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Monday, 01.03.2021

Mogens Schou’s My Journey with Lithium, written on the invitation of Johan Schioldann

Barry Blackwell’s additional comments

 

       All those who have participated in the historical recapitulation of the lithium controversy (Blackwell 2014) should be grateful to Mogens Schou for describing his cardinal contributions to that saga, to Johan Schioldann for inviting him to do so and to Paul Grof for commenting.

       Those familiar with the INHN material will recall my late-life opinion of the criticism we made half a century earlier (Blackwell and Shepherd  1968) that “we were wrong for the right reasons.” This enigmatic statement deserves personal  clarification due  Mogens Schou  by me for any slur perceived but not intended.

       What I quickly learned after graduating from residency at the Maudsley Hospital, after I developed a practice of my own, was that the prophylactic action of lithium in bipolar disorder was almost invariable and so  rapid that we were wrong to suggest any need for a double-blind controlled study against placebo.  

        Those  familiar with the literature will recall this was equally true for chlorpromazine in schizophrenia and imipramine in melancholia, the first effective treatments whose use spread like wildfire well in advance of well-controlled proof of efficacy.

       So, in what way were we “right” to make such a suggestion? The fact that comments we made about the trial methodology were valid relates to the time and place where and when we expressed them.

        Until the turn of the 20th century there were a multitude of placebos and panaceas on the market, lacking scientific means to assess their efficacy and safety, often endorsed by self-proclaimed experts. Such constraints waited on the thalidomide disaster in America and action taken by Congress and the FDA in the mid 1960s to define criteria including double-blind placebo-controlled studies for new drugs prior to approval.

       Michael Shepherd was one of only three British psychiatrists to attend the First International Congress of the CINP held in Rome in 1956. Mogens Schou also attended and many years later recalled: “The CINP and lithium had little to do with each other during the early years of the organization. The proceedings of the first congress in Rome in 1958 do not show a single paper with the word ‘lithium’ in the title. The very last presentation under the heading General Discussion… contained elements of prophetic truth. On the therapeutic firmament lithium is one of the smaller stars, and until now it may not have been noticed by all psychiatrists. But its light appears unmistakable, and it may turn out to be more steady [sic] than that of several other of the celestial bodies which now shine so brightly” (Schou 1998).  

        Parenthetically, the same volume describing the CINP and First Congress also includes a paper by Abram Hoffer on the Introduction of Megavitamin Therapy for Treating Schizophrenia (Hoffer 1998). He commented: “I am convinced that the double-blind is a ‘dud’ method, only used by clinicians and administrators who have a lot of money and little imagination.”

      We have no way of knowing if Shepherd heard the comments by Schou about lithium or the disparagement of double-blind studies by Hoffer, but I have no doubt Shepherd would have upheld the Maudsley credo, a combination of skepticism and scientific rigor to be scrupulously applied towards novel claims like those Schou enthusiastically made on behalf of lithium and including approval for the double-blind studies that effectively stifled megavitamin therapy in schizophrenia.

      The sole purpose of placebo-controlled double-blind studies is to protect investigators from their own  (often empathic) beliefs, hopes, expectations and enthusiasm. That such protection might be inferred to imply derogatory or insulting implications is clearly an unintended, perhaps inevitable, “ear of the listener” outcome.

       That Schou’s father knew of Lange’s work in recurrent outpatient depression (perhaps with mild hypomanic episodes welcomed but not mentioned by his patients) but that Mogens was unaware of this so did not couple it with Cade’s discovery is surprising. However, Paul Grof  reminds us that the last study of Mogens life was devoted to exploring this hypothesis. There is no evidence that Cade knew of Lange’s work either through his own reading or from Mogen’s late life study.

       Mogen’s contribution to the controversial study (Baastrup and Schou 1967) is not completely defined. It reads as if he was mainly concerned with plasma lithium measurements and trial methodology without direct patient contact due to the distance between Risko where he worked and Glostrup where Baastrup and the patients were located.

       In designing a new study Mogens notes, “Baastrup and I went over the first paper’s many misinterpretations and erroneous calculations.” The outcome was an ingenious design that avoided suicide risk in the patients but remained double-blind with random allocation to lithium or placebo until the patient relapsed and, if so, was switched to lithium by a non-blind observer.

       This definitive trial was published (Baastrup et al. 1970) and Mogen notes  that Shepherd failed to comment. Neither did I. In 1968 I emigrated to America and in 1970, together with my mentor, friend and colleague Frank Ayd, convened the First Taylor Manor Conference in Baltimore to which Frank invited all the scientists and clinicians who made the original discoveries in modern psychopharmacology to give first-person accounts and receive a commendation (Ayd and Blackwell 1970).

       John Cade was included and, like Frank a devout Catholic, was recognized by the Pope’s emissary to the White House. Cade recapitulated his work in guinea pigs leading up to treatment of acutely manic patients but he failed to mention the death of his first patient due to lithium toxicity implying a prolonged permanent recovery and also failing to mention Trautner’s work on plasma monitoring performed and published at his own university in Melbourne. Shortly after the Baltimore conference the FDA lifted the 30-year ban imposed on lithium for treatment of mania but not for prophylaxis. 

      In this interesting tale of three pioneers Mogens describes each of them: himself “a systematic scientist,” Baastrup as “persevering” and Cade as “artistic”; eponyms with which I concur. 

       There remains lack of agreement about the role of serendipity in their discoveries. In Cade’s case the combination of an artistic temperament, a deductive cognitive style and the failure of Schou and others to replicate or understand his work in guinea pigs suggest that serendipity would be an appropriate term, certainly abetted by a prepared and determined mind set (Blackwell 2017).

        On the other hand, Schou’s contribution to prophylaxis differs markedly. His work was the product of classical inductive reasoning with a defined hypothesis rigorously tested and validated in both an uncontrolled study and a creatively designed double-blind comparison with placebo.

 

References:

Ayd F, Blackwell B (ed). Discoveries in Biological Psychiatry Philadelphia: Lippincott; 1970.

Baastrup PC, Schou M. Lithium as a prophylactic agent. Arch. Gen. Psychiat. 1967; 16: 162-72.

Blackwell B. The lithium controversy; a historical autopsy. inhn.org.controversies June 19, 2014.

Blackwell B. Book review of de Moore G, Westmore A. Finding Sanity: John Cade, Lithium and the Taming of Bipolar Disorder. Melbourne: Allen & Unwin; 2016. inhn.org.biographies February 2, 2017.

Blackwell B, Shepherd M. Prophylactic lithium; another therapeutic myth. Lancet 1968; 1: 968.

Hoffer A. The introduction of mega-vitamin therapy for treating schizophrenia. In: Ban TA, Healy D, Shorter E (ed). The Rise of Psychopharmacology and the Story of CINP. Budapest: Animula; 1998, 36 -40.

Schou M. The rise of lithium treatment in the 1960’s. In: Ban TA, Healy D, Shorter E (ed). The Rise of Psychopharmacology and the Story of CINP. Budapest: Animula; 1998, 95-7. 

 

June 6, 2019