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Saturday, 21.07.2018

Samuel Gershon: Lithium history

Introduction

 

Lithium preparations have been mentioned in medical writings since ancient times. They have, on occasion, been proposed as treatments for a variety of conditions. Sometimes these were accompanied by explanations of their possible modes of action. There have even been previous publications suggesting the usage in various forms of manic-depressive illness. However, for our purposes at this time, we plan to focus primarily on the period from 1947 to 2018.

            Our focus on this 80-year period is selected because during this time Lithium generated world-wide interest in its possible clinical utility and generated equally a real commitment to mode-of-action studies in the neurosciences. Of minor importance, this period coincides with my own professional life in psychiatry.

This 80-year period was marked by the publication of two seminal papers by Dr. John Cade, the first in 1947, the second in 1949. These two papers require careful evaluation and interpretation of what they stated and how clearly: The Anticonvulsant Properties of Creatinine (1947) and Lithium Salts in the treatment of Psychotic Excitement (1949). 

In order to present the scope of Cade’s broader thinking, I would like to mention two other original papers he published: The Etiology of Schizophrenia (1956) and Manganese and Mongolism (1958). These reports were, I think, related to his earlier thoughts about diet and mental function.  The former could derive its data from the admission sheets to Royal Park Receiving Hospital, which was the acute receiving hospital for the city of Melbourne. This data could provide patient names, last address for admission and admission diagnosis. This 1956 paper looked at the intake of stone fruits (peaches, etc.) and diagnosis. It showed that this patient population from the inner city did not seem to have access to this sort of fruit diet. It proposed that this lack in the diet could be causal of schizophrenia.

 

                                               Significance of 1947 and 1949 Papers

 

            In presenting this discussion I wish to clarify the limitations of this section. As I mentioned, we are concentrating on a limited time frame of 80 years. In addition to that, we still have to set fixed parameters in which we can elaborate the questions that have been raised by other authors and the many INHN contributors.

            Tom Ban, our editor in chief, asked me to try my hand at this resume. I therefore wish to state at the outset, that our main marker is Johan Schioldann’s masterly work: History of the Introduction of Lithium into Medicine and Psychiatry; Birth of Modern Psychopharmacology 1949 (2009). The author is a Norwegian psychiatrist educated at the University of Copenhagen, living in Australia since 1984, and is now Emeritus Professor of Psychiatry at the University of Adelaide. This document became our foundation to present the rest of the story. Next, we asked Barry Blackwell to review Johan’s book and publish his review on the INHN website. A brief correspondence then occurred between these two, Tom Ban and myself.

 

                                               The Parameters of this Review

            Schioldann’s book is a major compendium of most publications in the history of Lithium. The author attempted to cover the entire world literature in English and several other languages in his volume. His book includes the citation of 1,245 references, going back to the 19th century. Thus, it became clear that this unique and massive work was our main cornerstone of discussion.

            The secondary cornerstone for our exercise is Barry Blackwell’s extensive review of Johan’s book. Blackwell undertakes a careful, thorough and detailed review with a discussion of some of the questions raised by Schioldann about Cade’s work and other comments and questions raised by contributors to the INHN network. For example, some of these touch on questions such as: Why Cade did not mention any prior publications on this general subject before his own?; How did Cade very quickly move from his guinea pig experiments to the use of Lithium in man?; and especially, how was he able to develop an appropriate human dose from his work with these animals? One topic that has also been a matter of fundamental conjecture is the use of the word “serendipity” to describe Cade’s discovery and the antipathy that this word is applied at all.

            Schioldann responded to Blackwell’s review of his book and did criticize Blackwell’s acceptance of the term “serendipity” to adequately describe Cade’s use of Lithium in man. My personal view is that it does matter who obtains the credit (full or partial) for a particular scientific discovery. The actual inventor has the responsibility to demonstrate the steps taken to build the structure necessary to explain the logic and thinking processes to achieve the endpoint.

            I think it is necessary to deconstruct the details and specifics of some of these studies and attempt to reorder them so we can obtain a clear and more satisfying explanation of the events that have been recorded, reinterpreted and restated in different colors.

            Now, we turn to the Editors.

 

Exhibit 1. 1947 Guinea Pigs

I quote from Schioldann’s response to Blackwell: “Cade started by injecting urine from manic patients and, in way of control, urine from normal, schizophrenic and melancholic individuals, into the abdominal cavity of guinea pigs. All animals died… he [then] proceeded to inject the animals with the ‘end-products’ of protein metabolism, the nitrogenous constituents of urine: creatinine, urea and uric acid, and found that urea was the ‘guilty substance.’… In his belief that the urine from manic patients was more or less more toxic than that from non-manic patients… he finally postulated a third toxic substance… At no later time did Cade make any mention of such a third substance… I concluded that Cade’s observations cannot be considered to be documentation of scientific fact.”

            In addition, Schioldann hears directly from Schou that Schou could not replicate Cade’s findings in these guinea pig experiments.

            What behavioral observations did Cade record on these animals?  He stated that after these IP injections of Lithium carbonate to these previously active animals, they were seen lying quietly on their side in the cage for some time. It is also not clear why he used Lithium carbonate for these IP injections as it is relatively insoluble. Thus, this quiet, apparently immobile behavior was the only behavior recorded by Cade. (This has been mostly interpreted as Lithium intoxication.) He then rapidly moved on to his human experiments.

 

Exhibit 2. Human Studies

            Cade began his patient experiments using a Lithium dose of 1200 mg. of the citrate thrice daily or 600 mg. of the carbonate. With no references, on his part, to prior publications in the world literature and with no real ability to develop a dose for human patients with mania from these guinea pig experiments, it is extremely hard to understand how Cade could proceed to an appropriate human dose at all. Here, we have to consider that he had to determine, not one safe dose for one day in a manic patient, but the long-term dosage plan. As an aside, the Lange brothers and Hammond both published the actual prescriptions of Lithium salt doses they had been using chronically in patients. Hammond even considered the need to increase the doses if the mania was not controlled.

            To return to Cade’s report: In his 1949 paper he stated he had included 10 manic patients, three with chronic mania and seven with recurrent episodes. He reported that within a couple of weeks all manic patients were recovered. At a later date, he reported that two patients diagnosed as schizophrenic also responded. This last observation is a little difficult to interpret, as generally schizophrenic patients do not do well on Lithium treatment. After this 1949 paper was published, it was reported that the first patient (WB) subsequently died. The clinical notes indicate that “patient continued well with occasional biliousness.” This is evidence of Lithium toxicity. However, on March 8th, 1950, WB was readmitted with Lithium toxicity and the drug was discontinued. These effects were not included in his 1950 Lithium efficacy paper. At this time, Cade further commented: “Under all circumstances it seems that he would be better off as a care-free restless case of mania rather than the dyspeptic, frail little man he looks on adequate lithium… on May 12, 1950, Lithium was reinstituted because his manic state worsened. This state seems as much a menace to life as any possible side effects of lithium… on May 22, W.B…. died.” Cade recorded the death as “toxemia due to Lithium salts therapeutically administered. This was the coroner’s verdict in October 1950.” (Cade never publicly admitted the cause of death and years later in four publications he portrayed the final outcome as successful.)

            However, in 1950 Cade banned the use of Lithium in his own hospital. In these toxic experiences, it seems that Cade may not have been aware of this possibility even though this had been published by Garrod in 1859. Furthermore, the FDA had received reports of Lithium toxicity from a product marketed in the US as a substitute for sodium in cardiac patients. The FDA finally banned the sale of Lithium containing products in 1950.

            In addition to this knowledge, there was an ongoing study underway in Melbourne, Australia, which reported on 100 manic patients treated with Lithium. This study, conducted by Noack and Trautner, was published in 1951 and, at that time, it was the largest data base on Lithium usage in mania. The other unique feature of this study was that it was it was done under regular Lithium plasma assays and no deaths or serious deaths or serious toxicities were reported.

            In summary, several reports by Schou (1992, 1996, 1996, 1998, 2001) and others, find Cade’s work “indeed strange.” The hypothesis that started his work was crude. His experimental design was not clear and, indeed, his interpretation of his animal data may well have been wrong, especially so, as the behavioral changes in the animals to immobility may simply have been due to Lithium toxicity. Also, and importantly, Schou’s own attempts to replicate the guinea pig experiments failed.

            When it came to the big jump into human studies, Cade says himself: “the original therapeutic dose, decided on fortuitously, proved to be the optimum, that is 1200 mg citrate twice daily or 600 mg carbonate.”

            This single statement rings loud as phenomenal since Cade did no dose range studies in animals or man.

            To sum up, I conclude the simple recorded facts that:

1.     The Lange brothers were the First to establish the use of Lithium for the treatment of a depressive episode if occurring as a single manifestation or recurrently;

2.     They also recorded a copy of a medical prescription for a standard dose and course of Lithium. This is the dose that Cade himself uses in his human study. The Lange brothers continued and then reported that in many of these cases the depression was recurrent and then routinely recommended continued treatment to prevent a recurrence of the depression. Thus, the Langes are First to introduce the concept of prophylactic therapy (at least) for recurrent depression; and

3.     The report by Hammond describing, in his textbook, the use of Lithium to treat manic excitement thus, Hammond, in 1871 in New York, USA, becomes the First person to describe the therapeutic effects of Lithium in mania.

 

            Thus, after reviewing all the material available to me, I concluded that the animal experiments of Cade were not explained as a basis for any planned outcome related therapeutics. His clinical trial, therefore, raises as many questions as it answers, as do his reports that two schizophrenic patients were also given Lithium treatment, yet both were reported to benefit. It is somewhat unusual for schizophrenics to gain any significant benefit from Lithium.

             Neither Schioldann nor I can reach a conclusion that Cade’s work had the prior information necessary to plan the animal experiments and that he had no clear idea of what he intended to find out from these animal experiments. Yet he proceeded to a clinical trial with a lucky guess and to the correct initial safe therapeutic dose with no information as to the safety of continuing to treat at this dose long term.

            It appears that there was no established claim developed for long-term treatment with Lithium. The starting dose, as he himself states, was a fortunate guess. He was not aware of the reports on toxicity in the older literature or the more recent warnings from 1945/50 reported in the US ending with the complete ban of Lithium salts by the FDA in 1950. During his clinical trial there was another major study going on in Melbourne by Noack and Trautner. However, I know for a fact that Cade never approached Trautner to discuss these concerns of toxicity. Trautner had a well-trained team of Lithium researchers working with him at the University of Melbourne. Cade, as superintendent of Royal Park, could have readily obtained additional information on the serious concerns by contacting any member of this group, including the chairman Professor Wright.

            In summary, the reader has been presented with two documents by Schioldann and two by Blackwell, plus my document presented here.

            Schioldann and I cannot offer our endorsement of the scientific pattern of Cade’s two papers on Lithium or that either one gave a clear and definitive presentation of rational, logical facts acquired in a methodical series of studies to establish it as an authentic original contribution.

            However, as this entire set of papers has danced around the word “serendipity,” we need to consider this aspect of the debate in more detail.  Blackwell’s response to Schioldann references a very elegant and learned article on the 300-year history of the word by Tom Ban. His exegesis and discussion of serendipity diffuses, rather than clarifies, the attempts at factual evaluation presented in our discussion. One could also side-step specificity by offering a new word altogether: pseudo-serendipitous. Portmanteau words like serendipity are often used to provide a form of over-inclusion to bypass the specific problem of the debate. One could also add other words or descriptions, such as “scientifically serendipitous” or “serendipitous and deductive.”

            I must end with significant doubts as to how this history has become legend.

 

References:

Cade, JF. The Anticonvulsant Properties of Creatinine. Med. J. Aust. 1947; 2, 621-623.

Cade, JF. Lithium Salts in the treatment of Psychotic Excitement. Med. J. Aust. 1949; 2, 349-352. 

Cade, JF. The Etiology of Schizophrenia. Med. J. Aust. 1956; 2, 135-139.

Cade, JF. Manganese and Mongolism. Med. J. Aust. 1958; 2, 848-849.

Schioldann, J. History of the Introduction of Lithium into Medicine and Psychiatry; Birth of Modern Psychopharmacology 1949. Adelaide Academic Press, c2009 xxv, 363 p.

 

May 3, 2018