Sunday, 24.02.2019

Edward Shorter’s 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)

Preliminary notes

            It was a momentous moment in the history of psychopharmacology when on January 18, 1956,  Roland Kuhn, a ward chief at Münsterlingen Mental Hospital, which is the cantonal psychiatric facility of Thurgau Canton, administered a substance called G22355 to a "severely endogenously depressed female patient."  The Basel drug company Geigy, in the hopes of gaining another chlorpromazine, had synthesized G22355 at Kuhn's request.  The compound lifted the patient's depression, as it indeed relieved the depressive illnesses of two further patients.  The drug was, aside from opium, history's first effective treatment of severe, melancholic depression.  Over the next year and a half, Kuhn and colleagues administered imipramine to 40 more depressed patients at Münsterlingen with impressive results.  At the World Congress of Psychiatry in Zurich in 1957, Kuhn reported the results, to a room half filled with indifferent auditors.  That severe depressions might be treated with a "pill" was a concept to which psychiatry, until then accustomed to seeing melancholic illness as a terrible scourge from which one either recovered spontaneously, or not.  But Kuhn's success was so stunning that imipramine soon became a world-beater and gave hundreds of thousands if not millions of patients back their lives.

            Kuhn's memoir, reprinted in this issue, is memorable for a second reason as well.  He describes a technique of drug discovery that owes nothing to controlled studies, placebos or rating scales.  He simply observed a small number of patients very closely using "purely clinical methods."  He didn't have to compute statistical averages, chi squares or T-tests, nor did the discoverers of penicillin.  Their discoveries were so obviously effective that clinical "trials," which are used mainly to determine small differences within groups of very similar agents, were unnecessary.
            Thus, we owe Roland Kuhn two massive achievements: the discovery of imipramine as a remedy for serious, melancholic depressive illness, and the validation of the "clinical method," as opposed to the "statistical method," in drug discovery.

            Now, what has become of these legacies?

            The "clinical method" of drug discovery has been cast aside as irreconcilable with modern methods of psychopharmacology.  In the United States, the Kefauver-Harris legislation of 1962 mandated "well controlled" trials in drug discovery -- without specifying exactly what that meant -- and the FDA and industry took it to require double-blind, placebo-controlled statistical trials including upwards of fifty patients.  Was your drug effective?  The numbers did the talking.  Yet the numbers turned out to be so vulnerable to commercial spin and manipulation that it is not entirely clear, even today, whether the current crop of "antidepressants," the SSRIs, are actually effective in real depression, though they may be effective in nervous illnesses of various kinds.

            What is more moving, however, is what has become of Kuhn's personal legacy in Switzerland today.  One would expect that a discovery of this magnitude would be honored in buildings, streets and academic centers named after Kuhn.  Instead, his memory is being treated like the memory of a Nazi war criminal.  Kuhn's crime?  He gave "unauthorized substances" to patients (the horror), what's more "without their permission" (surely not!).  Motivated by the subsequent complaints of a dissatisfied patient at Münsterlingen, a self-important commission in Switzerland has been constituted to investigate the bioethics of Kuhn and his colleagues in the 1950s.  A preliminary survey of patient records at the cantonal psychiatric hospital in Basel, led by someone named Urs Germann,  the administrator of the Rorschach Archive, has determined that express consent at Basel was not obtained, and that the drugs administered were not already included in the official pharmacopoeia.  (Bericht_Medikamentenprüfungen_PUK_Basel_1953-1980.pdf)  The mind reels at such a flagrant abuse of patient rights.

            The problem with all this self-righteous hand-waving is that in the 1950s nobody had ever heard of "patient rights."  The physician's professional training was thought sufficient to safeguard his or her patients from harm.  After all, virtually every physician in the western world had sworn an oath, "above all, to do not harm."  Why would they violate that trust?  Nor is there evidence that at the Basel asylum under Paul Kielholz (where the clinical efficacy of chlorpromazine was first confirmed), nor at Münsterlingen under Kuhn, the best interests of the patients were ever violated.  They were treated under the highest, admittedly patriarchal, clinical standards of the day.  One cannot reproach these clinicians for not having applied ethical standards that would be discovered only twenty or thirty years later.

            Yet that is exactly what the Swiss are doing today.  The Germann report has prim disapproval and ethical zealotry etched on every page.  Kuhn and his lot must be cast out!  History is watching.  Yeah, and the historic achievements of Swiss psychiatry are being rubbished as well.  It is extraordinary that a medium-sized land such as Switzerland could have been the font of so much important innovation in modern psychiatry and psychopharmacology.  But, Lordy, we'll strip those achievements away and reduce Switzerland to the scientific status of Portugal.


October 5, 2017