department of doubtful whether the costs of extensive randomized con- Pharmacology at the National Institutes of Health in trolled clinical studies with clomipramine would be worth the Bethesda, MD, and winner of the Lasker Award in 1967. In money. Clomipramine had quite certain tremendous advan- 1960 and 1961, he carried out clinical studies on the effect of tages in the view of many European clinicians, especially a desmethyl derivative of imipramine (), which with respect to the possibility of intravenous application. In was considered to be the effective metabolite of imipr- 1967, Geigy Company Great Britain recognized the favor- .15 Desipramine was brought out with convincing data able effects on panic and obsessive-compulsive disorder in these studies in several centers in Switzerland and (OCD) in some French and Spanish studies. The results Germany. It became Geigy’s second antidepressant drug on were reproduced in several further studies.19 This was the the market and was ultimately approved by the Federal Drug basis for clomipramine approval for treatment of depres- Administration, for treatment of depressive disorders in the sion and obsessive-compulsive symptoms in Great Britain United States in 1964. in 1975. In 1990, it was also approved in the United A whole series of tricyclic antidepressants was devel- States by the FDA for OCD. Since this time, OCD treat- oped in these years. In 1963, was approved in ment has not been limited only to psychotherapy but Great Britain as BAllegron[ and in the United States by the also includes pharmacology with the ingestion of an effec- FDA in November 1964. By the end of 1965, M.M. tive drug.4,19,20 Salzmann and B.H. Burns reported their first clinical experiences with ,16,17 which was introduced in TETRACYCLIC ANTIDEPRESSANTS 1966 in Great Britain and other European countries under the In the 1960s, many modifications of the name BSurmontil.[ FDA approval in the United States structure of imipramine were manufactured in order to get ultimately followed in June of 1979. The introduction of new antidepressants. Aside from the 6-7-6-tricyclic antide- further tricyclic antidepressants followed: 1966 pressants with a Bclassical[ side chain (imipramine, clomipr- as BConcordin,[ in the United States BVivactil[;1967 amine, amitriptyline, trimipramine, dothiepin, , etc) as BProndol[; and 1969 dothiepin as BProthiaden,[ mentioned above, pharmaceutical companies developed 6-7- not approved in the United States, and doxepine. 6-tricyclics with modified Btypically located[ side chains Doxepine did not emerge through Btrial and error[ but as (opipramole, , ) and side chains at a result of a theory-based development. In 1962, derivatives of 10,11-bridge (dibenzepine, , ), 6-6-6- dibenzoxepine were given to Kurt Stach working for the tricyclics (fluotracene, , melitracene), and one pharmaceutical company Boehringer. Considering the 3- 6-5-8-tricyclic (iprindole). The clinical relevance of those dimensional structure, Stach and his Austrian colleague Walter substances remained meager, however. Except for opipra- Po¨ldinger proposed doxepine to have antidepressant proper- mole, only 6-7-6-tricyclic antidepressants with classical side ties. Simultaneously, the pharmaceutical company Pfizer chain became frequently used drugs.4 developed the substance doxepine in the United States. Up There was a very close investigation on the dependence until 1966, clinical studies were conducted at 19 German and of drug efficacy from core, constitution, and configuration of Swiss hospital sites, ultimately leading to the introduction of side chain and basic center. These experiences led to the doxepine, BAponal,[ by the Boehringer affiliate Galenus onto creation of a Bsecond generation of antidepressants.[4 In the European market. In the United States, Pfizer received the 1967, Max Wilhelm und Paul Schmidt, chemists at Swiss approval for the brand name BSinequan.[18 Due to out- pharmaceutical company Ciba, developed . Clin- standing sedative properties and comparatively good toler- ical research was performed once again by Roland Kuhn. ability, doxepine found broad acceptance, particularly for After the observation of 320 patients, he considered maproti- severe depressive episodes with suicidal ideations. line to be a good, specific antidepressant. Finally, in 1972, the The clinical introduction of other substances lasted year of the merger with Geigy, Ciba launched maprotiline longer. Although already developed in 1958, clomipramine onto the European and Japanese markets, where it became a was introduced in Europe no earlier than 1975 and was not tremendous commercial success.4 A few years later, a second approved in the United States. Today, it is widely known tetracyclic antidepressant, , was introduced; how- under the brand name BAnafranil.[ At that time, clomipr- ever, mianserin turned out to increase therapeutic possibilities amine was already accepted as a potent thymoleptic agent by only marginally. It was used in depression of the elderly due many psychiatrists. Walter Po¨ldinger, head of the department to its low effects and for the relief and of psychiatry at the University of Basel, Switzerland, modulation of pain.

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TRICYCLICS AT THE PRESENT TIME inhibitors, tricyclics, and tetracyclics. Part I: Monoamine oxidase inhibitors. J Clin Psychopharmacol. 2007;27:555–559. As a consequence of the Prozac euphoria in the 1990s, 2. Harrer G. Die Antidepressiva-A¨ ra und die Zeit davor. In: Linde OK, ed. a variety of new substances was introduced with differing Pharmakopsychiatrie im Wandel der Zeit. Klingenmu¨nster: Tilia-Verlag; mechanisms of action. Nevertheless, tricyclic antidepressants 1988;217–225. still remain broadly used at the beginning of the 21st century. 3. Mo¨ller HJ, Volz HP. Drug treatment of depression in the 1990s. An In the list of the most frequently prescribed drugs in the overview of achievements and future possibilities. Drugs. 1996;52: 625–638. United States, published by the FDA, amitriptyline was 4. Healy D. The Antidepressant Era. Cambridge, MA: Harvard University placed at position 54 in 1995 and, in 2002, had even climbed Press; 1997. to position 40, ahead of the best non–SSRI-antidepressant 5. Kipnis A. Kurzbiographien deutscher Wissenschaftler. Bernthsen A. . Also, nortriptyline was recorded in the top 200 Available at: http://www.kipnis.de/. Accessed October 19, 2006. 21 6. Schindler W, Ha¨fliger F. Derivate des Iminodibenzyl. Helv Chim Acta. list and, in 2002, ranked at position 186. The reason for 1954;37:427. amitriptyline to be a top seller was the good clinical 7. Kuhn R. The imipramine story. In: Ayd F, Blackwell B, eds. Discoveries experiences, which had enlarged the scope of tricyclic in Biological Psychiatry. Philadelphia: JB Lippincott; 1970:205–217. antidepressants. Clomipramine is still a proven therapy for 8. Shorter E. A history of psychiatry. From the Era of the Asylum to the Age treatment of fear and OCD. Because of the sedative profile of of Prozac. New York: Wiley & Sons; 1997. 9. Healy D. Obituary: Roland Kuhn (1912–2005). Hist Psychiatry. 2006; trimipramine at low dosage, its lack of addictive properties, 17:253–255. and its moderate side effects, it is still used as a sedative. 10. Kuhn R. U¨ ber die Behandlung depressiver Zusta¨nde mit einem Doxepine is administered for relief of uneasiness and Iminodibenzylderivat (G 22355). Schweiz Med Wochenschr 1957;87: restlessness, especially in opiate withdrawal syndromes. As 1135–1140. 11. Kuhn R. The treatment of depressive states with G 22355 (imipramine for amitriptyline, its efficacy on pain syndromes led to an hydrochloride). Am J Psychiatry. 1958;115:459–464. increasing application in the emerging field of pain therapy. 12. Domenjoz R, Theobald W. Zur Pharmakologie des Tofranil (N-3- In 2001, Corrado Barbui and Matthew Hotopf from dimethylaminopropyl-iminodibenzylhydrochlorid). Arch Int Pharmako- London conducted a large meta-analysis with all available dyn Ther. 1959;CXX:450–489. randomized controlled studies concerning the efficacy and 13. Lehmann HE, Cahn CH, De Verteuil RL. The treatment of depressive conditions with imipramine (G 22355). Can Psychiatr Assoc J. 1958;3: tolerability of amitriptyline and other tricyclic antidepressants 155–164. compared with those of SSRIs, then publishing their data in a 14. Lassen N. Die Geschichte der . In: Linde OK, ed. broadly acknowledged review. Amitriptyline and, to some Pharmakopsychiatrie im Wandel der Zeit. Klingenmu¨nster: Tilia-Verlag, extent, the internationally less used dothiepin had at least 1988:170–183. 15. Brodie BB, Bickel MH, Sulser F. Desmethylimipramine, a new type of similar efficacy compared to SSRIs, but tolerability was antidepressant drug. Med Exp. 1961;5:454–458. slightly worse. Barbui and Hotopf even concluded to choose 16. Burns BH. Preliminary evaluation of a new antidepressant, trimipramine, amitriptyline as their first choice ahead of SSRIs.22 As was to by a sequential method. Br J Psychiatry. 1965;111:1155–1157. be expected, a controversial discussion followed, and today, 17. Salzmann MM. A controlled trial with trimipramine, a new antidepres- there is still no consensus on first-choice therapy regarding sant drug. Br J Psychiatry. 1965;111:1105–1106. 18. Po¨ldinger W. Die Geschichte des Doxepin. In: Linde OK, ed. efficacy, safety, tolerability, and financial aspects of the Pharmakopsychiatrie im Wandel der Zeit. Klingenmu¨nster: Tilia-Verlag; various pharmacological compounds. Nevertheless, antide- 1988:266–270. pressants are enriching our therapeutic spectrum of treatment 19. Beaumont G, Healy D. The place of clomipramine in the development of options. psychopharmacology. J Psychopharmacol. 1993;7:383–393. 20. Owens D, House A. Declarations of interest. Br J Psychiatry. 2001; 179:175. 21. RxList. Available at: http://www.rxlist.com. Accessed August 30, 2007. REFERENCES 22. Barbui C, Hotopf M. Amitriptyline vs. the rest: still leading antidepres- 1. Lo´pez-Mun˜oz F, A´ lamo C, Juckel G, et al. Half a century of sant after 40 years of randomised controlled trials. Br J Psychiatry. 2001; antidepressant drugs: on the clinical introduction of monoamine oxidase 178:129–144.

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