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Friday, 07.08.2020

Samuel Gershon: Lithium history
Samuel Gershon’s reply to Malcolm Lader’s comment

 

         I am very pleased to have Malcom Lader’s views on these discussions that have been ongoing for some years. I am familiar with Malcolm’s own  publication in psychopharmacology and it clearly sets out the project with clear goals and a well-developed path to attain these targets.

            He has done no less in his presentation here. Firstly, in response, I wish to clearly state that I agree fully with all of the questions and concerns he raises about the development of the lithium story over the years. Therefore, I will take as my main goal a response in some detail to the very critical question he has raised.

            Professor German Berrios has written that in studying history (of psychiatry) we must still be aware of what other winds or other forces may affect the interpretation of history. This caution also applies in this record of history. There were institutional differences, as well as the effects of political, social religious and pragmatic factors, that do indeed play a role in the development of this history. But, in short, what Lader is asking us “…how could your contributors be debating neon road signs sending you in one direction and you ignored them and drove us over the cliff.” I hope these few comments will be shown to support Malcolm’s comments and his skills recently acquired from obtaining an MA in history; congratulations!!

            So, toxicity was an important issue for all the early users of lithium. However, in John Cade’s case he could have gotten help and advice from an expert group at Melbourne University. It has been stated by one author, about how Cade could feel comfortable dealing with Edward Trautner, an elderly German gentleman (with a strong accent). I will try to go on and continue to answer Lader’s questions about filling in a historical background that may be a cause for influencing the direction of the story. The physicians working in the Australia’s Department of Mental Health did not have any significant contact with the faculty at the University. Cade could of course have gone to the chair of physiology,  Professor R.D. Wright, to seek advice from him or from faculty in the department who had many answers to these problems of toxicity and their treatment.

            Lader’s first question is so elemental in the presentation of any new findings; their absence in Cade’s 1949 paper raises a major concern. One would expect, and really demand, the presentation to have at the outset the background on relevant references, as well as the background data that leads to the origin of the current clinical findings. It will be appropriate also to provide attribution of prior work in the basic sciences and clinical aspects that support the logical launching of his clinical studies . Lader goes on to ask: “Why did Cade not acknowledge the antecedents of his work?” This question continues throughout the lithium history we have been discussing. These various questions raised by Lader are obvious neon light deficiencies in the presentation of the original 1949 report.

            Toxicity with lithium is a problem that comes up early in all of this work. About the time Cade’s 1949 paper appeared concerns were being reported about the toxicity of a salt substitute in the U.S. in medical journals; the FDA was then forced to act and banned the marketing of this product altogether. So these deaths were reported and changed the attitude to lithium use generally. It was a potential lethal substance.

            So now we must go back and see how the dosage was originally derived by Cade. First, were the guinea pig studies. The main observation was that active guinea pigs in the cage after I.P. lithium injection would lie quietly on their side. This behavioral observation was apparently a factor in moving studies to man…with an indication for mania. Johan Schioldann has carefully looked through Cade’s laboratory cards that recorded the guinea pig experiments and finds them difficult to follow. Schioldann quotes Schou’s comments on the guinea pig experiments, saying “that he could not replicate them.” Cade writes elsewhere that he tried different doses of lithium salts on himself to ensure their safety in man.

            Now, everyone in psychopharmacology must know very well that it is not easy, even in the pharmaceutical industry with all of its experience and technology, to develop a safe and effective dose of a brand-new product for humans. In Cade’s case, he did the testing on himself, that is, he gave his selected doses to a healthy, normal, male and then decided that this single dosage trial made it safe and effective for a psychiatric disorder like mania.

            There is an interesting derivative question in regard to toxicity and lethality. We only know of Cade’s one case of death after he published his paper. In a later statement he described this one patient as a sick little man moving from a manic episode to lithium toxicity. As a further illustration of this problem, I can offer a statement made by a senior medical officer of the Mental Health Authority, stated that Trautner’s work at the University had no real value for practicing physicians. Looking at this statement at face value, one can see that the University was a separate and distant entity. In looking back at this sort of thinking one can see that it is just a strongly negative view of what happened at the University. Furthermore, the idea of this having no value was quickly overturned - that Trautner et al.’s work at the University was absolutely crucial (Trautner, Morris, Noack and Gershon 1955).  These studies enable all psychiatrists, including practicing clinicians, to use lithium safely for the first time in the lithium history. Furthermore, it produced a functional concept of therapeutic ranges for lithium, and it could and did save lives. Not bad work for an old guy! Morgen Schou, himself, at the time wrote that these lab findings enabled lithium to be used worldwide under monitored and safe conditions.

 

References:

Trautner EM, Morris R, Noack CH, Gershon S. The excretion and retention of ingested lithium and its effect on ionic balance of man. Med J Austr 1955; 2: 20 – 91.

 

March 28, 2019