Thomas A. Ban
Neuropsychopharmacology in Historical Perspective.
Education in the field in the Post-Psychopharmacology Era
Neuropsychopharmacology in Historical Perspective.
Thomas A. Ban: Lithium
3. Early Years
Samuel Gershon: First-Hand Accounts
Samuel Gershon: Events and Memories 1. Lithium
Samuel Gershon: Lithium History
Samuel Gershon: Events and Memories. 1. Lithium
I have been pressured by my colleagues in INHN to write about some of the events and memories of my professional life in psychopharmacology. Barry Blackwell has written a memoir titled Bits and Pieces of a Psychiatrist’s Life (2012), a complete account of his personal and professional accomplishments. I could not do that, but Tom Ban suggested I contribute an account of each of the drugs I helped develop - “bits and pieces” - if not a full memoir. I have accepted the challenge and will stick mainly to professional aspects told through work events and scientific episodes.
I graduated from medical school at the University of Sydney in 1950 and then did a rotating internship. During 1951, I took a rotation through the psychiatric inpatient facility at the Royal Prince Alfred Hospital attached to the University. The psychiatrist in charge of the institute was a very liberal fellow, not convinced he knew all the answers and willing to admit we had very few. Australia at that time was a fairly isolated place, but we heard a lot about Dr. Cade including his talks in 1948 and article in 1949 on lithium treatment of mania and the enormous success he reported (Cade 1949). So, it was possible to use lithium therapeutically during this elective. In the few cases I treated, lithium seemed effective, using it cautiously over 7-10 days, since deaths from lithium had been reported by others in Australia.
The next year, 1952, I transferred to the University of Melbourne and joined the Department of Mental Health. I was assigned to the Royal Park Mental Hospital in Melbourne, where Cade was the Superintendent. At the same time, I enrolled at the University where mandated courses in psychiatry were given and exams over the next four years were administered. Unlike the boards in Psychiatry in the US, we had to pass every subject in the curriculum each year or do it again.
Royal Park Hospital was the acute receiving hospital for Melbourne. So, this seemed the greatest place in the world to actually study lithium - the first significant discovery in psychiatry.
At this point, I only wanted to evaluate and understand its therapeutic profile, clinical effects and process of improvement. So, I asked senior colleagues who I should speak to about getting supervision. They told me this was not a good idea as Dr. Cade had banned lithium in the hospital because of the deaths and serious toxicities that had occurred, including one of his own patients in the original 1949 report. This was not a great start and after a lot of psychological turmoil I decided I would have to find another route.
Also at this point, I only thought of personal observation of lithium’s effects and course of treatment; I had done no research and did not know of anyone doing research. My choice of action was born of desperation; I contacted a Professor at the University of Melbourne known as approachable to students and faculty. This was Professor Wright, Chair of Physiology. I went without an appointment, a young dopey kid, but he was nice and kind. He elicited what I wanted to do and evaluated me carefully. After further questioning and discussion, the meeting ended when he said, “Well, you should go up and see ‘Trautie.’” So, I went upstairs and found Dr. Trautner in his lab with a couple of doctoral students… I had found my research mentor and a future friend.
Trautner was an elderly, wrinkled gentleman with a heavy German accent. I am ashamed to say I have no photo of him. We had a general discussion about his published 1951 study of 100 hospitalized psychiatric patients treated with lithium. An important feature was that it was the first lithium study in the world in which patients had their lithium assays monitored and no patients had died. Also, this was the first study to use flame photometry to monitor the plasma levels of sodium and potassium, the result of Dr. Victor Wynn’s first use of the assay. Dr. Wynn was also a faculty member in the Department of Physiology at the University of Melbourne, so the University faculty played the main role in a broad range of studies on the physiology of lithium.
They established the procedures for safe use of lithium in humans, keeping it alive in psychiatry. As I mentioned, Cade banned the use of lithium in his hospital and Roberts and Ashburner at two other state hospitals in Victoria reported deaths of a patient at each hospital and that was the death knell for lithium therapy in Australia. However, two other psychiatrists (both new immigrants) in two other states in Australia also contacted Trautner and he advised them to carry out their own mania studies. Both Glesinger (1954) and Margulies (1955), published papers confirming their findings in the large study by Noack and Trautner (1951); both used plasma assays and had no untoward effects.
Thus, my encounter with Trautner generated enthusiasm for how one might treat and understand at least one psychiatric disorder. As a novice, I had no research funds or assistants but was encouraged and supported with help and advice by colleagues at the University of Melbourne who gave their knowledge and time unconditionally.
The first major lithium project (Trautner, Morris, Noack and Gershon 1955), was on the differential retention and excretion between manic and non-manic phase patients. We found that classic manic bipolar 1 patients would retain more of the lithium ion ingested over a one-week period than normal or control subjects, whose retention and excretion was more in daily balance. When the manic phase remitted, they excreted the retained lithium, exceeding their daily dose until they reached homeostasis. This new and exciting finding was state and trait dependent.
This study also gave us clues about other ionic effects, including sodium and potassium losses. This was time consuming, taking a couple of years, but provided the groundwork for later studies. Our findings also dictated we develop a treatment plan for lithium toxicity. Again, we went to our colleague at the University of Melbourne, Dr. Douglas Coats, an expert in electrolyte and renal physiology who agreed to work with us on this urgent and important topic. Our paper (Coats, Trautner and Gershon 1957) offered an explanation of the aberration in water and electrolyte balance found in bipolar disorder and proposed a treatment plan that followed logically from the previous study. We had occasion to use our results to help other psychiatrists deal with toxic patients to obtain positive outcomes.
The next lithium report came after I arrived in the U.S. at the University of Michigan on a scholarship awarded after an Australia-wide competition; it had a large grant to establish Schizophrenia and Psychopharmacology Research projects. This paper summarized laboratory and clinical experiences to date (Gershon and Yuwiler 1960). Art Yuwiler was head of the biochemistry research division. The views presented are still those I hold today. After an additional 55 years of study and observation, lithium is one of the few examples of psychopharmacological specificity in psychiatric treatment.
During this period, we established the efficacy of lithium in mania; demonstrated the effect of lithium on water and electrolyte physiology; reported the differential retention and excretion of lithium in the manic phase; elucidated the therapeutic range for treatment of mania; and also studied the clinical picture of lithium toxicity, as well as demonstrated an effective treatment plan for it.
The next issue we thought urgent was potential toxic effects to the embryo. Now that safe clinical usage was possible, we realized special risk could exist in pregnant women, but the best we could do was an animal study on the results of prolonged sub-toxic lithium in rats (Trautner, Pennycuik, Morris et al. 1958). All animals went through pregnancy with good weight and general health. On examination of the uterus near term, the one finding was that lithium-treated rats retained fewer intact fetuses than controls, indicating that some toxic effects would have to be studied in higher species. This was the case in humans, where a low incidence of some cardiac defects occurred. The authors were all University of Melbourne colleagues.
Our next study may seem esoteric by current standards. However, it demonstrated important findings. Maintenance ECT was used in many cases of patients who suffered from recurrent depression, recurrent bipolar disorder and resistant schizophrenia unresponsive to other treatments. This study examined the use of lithium in bipolar cases and found that it could provide a maintenance medication to replace the use of recurrent treatments with ECT (Gershon and Trautner 1956).
In Australia, we also did some experiments in Trautner’s lab using Warburg brain biochemical techniques. With the simple belief that mania had an increase in brain cell activity, we embarked on our first experiment. We also knew that we could increase brain slice energy activity with di-nitro-phenol (DNP). Would the addition of lithium have an effect on this system? After a non-toxic concentration of lithium was added to the DNP activated system, we consistently found a decrease in metabolic activity. This was an exciting finding but due to the usual “circumstances beyond our control” we never continued with these experiments.
All of the studies cited were conducted without grants or research funds, contributed to by the faculty and the meager resources of their labs. They were all unblinded because we could not afford elaborate designs.
Blackwell B. Bits and Pieces of a Psychiatrist’s Life. United States; XLibris Corporation: 2012.
Cade J. Lithium salts in the treatment of psychotic excitement. Med J Austr 1949; 2: 349-52.
Coats DA, Trautner EM, Gershon S. The treatment of lithium poisoning. Austr Ann Med 1957; 6: 11-15.
Gershon S, Trautner EM. The treatment of shock dependency by pharmacological agents. Med J Austr 1956; 43: 783-7.
Gershon S, Yuwiler A. Lithium ion. A specific psychopharmacological approach to the treatment of mania. J Neuropsychiat 1960; 1: 229-41.
Glesinger B. Evaluation of lithium in treatment of psychotic excitement. Med J Austr. 1954; 41: 277-81.
Margulies M. Suggestions for the treatment of schizophrenic and manic depressive patients. Med J Austr 1955; 1: 137-43.
Noack CH, Trautner EM. The lithium treatment of maniacal psychosis. Med J Austr 1951; 2: 219-22.
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 Austr 1955; 2: 280-91.
Trautner EM, Pennycuik PR, Morris RJH, Gershon S, Shankly KH. The effects of prolonged subtoxic lithium ingestion in rats. Aust J Exp Biol Med Sci 1958; 36: 305-21.
June 25, 2015
Samuel Gershon: Lithium history
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, The Anticonvulsant Properties of Creatinine (1947) and Lithium Salts in the treatment of Psychotic Excitement (1949), require careful evaluation and interpretation of what they stated and how clearly.
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 Danish psychiatrist educated at the University of Copenhagen, living in Australia since 1984 and 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 me.
The parameter 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 8, 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, 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, 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 is 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.
Cade, JF.The Anticonvulsant Properties of Creatinine. Med. J. Aust. 1947; 2, 621-3.
Cade, JF. Lithium Salts in the treatment of Psychotic Excitement. Med. J. Aust. 1949; 2, 349-52.
Cade, JF. The Etiology of Schizophrenia. Med. J. Aust. 1956; 2, 135-9.
Cade, JF. Manganese and Mongolism. Med. J. Aust. 1958; 2, 848-9.
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
May 28, 2020