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lørdag, 23-10-2021

Barry Blackwell: A Tale of Two Pioneers

 

       John Cade and Roland Kuhn were born three days apart in March 1912 but in different hemispheres, separated by the equator; Cade in Australia, which was a former English penal colony, striving successfully to become emancipated from the Empire;  Kuhn in Switzerland, a neutral nation since 1215, fully developed but surrounded and threatened by fascist nations.

       Both were born on the threshold of modern psychopharmacology, the three productive decades from 1950 to 1980, when effective drugs were discovered for all the major psychiatric disorders, often with serendipity (Blackwell 2020).

       Cade and Kuhn were among the pioneers who made those discoveries, Cade with lithium (Cade 1949), Kuhn with imipramine (Kuhn 1957). Both in mid-life and each adamant their discovery was independent of help from others or tinged with serendipity.

       In 1970, both aged 58, they each told their story in back-to-back accounts at the Taylor Manor Conference in Baltimore where, with 14 other pioneers, they received the same award (Ayd and Blackwell 1970).

       Cade died prematurely, aged 68, at the height of his popularity and acclaim, idolized in his native country. Kuhn died in 2005, aged 93, just a few years before his name and reputation were sullied by a Canton Commission that alleged his research between 1940 and 1970 at the asylum was marred by faulty ethics. This was a finding of four historians, popular with the public but considered by his surviving peers to have been a witch hunt based on modern ethical norms retrospectively applied, possibly stirred up by citizen complicity and guilt over war time Nazi crimes.

 

John Frederick Joseph Cade

1912-1980

 

       Cade was named after three generations of grandparents, a dynasty of doctors and pharmacists. His father was a general practitioner turned psychiatrist and his mother a devout Catholic nurse turned Matron. The time was formative, born parents scorched by the First World War; in early adulthood he volunteered to join the army shortly before the outbreak of World War Two in 1938 (de Moore and Westmore 2017).

       A medical officer with the rank of major he was drafted to serve in Singapore. Captured by the Japanese he spent three years as a prisoner of war caring devoutly for wounded colleagues, many of whom suffered from psychiatric disorders that kindled a conviction they must have a biological etiology.

        At wars end, re-patriated, he was assigned to direct a small asylum. He immersed himself in dual roles, a dedicated and scrupulous physician and a tireless researcher (first on guinea pigs, then on himself) entirely without training.. He focused on manic depressed patients testing the hypothesis that bipolar symptoms might emulate thyroid disorders in lack or excess of some vital substance.

       In a series of experiments in guinea pigs nobody has been able to replicate he arrived at lithium as effective for manic episodes, demonstrated it in patients and published his life changing paper in September 1949 (Cade 1949).

       Cade’s clinical modus operandi was scrupulous and obsessive when clinicians in that era prided themselves on their bedside skills, and many like Cade viewed the increasing availability of technical tests as intrusive or unnecessary. He recognized lithium could be toxic but felt his clinical skills could deal with that. He learned otherwise when his first patient after months of effective management eventually died of lithium toxicity. After other deaths were reported around Melbourne he banned the use of lithium at his hospital.

       When an enthusiastic young resident applied to Cade’s program to learn about lithium he was disappointed to find it had been discontinued because of toxicity. Even if a method of measuring its presence in body fluids became available it was unnecessary, “good clinicians could recognize and deal with toxicity.”

       Sam Gershon was sent elsewhere to continue his training. When he asked the Professor of Physiology at Melbourne University about lithium he was introduced to a German researcher named Edward Trautner who had developed a method of measuring lithium in body fluids. They became friends, worked together and published their findings (Trautner, Morris, Noack and Gershon 1955). Sam became well known and eventually moved to America where he remained a lifelong advocate for lithium.

      Fast forward to 1970, the Baltimore Conference, and Cade’s 13-page dissertation on the discovery of lithium (Cade 1970). Surprisingly, he begins by citing the FDA ban on lithium in America when used as a salt substitute in cardiovascular disorders published in JAMA shortly before his own publication in the Medical Journal of Australia.

       He continues, “One can hardly imagine a less propitious year in which to attempt the pharmacologic rehabilitation of lithium. That the attempt was made by an unknown psychiatrist, working alone in a small chronic hospital with no research training, primitive techniques and negligible equipment was hardly likely to be compellingly persuasive, especially in the United States. And so it turned out. It is a source of singular satisfaction to me that after the lapse of years the therapeutic and theoretical importance of lithium has at last been recognized. The person who has done most to achieve this recognition by validating and extending my original observation has been Mogens Schou in Denmark.”

       There  was no mention of Trautner’s work or the role of safety in supporting the use of lithium although it was the trigger that inspired Schou’s work (Trautner, Morris, Noack and Gershon 1955). Although Schou’s discovery of lithium clearly rehabilitated and vastly extended the use of lithium it was for a totally different indication, the prevention of recurrent relapses in bipolar disorder, not the treatment of acute mania which was rapidly overtaken by the use of neuroleptics.

      Later in Cade’s presentation he provides selective clinical information about the 10 patients in the original study including an almost entire account of “the very first patient successfully treated with lithium salts.” It concludes: “a month later he is recorded as completely well and ready to return home and work.” What is left unsaid is that months later the patient became non-compliant, relapsed and was readmitted. After a long and troubling attempt at treatment he died. The autopsy confirmed death due to lithium toxicity.  

       Ten years after the Baltimore Conference Schou died a premature and lingering death in 1980 due to multiple causes.

 

Roland Kuhn

1912-2005

 

       Roland Kuhn was born on March 4, 1912 in Biel Switzerland into a Catholic German speaking family with local roots and, like Cade in Australia, with some medical traditions; one of his maternal ancestors had founded a children’s hospital. In 1957, the year of his discovery of imipramine, he married his medical colleague and co-worker Verena. Despite middle age they had three daughters, Regula, Beatrix and Ursula, later becoming grandparents of Ursula’s three children.

       The little we know of Kuhn’s early life is from Leonardo Tondo’s lengthy interview (Tondo 2021). It was conducted in Kuhn’s cottage on Lake Constance in the village of Scherzingen. “It had all the characteristics of the Swiss countryside with perfect green lawns set in rolling hills with grazing cows. The cottage was simply furnished, functional, elegant but perfectly in keeping with local taste.”

        Kuhn studied medicine in Bern and Paris, graduating in 1937 with a dissertation on “Iodine Excretion in Cretins.” Perhaps an interest in thyroid metabolism suggests that like Cade he might connect thyroid function to the etiology of mental illness. However, his first choice of career was surgery. But the surgeon he admired died and when the program was cancelled, he switched to psychiatry. He first studied under Jakob Klasi, learning sleep therapy and became introduced to psychotherapy,  first by Otto Briner and later with Ludwig Binswanger. He also attended seminars by pupils of Hermann Rorschach and became a skilled admirer of the projective technique he viewed as an ideal opening for a psychological dialog with his patients.

       In 1939, at the outbreak of the Second World War he became Consultant and Deputy Director of Münsterlingen, a 700-bed asylum, a post he held until his retirement in 1980 at age 68. As a neutral but armed nation there is no mention of Kuhn serving in the military.

       Kuhn had worked at Münsterlingen for almost two decades before he began collaborating with Geigy. He quickly became an esteemed investigator mainly because of his modus operandi. Kuhn prided himself on a clinical style of close detailed and meticulous attention to his patients’ thoughts, feelings and behaviors as well as feedback from family members. He also claimed an understanding of the chemical structure of the drugs he prescribed and the effects that structure dictated. At the same time, he eschewed and disparaged, like Cade, the evolving technologies of clinical psychopharmacology including rating scales, statistics and standardized clinical trials. In addition, Kuhn viewed himself as firmly in charge and the sole person responsible for findings and opinions on the compounds he studied. He did not share credit with others; neither his own staff nor the Geigy employees.

       In the interview with Tondo, Kuhn describes the situation at the asylum leading up to the discovery of imipramine. “There were a lot of patients with vital depression without psychotic symptoms and often with manifestations of the neurovegetative system. It wasn’t justifiable to treat them with electroshock. It was necessary to treat them with drugs… the ancient treatment of opium extract we used for 20 years had an antidepressant effect. It took weeks if not months to act and it caused constipation. In addition, administration was not simple. It started with one drop a day, increasing daily to 30 drops three times a day so we were forced to find a family member charged with this complicated gradual regime. We were not sure about the potential problem of dependency. I was always of the opinion opium treatment must be improved. That was my idea.  There must be a substance which had the same effect as morphine without the disadvantages.”

       Clearly Kuhn was a man with his eyes open and a prepared mind when chlorpromazine appeared on the horizon.  But it was too expensive and Geigy gave him another antihistamine to study. Geigy described it as a narcotic (they knew what he was looking for) but it clearly had antipsychotic properties and two bad side effects. Kuhn suggested a change in the molecular structure, nearer to chlorpromazine. Expecting a neuroleptic he found instead that this new compound (G-22355) had effects on vital depression. Kuhn’s clinical description of vital depression is borrowed from Kurt Schneider and reads as follows: “It consists of tiredness, feelings of heaviness and dejection or depression, slowed or obstructed thinking, decision making and interaction; loss of ability to enjoy oneself and to sustain interests and daily fluctuations with worsening in the morning” (Kuhn 1957). This brilliant succinct description became lost in the fog of DSM major depression and with it imipramine vanished, replaced by endless and often useless second generation antidepressants.

         After imipramine Kuhn claimed he also made suggestions for another compound which turned out to be maprotiline, also an antidepressant.        

       As described by Tondo, Kuhn was always interested in an academic life. After his discovery he became a docent and honorary Professor at the University of Zurich until 1998, at age 86. He had a close relationship with Binswanger who was Director of Bellevue Sanatorium, a few miles from  Münsterlingen. They gathered at Binswanger’s house “with great  thinkers, scientists and artists.”

         In addition, Kuhn held fortnightly courses in his own residence on philosophical and phenomenological topics from which he kept records amounting to thousands of pages. In 1992 at age 80 Kuhn attended a colloquium at Münsterlingen on “Ethics and aesthetics in philosophy and psychiatry.”

       In 1997, the 50th anniversary of imipramine’s discovery, a symposium was convened in Kuhn’s honor. Karl Rickels, a German immigrant and Professor at the University of Pennsylvania, concluded his remarks saying, “Progress needs two things: ideas and good primary clinical observations: we need more Kuhns!” (Rickels 1997).

In 2002, three years before his death, he was a speaker, again at Münsterlingen, where 12 scientists and philosophers spoke on “style in scientific research and medical treatment.”

       Kuhn was much in demand as a lecturer in different countries. He received doctor honoris causa degrees in medicine at Louvain and Basle and doctor honoris causa in philosophy from the Sorbonne in Paris.

       Tondo provides a bibliography of Kuhn’s publications. He was multilingual. There are 43 articles, on 38 he is the only author; 19 are in German; 22 in English; and one each in French and Spanish. Only a third are on psychopharmacology. The remainder are an erudite compilation of phenomenology, philosophy and clinical psychiatry.

An informative interlude

       Tondo engaged in a probing analysis of Kuhn’s discovery of imipramine that elicited Kuhn’s well known didactic style.  

       Asked whether, after 30 years, imipramine remains the best antidepressant Kuhn mentions clomipramine, maprotiline and lithium but does not provide a detailed assessment or comparison.

        Tondo enquires about the second-generation atypical antidepressants and Kuhn states he sees no advantage to these new drugs.

        Tondo now asks about the unpleasant side effects of tricyclic compounds. Kuhn lists the usual anticholinergic effects and agitation as the most unpleasant. He does not mention suicidal risk.

       Tondo asks what are the major indications for use of imipramine? Kuhn names vital depression as essential.  

       Tondo asks about panic disorder with vital symptoms. Kuhn states only if a good and clear examination reveals trouble in the vital sphere.

        Tondo asks do you mean you look for vital depression in a psychodynamic way? Kuhn denies he makes this distinction and describes how he interviews family members to elicit vital symptoms. He denigrates psychodynamic and theoretical constructions and states everything is in the books by Kraepelin and Bleuler, but “nobody reads them today.”

The conversation becomes mildly rancorous about the difference between Kraepelin and Bleuler with Kuhn recommending books and articles Tondo might read, reinforced by Kuhn going back and forth to his bookshelf to show Tondo several of them.

       Tondo, perplexed, asks Kuhn, “How do you put everything together?”  and Kuhn replies that doing so is absolutely necessary because every case has its neurobiological and psychologic aspects.

       Tondo asks if Kuhn is more interested in patients or research, Kuhn responds, more in patients.

       Tondo asks Kuhn what he thinks of treatment for depression by psychotherapy? Kuhn believes it is possible but denounces Freud and suggests an existential and analytical approach. Free association is not possible in depressed patients.

       Tondo asks, not even in mild depression? Kuhn states it is not possible but perhaps such an approach remains to be discovered.

      Tondo probes Kuhn’s psychotherapy beliefs further. What does Kuhn think of Jung?  Kuhn believes he is a genius but undisciplined, unable to develop ideas in a fruitful way.

      Asked about Binswanger Kuhn becomes animated and lapses into French as he extols his virtues and describes their close relationship.

       Asked about any episode involving Binswanger particularly impressed him Kuhn returns to English and mentions an occasion when Binswanger denied that etiology had any role to play in depression or its treatment.

       Tondo asks a final question about whether the tricyclics can trigger mania? Kuhn denies this and believes when it occurs it must be hereditary.

Cade later in life

       After his discovery in 1949 Cade became Director of the largest mental institution in Melbourne. His interest in lithium waned after he banned its use and his interest turned to schizophrenia and insulin coma therapy. The university was soon to appoint its first Professor (Brian Davies from the Maudsley) and the city recruited a talented mental health administrator from UK to modernize the entire mental health system of the region. He dispatched Cade to visit the UK and gather fresh ideas. Cade flourished as a somewhat conservative administrator and was an admired and respected educator of medical students and psychiatric residents as well as the public in both mental health issues and Catholic ethics (de Moore and Westmore 2017).

       After Mogens Schou discovered the effects of lithium as a prophylactic agent to prevent the recurrence of bipolar disorders in 1968 he reached out to congratulate Cade. They began a correspondence that evolved into a symbiotic relationship that served them both well. For Cade it was rehabilitation after self-imposed years in the scientific wilderness. Prophylaxis in bipolar disorder was vastly more important than treating acute episodes of mania, soon taken over by neuroleptics. The two shared widespread adulation and awards. For Schou the benefits were more subtle. Scandinavia had a long and turbulent love affair with lithium, including Schou’s father, Hans Jacob Schou, and the Lange brothers, Carl and Frederik, whose research findings missed the possibility of prophylaxis by a hair’s breadth (Schioldann 2000). Schou’s adulation of Cade was despite his plain spoken failure to replicate the animal research on which it was based.

Kuhn’s late life and beyond.

Tondo’s article (Tondo 2021) reviews Kuhn’s late life activities up until his death in 2005, including two symposia at Münsterlingen long after his retirement where he showed a prescient interest in research ethics and aesthetics.

       Hopefully, Kuhn died unaware of events that would begin to unfold in 2013. In that year concerns about conditions at the hospital during the Kuhn era, especially relating to research on drugs, were raised by former nurses and staff members in the newspapers. Two years later The Canton of Thurgau appointed a Commission to study research undertaken by Kuhn and the pharmaceutical companies between 1950 to 1980, when Kuhn retired. Membership of the Commission was originally intended to include both historians and scientists but when the book was published recently in German only four historians were identified as authors. The lead author has since provided an English translation of the Press Conference issued at publication. The findings have never been peer reviewed, the motivation for only historical authors is unclear and the opinions of scientists named as reviewers have never provided independent comments on the findings. The attention of INHN was drawn to the Commission by two member psychiatrists, Pierre Baumann and François Ferrero, seeking to find the means to alert the International  community of psychiatrists to the findings. In 2016 they posted their concerns on inhn.org.

The Evolution of Contemporary Ethical Research Standards

       The Nuremberg trials of leading Nazi officers and perpetrators of the “Final Solution” and related crimes convened in November 1945 and delivered verdicts for 22 criminals. This was followed in December 1946 by the trial of 21 doctors for war crimes in concentration camps delivering sentences in August including  seven death sentences, seven prison terms (10 years to life) and seven acquittals.

       Following that trial “The Nuremberg Code” of medical ethics was drafted. Based on the Hippocratic Oath it defined the criteria for experiments on human volunteers. Included were informed consent, absence of coercion, well-defined experiments, beneficence towards volunteers, fruitful results, limited defined risks, termination at volunteers request and termination to avoid harm.  In 1964 the World Medical Association developed the “Helsinki Declaration” which re-affirmed the Nuremberg Code.

In February 1966 the U.S. Public Health Service  issued a policy statement on the need for Institutional Review Boards  and in September1978 the Belmont Report, convened by the National Commission for Protection of Human Subjects, issued the criteria for Review (Ethics) Boards in America.

The Contemporary Significance of the Nuremburg Code

       To understand and explain the impact on modern Switzerland of the events in Germany leading to the Nazi atrocities and the Nuremburg Code an excellent source is The Nuremberg Code 70 years later (Moreno, Schmidt and Joffe 2017). It states: “The circumstances in which the Code evolved reflected a tension between professional standards and duties of the State. The increased demands placed on modern States to promote health and welfare in the 20th Century required State agencies to respond to public pressure to protect subjects in clinical trials. More recent scholarship has found pre-occupation with medical ethics in countries owing to their proximity to concentration camps, the collective experience of the Second World War and the need to assert professional ethics against a background of authoritarian rule.”

       In and following the Second World War Switzerland offers a textbook example of this conflict. Swiss neutrality goes back to 1515 and is the oldest and most permanent among nations. At the outset of the war Switzerland was surrounded by fascist nations, aware that Germany and Italy had plans to invade (Operation Tannenbaum). The Swiss response was to mobilize 850,000 troops in the Redoubt Plan to deploy troops to the Alps if necessary and use guerrilla tactics. This did not occur because of Swiss interdependence with Germany. The economy was heavily dependent on German goods and energy. Business, social and economic relationships were entangled. Throughout the war there was tension about the Holocaust. Swiss banks catered to Nazi elite, storing their stolen goods.  The 1997 PBS Frontline program “Nazi Gold” told of how 581,000 francs worth of “melmer” gold retrieved from the ovens in concentration camps was placed in Swiss banks. In 1942 Jews were denied entrance to Switzerland because, “our little boat is full” and Jewish passports were marked with a red J. It is not surprising if, post war, there was significant soul searching and some scapegoating among the Swiss population (Olgiati 1997).

       Without singling out Switzerland or citing the Kuhn controversy the authors propose their remedy. “The story of the Nuremburg Code is not one of ethical norms taking the force of law. Rather its legacy shows the fundamental importance of a robust organized medical profession that protects its independence from political interests and its ability to plot its own moral course.”

Documents on the INHN website include the views of members. The most emphatic and pertinent comments were made by Edward Shorter, a distinguished International history expert, whose thoughts mirror that suggestion (Shorter 2017).

      Shorter wrote: “Kuhn’s memory is being treated like a Nazi war criminal. A self-important Commission in Switzerland has been constituted to investigate the bio-ethics of Kuhn and his colleagues in the 1950s.  Every physician in the western world has sworn an oath “above all do no harm.” Nor is there any evidence at Münsterlingen under Kuhn that the interests of patients were ever violated. They were treated under the highest, admittedly patriarchal clinical standards of the day. The German report has prim disapproval and ethical zealotry etched on every page.”

       In another posting and exchange of views (April 14, 2017- April 16, 2017) Shorter adds, “This strikes me as a perfect example of retrospective application of today’s standards to an earlier period when different values and standards prevailed. Informed consent was unheard of in the late 1950s. Far from being a Dr. Frankenstein Kuhn stumbled into psychopharmacology by chance but gifted with a sharp mind he immediately recognized the significance of his discovery and prevailed on Geigy to pursue it further” (Carroll, Shorter, Klein and Ban 2017).

Commentary

       The cultures into which these two pioneers were born were dramatically different although both families were Catholic with some background in medicine.

       Switzerland was a sophisticated and multilingual society with a long tradition of armed neutrality going back to 1515, now surrounded by fascist dictatorships at the time of Kuhn’s birth. Its academic tradition in psychiatry was familiar with and influenced by leaders like Kraepelin, Bleuler, Jung, Freud, Binswanger and Rorschach.

       Australia, a former English penal colony was developing, but still primitive by comparison and in its psychiatric infancy, isolated from both European and American psychiatry.

      The Second World War would deal differently but dramatically with these two pioneers. Cade would endure active service and brutal prisoner of war experiences that helped shape his ideology towards the etiology of mental illness. Kuhn, sheltered in a neutral nation, would avoid active service but have his career denigrated by the changing medical ethics directly connected to the Nazi atrocities during the war and their impact on Swiss society.

       In 1970 when Cade and Kuhn made back-to-back presentations of their discoveries at the Baltimore Conference it would be fair to say that their reputations in their profession and with the public in their native lands ran parallel and were positive. When Cade died his premature and tragic death in 1980 he  became a hero for an Australian nation badly in need of one. Kuhn’s long life to his death at 93 in the year 2005 found him unfairly denigrated by the public although still respected by the surviving pioneers in his profession.

References:

Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia, Lippincott; 1970.

Baumann P, Ferraro F. An Official Enquiry of the clinical research activities (1946-1974) of Roland Kuhn (1912-2005). inhn.org.controversies. February 11, 2016.

Blackwell B. Treating the Brain; An Odyssey. Cordoba, Argentina, INHN Publisher; 2020.

Cade FJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949;2:349-52.

Cade FJ. The Story of Lithium.  In: Ayd FJ, Blackwell B, editors, Discoveries in Biological Psychiatry. Philadelphia, Lippincott; 1970, pp. 218-29.

Carroll B, Shorter E, Klein DF, Ban TA. Comment exchange: Pierre Baumann and Francois Ferrero: An official inquiry of the clinical research activities (1946-1972) of Roland Kuhn (1912-2005) - Preliminary notes (Prepared by Olaf Fjetland). inhn.org.controversies. June 1, 2017

de Moore G, Westmore A. Finding Sanity: John Cade, Lithium and the Taming of Bipolar Disorder. Allen & Unwin; 2017.

Kuhn R. Treatment of depressive states with an iminodibenzyl derivative (G 22355). Schweiz Med Wochenschr 1957;87(35-36):1135-40.

Kuhn R. The Imipramine story. In: Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia, Lippincott; 1970, pp. 14-15.

Moreno JD, Schmidt U, Joffe S. The Nuremburg Code 70 years later. JAMA 2017;318(9):795-6.

Olgiati C. Nazi gold. BBC/WGBH Frontline/SF DRS Switzerland/NCP Israel coproduction; 1997.

Rickels K Proceedings, Jubiläum-symposium 40 years Imipramine, Franfurt am Main, December 6, 1997.

Schioldann J. Did lithium therapy of affective disorders turn up one hundred years ago or (only) fifty? Aust NZ J Psychiatr 2000;34(supp, A):60.

Shorter E. Commentary. A Momentous Discovery in the History of Psychopharmacology -- But Posterity Tries to Poison the Well. Pierre Baumann and Francois Ferrero:  (1946-1972) An Official Inquiry on the Clinical Research Activities of Roland Kuhn (1912-2005). inhn.org.controversies.  October 5, 2017.

Schou M. Phases in the Development of Lithium Treatment in Psychiatry. In: Sampson FE, Addman G, editors. The Neurosciences: Paths of Discovery II. Springer; 1992, pp. 149-66.

Tondo L. Leonardo Tondo: Interviews with pioneers. Leonardo Tondo’s interview of Roland Kuhn. inhn.org.centraloffice. February 25, 2021.

Trautner EM, Morris R, Noack CH, Gershon S. The excretion and retention of ingested lithium and its effect on ionic balance in man.  Med J Aust 1955;2:280-91.

 

June 17, 2021