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Tuesday, 26.05.2020

Pierre Baumann and Francois Ferrero: An official inquiry of the clinical research activities (1946-1972) of Roland Kuhn (1912-2005)  

Pierre Baumann and François Ferrero: The Report of the Official Commission

 

         In the history of psychopharmacology, Swiss psychiatrist Roland Kuhn (1912-2005) is often credited with the discovery of the antidepressant effect of imipramine (G 22355) in patients suffering from depression, although there is controversy with this claim (Ban, Healy and Shorter 2002). In 1939, Roland Kuhn started to work at the psychiatric hospital Münsterlingen (Canton of Thurgau, Switzerland), which he would later go on to direct between 1970 and 1979. Between 1946 and 1980, he carried out clinical and research activities in the field of psychopharmacology (psychopharmacotherapy as it was known in this hospital) in very close collaboration with pharmaceutical companies such as Geigy, Ciba and others, under the agreement of the political authorities of Thurgau.  Ciba and Geigy merged to Ciba-Geigy in 1970 and in 1996, with the subsequent merger with Sandoz, created the present day Novartis.

         Recently, we reported that between 2013 and 2015 several Swiss newspapers published complaints of nurses and patients which both highlighted the desolate medical conditions and poor treatment infrastructure at the hospital Münsterlingen, but also the fact that patients were medicated with new experimental drugs without their consent and sometimes against their will (Baumann and Ferrero 2016).

         In 2015 public reaction to these allegations prompted the political authorities of the Canton Thurgau to initiate an investigation “with the aim to carry out a scientific investigation about the research undertaken in this hospital during the period between1950-1970 and to evaluate the individual responsibility of Roland Kuhn, the authorities, as well as the pharmaceutical companies involved.” A report of the historical Commission was presented on September 23, 2019, and the final report was presented as a book, Testfall Münsterlingen (Test Case Münsterlingen) (Meier, König and Tornay 2019). It is important to note that both this book as well as the summary which was published on-line by the University of Zurich are only available in German. (An English translation would be beneficial in order to allow a worldwide discussion on the matter.) Regrettably, this report was also presented two weeks after the annual congress of the Swiss Society of Psychiatry and Psychotherapy and thus could not be discussed in that platform. Therefore, the aim of this short contribution is to give an English summary of these two documents, along with some preliminary comments.

         The research team created should have comprised eight members working in Switzerland, including the chief archivist of the Canton, professors of clinical pharmacology, psychiatry, history and private and economic law, the president of the Ethical Committee and two other representatives of the Canton Thurgau (Baumann and Ferrero 2016). However, in the final report, only professor M. Meier and Dr. M. König (both historians with experience in the field of history of psychiatry) and M. Tornay (historian in the field of economy, who died in 2018) were listed as authors. However, a long list of specialists in pharmacology, history, psychiatry, chemistry, law, archival science, etc., who contributed to this investigation as consultants were acknowledged.

         This research is based on witnesses, countless documents from the archives of the hospital Münsterlingen, pharmaceutical manufacturers and of the federal drug administration of Switzerland (Interkantonale Kontrollstelle für Heilmittel, today known as Swissmedic), as well as the private archives of Roland Kuhn (which was so large it was 45 meters in length). Altogether, these and other sources revealed that investigations of the utility of a “drug” or compound were carried out with about 120 pharmaceutical substances. Proofs of clinical studies performed were found for 67 pharmaceutical substances. Documents only exist for the administration of these substances to about 1,100 patients as identified by their names, but Kuhn mentioned that 3,000 patients were included. The exact number of patients could not be determined, but it is known that between 1946 and 1980, at least 3 million single drug doses were sent to the 700-bed hospital Münsterlingen by the pharmaceutical companies. Some of the drugs were administered for very short treatments in a few patients or for longer treatments in more than 1,000 patients. The administration of these substances included not only the psychiatric hospital Münsterlingen and the already mentioned pharmaceutical companies, but also a wide network of inpatients and outpatients and their practitioners from many other hospitals, institutions and offices. The patients were not selected according to gender or social status. Children and adolescents from orphanages or other institutions were also included. However, chronic and severely ill patients were preferentially recruited by Kuhn to test new compounds. 

         Clearly, the standards of research in the ‘40s and ‘50s are not those that we have today. However, Kuhn proceeded according to an exploratory approach, in contradiction with the progressive development of systematic and scientific procedures. Kuhn was aware at the time of his research that double-blind studies against placebo were generally recommended. An example being his presence and active participation at the 1957 World Congress of Psychiatry in Zurich, where he was vice-chairman at the session chaired by M. Gozzano (Rome, Italy) and titled “Ataraxies: phenothiazine, and others”. The proceedings of the congress show that Kuhn was the last (Kuhn and Faust, 1959) and the American W. Tuteur the first speaker (Tuteur, 1959). The latter presented data on megaphen and highlighted comprehensively the double-blind research methodology, including placebo-controlled studies.  

         Kuhn was highly interested and involved in Daseinsanalyse (analysis of Dasein) and claimed, like many other clinicians at the time, that he considered the patient as a whole and that a patient cannot be reduced to numbers, statistics and graphic presentations. The exploratory and unsystematic methodology used by Kuhn was welcomed by the pharmaceutical industry and the manufacturers allowed him to carry out long-term studies using his approach.  

         According to Kuhn, patients were continuously observed and monitored. This is likely impossible, because the size of the staff was insufficient to record all observations and to carry out the necessary exams. Over the course of his studies many incidents and even deaths were recorded; the report mentions that 36 patients died. Patients were very rarely informed about the nature of the substances they were taking and rarely participated voluntarily in a study. Kuhn seemed to have selectively informed only the ambulatory patients or those who had knowledge of psychiatry. He also rarely informed patients spontaneously, but rather the patients had to ask for the information. 

         The report (Meier, König and Tornay 2019) does not give many details about the knowledge base and the state of research about the compounds by the pharmaceutical companies before they were sent to Kuhn to trial on patients. There was no mention of toxicity studies in animals or status of Phase I clinical studies. Reportedly, for some compounds, Geigy forewent tolerance and safety studies and asked Kuhn, lauded as a “rapid investigator,” to carry out toxicological studies which were subsequently performed in chronic patients (again likely against their knowledge or consent). The report also states that many drugs were tested in a research and development setting where the substances were not tested for their therapeutic effects but rather for a better understanding of the relationship between their clinical effect and their chemical structures in order to aid in the development of future agents. 

         Kuhn was looking for international recognition, but he was also convinced that his recognition would come partly in the form of substantial financial support. During this period, he earned, by current standards, equivalent to approximately 8’000’000 SFr ($8.1 million US). Kuhn even argued that he did not perform these studies during his regular working time and that his institution, and therefore the Canton, saved costs as the medications were freely provided by the pharmaceutical companies.

         The full list of compounds tested is hard to decipher. The classes of drugs which were tested in Münsterlingen were, of course, imipramine but also many drugs with a similar structure. Just in 1956 alone, seven studies with Geigy compounds and one with a Ciba-produced compound were being conducted in Münsterlingen. Ketopramine was probably the most examined compound, but it was never commercialized. Tablets of some drugs were designated “red,” “white,” “green,” etc., according to their colors. Kuhn even asked the manufacturer to stain the tablets of a new drug with the same color as those of a previously tested substance in order to improve compliance of the patients who could have been reluctant to switch to another drug. If “necessary,” in patients who were hesitating to ingest medication, drugs were added to drinks.

         The present authors of this report on the investigation of Meier, König and Tornay (2019) apologized for its only partial description, but it is urgent that the international scientific and medical community is rapidly informed about the research carried out by Roland Kuhn between 1940 and 1980 in Münsterlingen, with the complicity of several Swiss pharmaceutical manufacturers. It should be added that the Swiss political authorities admit their errors of the past and have stated plans to build a memorial to those patients, although no plans for the memorial have yet to be presented.

         Acknowledgement: We thank Dr Yawei (Jenny) Yang for her help in reviewing and editing the manuscript

 

References:

Ban TA, Healy D, Shorter E, editors. The Imipramine Dossier. In: From Psychopharmacology to Neuropsychopharmacology in the 1980s and the Story of CINP as Told in Autobiography. Budapest: Animula; 2002, pp. 281-352.

Baumann P, Ferrero F. The Imipramine Controversy: An Official Inquiry on the Clinical Research Activities (1946 – 1972) of Roland Kuhn (1912 – 2005). Preliminary notes. inhn.org.controversies. February 11, 2016.

Kuhn W and Faust C. Zur Megaphenfrage in den Vereinigten Staaten von Amerika mit besonderer Berücksichtigung der Nachbehandlung entlassener Geisteskranker. In: W.A. Stoll, editor. IInd International Congress for Psychiatry, Zurich (Switzerland), September 1st to 7th 1957, Congress Report, volume 2, Zurich: Orell Füssli; 1959, p 422.

Meier M, König M, Tornay M. Testfall Münsterlingen. Klinische Versuche in der Psychiatrie, 1940 – 1980. Zurich: Chronos; 2019.

Tuteur W. Zur Megaphenfrage in den Vereinigten Staaten von Amerika mit besonderer Berücksichtigung der Nachbehandlung entlassener Geisteskranker. In: W.A. Stoll, editor. IInd International Congress for Psychiatry, Zurich (Switzerland), September 1st to 7th 1957, Congress Report, volume 2. Zurich:  Orell Füssli; 1959, pp 406-10.

 

 

December 26, 2019