You are here: Controversies / Pierre Baumann and Francois Ferrero: An official inqury of the clinical research activities (1946-1972) of Roland Kuhn (1912-2005) / Barry Blackwell’s comment on Pierre Baumann and François Ferrero’s corrected report of the official commission
onsdag, 01-12-2021

Pierre Bauman and Francois Ferrero

An oficial inquiry of the clinical research activities (1946-1980) of Roland Kuhn (1912-2005)

 

Barry Blackwell’s comment on Pierre Baumann and François Ferrero’s corrected report of the official commission

 

Background

       Münsterlingen Psychiatric Hospital has a distinguished history beginning as a medieval monastery, converted to a 700-bed lunatic asylum and now a sophisticated multidisciplinary psychiatric institution. Located in the NE of the Swiss Canton Thurgau, south of Lake Constance, situated in rural and farming community, it serves a predominantly German-speaking population of about 250,000.

       In its early days it was home to both Hermann Rorschach, the neuro-diagnostician, and later to Otto Binswanger whose anthropological interests led to existential psychiatry.

       Roland Kuhn was born and studied medicine in Berne and Paris graduating on the eve of the Second World War. When the surgeon he hoped to train under retired he switched to psychiatry and trained under Jakob Klaesi who invented “sleep therapy.” He began working at Münsterlingen in 1939 and remained there his entire career, eventually serving as Medical Director from 1970 to 1980, and dying in 2005 at age 93.

       However, the modern drugs developed by Geigy, antihistamines derived from dye, did not begin to appear until the early 1950s when chlorpromazine, discovered by Delay and Deniker in France, was first reported effective in 38 patients with acute psychoses (Deniker 1970).  Word spread rapidly and asylums around the world began to use chlorpromazine, initiating “deinstitutionalization” and encouraging experimentation with other antihistamine analogues.

       Kuhn became actively involved in research that included a substance named analogue G 22355, with the same side chain as chlorpromazine. After testing it in about 300 cases, with mixed results, in early 1956 he tested it in 40 closely observed cases of “vital depression” with excellent “antidepressant” effects. This eventually attracted international attention and launched Kuhn’s career as a full time psychopharmacologist, deeply involved with manufacturers who appreciated his clinical and research skills.

       A recent publication in French (Basso 2017) with the provocative title, “Complications and Ambivalences of Psychiatry; Münsterlingen and the 1954 Feast of Foolsdescribes a visit by Michel Foucault to Münsterlingen to meet with Kuhn and Binswanger in March 1954 on the occasion of a carnival when patients left the asylum wearing masks they had made.

A Commission of Enquiry

       Baumann and Ferrero’s initial posting in early 2015 announced that Thurgau had launched a commission of enquiry into Kuhn’s research between 1946 and 1980 which included them as two clinical members of an eight-membered team. The inquiry was triggered by complaints from nurses and patients published in Swiss newspapers between 2013 and 2015. Baumann and Ferrero wished to involve INHN because of the “urgency that the international scientific and medical community be rapidly informed about the research conducted by Kuhn.”

      A few members of INHN responded (to be discussed later) but nothing substantive was accomplished because all the proceedings were conducted in German without any English translation. In addition, a four-year hiatus of the inquiry was  contributed to by a change in commission membership and strategy.

      A recent update revealed that the Commission had separated into a fact-finding research team composed only of four female historians and a post-graduate student who had now published their findings as a book, also in German, authored by three of the four historians. The inclusion of historians was justified because “the core of the work required historical methodology.” There was also now a “supervisory board” of eight (including Baumann and Ferraro) and six unnamed individuals. The input of this board to the book published by the research team is not identified.

       However, the latest document does include a brief synopsis in English which follows. Samples of that text are provided in italics.

The English translation synopsis (Baumann and Ferrero)

       “This research is based on witnesses, countless documents from archives of the hospital, pharmaceutical manufacturers and the FDA of Switzerland as well as private archives of Kuhn, 45 meters in length.  Investigations were carried out on about 160 pharmaceutical substances, about 1,100 patients identified by name although Kuhn mentioned 3,000 were included. The exact number of patients could not be determined but at least 3 million single drug doses were sent to the hospital. Some were very short treatments in a few patients and longer for 1,000 patients. In addition to Münsterlingen there was a wide network of patients from many other hospitals, Institutions and offices. Patients were not selected by gender or social status but children and adolescents were included. Chronic and severely ill patients were preferentially recruited to test new compounds.

       “Kuhn proceeded according to an explanatory approach in contradiction to systematic and scientific procedures. He was aware that double-blind, studies against placebo were generally recommended but he claimed, like many other clinicians at the time to consider the patient as a whole, not reduced to numbers, statistics and graphic presentations. This method, used by Kuhn, was welcomed by the industry that allowed him to carry out long-term studies using this approach. According to Kuhn, patients were continuously observed and monitored. This is likely impossible because the size of staff was insufficient to record all observations or carry out the necessary exams. 36 patients died. They were rarely informed of the substances they were taking and rarely participated voluntarily. Kuhn seemed to selectively inform ambulatory patients or those who had a knowledge of psychiatry. He rarely informed patients spontaneously, who had to ask.

       “The historical report does not give many details of toxicity or Phase 1 clinical studies. Reportedly, many compounds were sent to Kuhn as a “rapid investigator”  to carry out toxicological  studies in chronic patients (again likely against their knowledge or consent.)

       “Kuhn was also looking for international recognition partly in the form of substantial support. He earned, by current standards approximately the equivalent of $8.1 million over the 34 years. (1946-1980).

       “Kuhn even asked the manufacturer to provide a drug the same color as one previously tested in order to improve compliance of patients reluctant to switch to another drug. Patients reluctant to ingest medication had drugs added to their drinks.”

      The synopsis ends by stressing the urgency that the international scientific and medical community be rapidly informed about the research carried out by Kuhn, adding that the Swiss political authorities admit their errors and have plans to build a memorial to his patients.

Editorial Comment

       In the four years between Baumann & Ferraro’s first and second postings there were few comments. Edward Shorter distinguished between two methods of establishing clinical integrity. First was the traditional, personified by the Hippocratic Oath “to do no harm,” so that integrity and safety were intrinsic to the physician role. Applied in routine practice this was sometimes experienced as “patriarchal.”

       This contrasted with the “statistical model,” established by federal regulatory agencies and with standards that evolved from the Nuremburg Code developed during the 1945-47 trials of  German physician behaviors in concentration camps during the Second World War and subsequently modified by the Declaration of Helsinki in 1964 (with seven modifications).

       The statistical model of well-controlled double-blind, placebo comparison studies was subject to significant commercial manipulation (Blackwell 2017).

       Shorter’s conclusion, backed by his international reputation as an historian, was that “one cannot reproach these physicians for not having applied ethical standards that would be discovered 20 or 30 years later. The Münsterlingen episode was “a perfect example of retrospective application of today’s standards to an earlier and difficult time.” As such, it was “self-righteous hand wringing.”

       Don Klein endorsed Shorter’s opinion emphasizing it was “skilled systematic clinical observation” of the kind practiced by Kuhn that led to valid discovery  He expressed hope that the historians should “openly declare their views on this key issue prior to any review of Kuhn’s career.”

       No one who has read Kuhn’s own first person account of the discovery of imipramine would doubt his unique skill and way of conducting a clinical  interview, getting to the bottom of his patient’s concerns. What follows is a brief synopsis of a lengthy account of how he discovered imipramine (Kuhn.1970).

       Kuhn describes how slowly, and with what difficulty, the concept of an antidepressant medication became credible and widely accepted. “The substance is particularly effective in typical endogenous depression provided there is a vital disturbance standing clearly in the foreground.” He went on to describe how this feature or its implications were understood by clinicians ignorant of Kraepelin or Schneider’s nosology which painted disparate pictures of melancholy.” Not the tearful, distracted, despairing, self-accusing person plagued by feelings of guilt and sin, with suicidal tendencies. But, instead, these drug responders complained of lassitude, inhibition, a slowing down with difficulty thinking and acting, an inability to feel pleasure; the whole picture subject to diurnal fluctuations with exacerbation in the morning. The discovery of imipramine has been the elaboration of a particular clinical disease picture that allows us to choose exactly those patients who will benefit from the drug among the great mass of persons who are mentally ill. Many doctors today are still incapable of making use of imipramine simply because they have pre-conceived notions of what a depression looks like and how it should be assessed, and because they largely or entirely neglect the patient’s own experiences. If we are to use the important drugs in the antidepressant group successfully, we must also learn to recognize something new, indeed, to discover something never before seen or recognized. It took time, skill and patience to elicit feelings the patient could often hardly describe himself.

       In the light of Baumann and Ferraro’s latest posting and their English language synopsis of the historian’s conclusion, I support my colleagues’ comments concerning Ronald Kuhn’s unique clinical skills and add the following observations.

      Strikingly absent from the synopsis is any mention of the governance and administrative structure at Münsterlingen during this period and any response to concerns about the quality of clinical care. Were the methods advocated at Nuremburg or Helsinki even considered? If not, why not? All the responsibility and blame is heaped onto the shoulders of a single world-renowned psychiatrist whose clinical modus operandi was identical to that carried out by those who discovered effective drugs for all of the major mental disorders between 1949 and 1970 (Ayd and Blackwell 1970; Pichot 1983).

       The volume of Kuhn’s own archives alone suggest he had nothing to hide and the slender conclusions drawn from the historian’s report are often qualified by words such as “likely,” “rarely,” “selectively” and “reportedly,” which are not precise scientific numerators.

       Finally, noteworthy is that the Thurgau historians extended the mandate of their commission backwards from 1964 to 1940, to the start of World War Two, when Kuhn began his work as a psychiatrist. This insidiously, by inference,  links Kuhn’s unblemished career to the unethical deeds of the Nazi physicians that triggered the Nuremburg Code in 1947.

       Condemned half a century after the events and 15 years after his death Kuhn may become remembered by many as a scapegoat for those seeking to atone their father’s sins.

OED: “scapegoat”: a person blamed for the wrongdoings or mistakes of others. “origin”: a goat sent into the wilderness after the Jewish priest symbolically laid the sins of the people on it.

 

References:

Ayd FA, Blackwell B, editors. Discoveries in Biological Psychiatry Philadelphia, JB Lippincott. 1970.

Basso E. Complicities and ambivalences of psychiatry: Münsterlingen and the 1954 feast of fools.  Med Sci (Paris). 2017; 33(1):99-104.

Blackwell B. Corporate Corruption in the Pharmaceutical Industry (revised). inhn.org.controversies. March 16, 2017.

Deniker P.  Introduction of Neuroleptic Chemotherapy in Psychiatry. In: Ayd FA, Blackwell B, editors. Discoveries in Biological Psychiatry Philadelphia, JB Lippincott. 1970.

Kuhn R. The Imipramine Story In: Ayd FA, Blackwell B, editors. Discoveries in Biological Psychiatry Philadelphia, JB Lippincott. 1970.

Pichot P. A Century of Psychiatry. Roger Dacosta, Paris. 1983, p. 171.

 

October 1, 2020