mandag, 25-10-2021

Johan Schioldann’s comment
Ripostes and Historical Annotations
to Barry Blackwell’s review of his
The History of the Introduction of Lithium
into Medicine and Psychiatry
Birth of Modern Psychopharmacology 1949

 

            I read with interest Barry Blackwell’s review of my work (Schioldann 2009) at the invitation of Thomas Ban and Samuel Gershon, eight years after its publication!

Blackwell’s opinion with respect to Part II of my work (Note 1) reads like I had made claims which are not supported by the available sources which I had collected. My aim was to provide an in-depth systematic historiography with consideration of metabolic disorder, auto-intoxication, uric acid diathesis, and, moreover, the use of lithium salts in a variety of illnesses, to establish, as far as possible, what John Cade had been, or might have been, inspired and influenced by, when from the mid to the late 1930s to 1947-49 he formulated his hypothesis about the pathogenesis of manic-depressive illness and schizophrenia, not dissimilar to what a considerable number of investigators had held.

In his book on the history of psychiatry, Mending the Mind (Cade 1979), published one year before his death in 1980, Cade recounts that what caused manic-depressive psychosis "was anybody’s guess up to the mid-1930, [but] by that time there was a certain amount of presumptive evidence favoring a pathophysiological or medical rather than a psychopathological explanation.” And, “certainly, manic-depressive patients appeared to me to be sick in the medical sense.” This made Cade wonder “what medical conditions appeared to provide some sort of analogy?” In this respect he was guided by the view that “manic patients behave in many ways as if they were intoxicated – noisy, restless, disinhibited and flamboyant.” Therefore, he raised the question could it be “that they were in fact intoxicated, perhaps by a normal product of metabolism circulating in excess?” If that was the case, melancholia could be explained as the opposite of this condition. Therefore, “the parallel between manic-depressive illness and thyreotoxicosis/myxoedema seemed an attractive proposition and a promising jumping off point” – his “explanatory hypothesis”, as he later termed it (Cade 1978, 1979). Further, “if this hypothesis is accepted as a working basis for investigation, it is evident that the key to the problem lies in the study of the manic patient, who ex hypothesi is producing the intoxicating agent in excess.” In fact, “if indeed this is so it is not unlikely that, as with other substances circulating in excess, it is being excreted in the urine and may be demonstrable therein” (Cade 1947).

Cade was acquainted with the famous work of Garrod (1859) which appeared in several revised editions (Garrod 1863, 1876) and also with a number of mainly British medical and psychiatric textbooks and journal articles, which presented the views held by many investigators of the connection between “gouty conditions,” nutrition impurities, the presence of some poison in the blood and affective disorders. He was also aware of their treatment with “alkalies,” e.g., lithium salts. Of special interest to him other than Garrod’s work, were the contributions of  Maudsley (1868, 1879, 1895), Mitchell (1870), Hammond (1871), Da Costa (1881) (Note 2), Gray (1886), Lange (1886), Aulde (1887), Clouston (1887, 1904), Haig (1888a,b, 1891, 1892, 1893, 1894, 1895, 1896 1897, 1898, 2000, 1899,1900, 1901, 1902, 1903, 1904, 1905, 1906, 1907), Hibbard (1898), Luff (1897, 1898, 1903, 1907a,b, 1908, 1909), Good (1903), London (1903), Folin (1904-1905, 1924), Bruce (1906, 1908), Squire (1908, 1916), Craig (1917, 1926), Kraepelin (1921), Devine (1921), Gjessing (1938), Price (1937) and Bollinger (1947).

To test his hypothesis, 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 (Cade 1947). All the animals died (Cade 1947, 1967, 1978). To test whether the same “toxic agent” was operant, he 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.” He continued his search for the “actual toxic agent,” querying what substances might have a modifying effect on the toxicity of urea. To this end he injected the animals with urea, uric acid (and creatinine). Uric acid showed “a slightly enhancing effect,” not immediately explainable, as “the specimens were more toxic than could be explained by the concentrations of urea actually present even if it were being enhanced maximally by uric acid;” as he had already stated, one would have to postulate an impossible concentration of 8% to 16% of urea. In his belief that the urine from manic patients was more or less more toxic than that from non-manic patients, but not established quantitatively, he finally postulated a third toxic substance, which he thought might be “operative” in neutralizing a protective effect of creatinine or an enhancement of the toxic effect of urea. It is here that lithium enters Cade’s animal experiments. At no later time did Cade make any mention of such a substance.

Cade (1949) first mentioned lithium in his paper, Lithium Salts in the Treatment of Psychotic Excitement, where he recounts that

“in the course of some investigations by the writer into the toxicity of urea when injected intraperitoneally into guinea pigs, it appeared desirable to ascertain whether uric acid enhanced this toxicity’, but ‘the great difficulty was the insolubility of uric acid in water, so the most soluble urate was chosen – lithium salts.”

Injecting “an aqueous solution of urea 8%, saturated with lithium urate,” Cade observed that “the toxicity was far less than expected, the great paradox” (Cade 1967). This solution of saturated lithium urate killed half of the animals tested, so “it looked as if the lithium ion might have been exerting a protective effect.” To test this further, he now injected solutions of lithium carbonate, carbonate substituted for urate. All test animals survived. This, he argued, showed “the lithium ion to have a strong protective effect against toxic, lethal effect of urea” (Cade 1949).

Cade’s next step was to test “whether lithium salts per se had any discernible effects on guinea pigs.” He now injected the animals “with large doses of 0.5% aqueous solutions of lithium carbonate” (Cade 1949):

“A noteworthy result was that after a latent period of about two hours the animals although fully conscious became extremely lethargic and unresponsive to stimuli for one to two hours before again becoming normally active and timid.”

The 1949 paper appears to be the only extant record of Cade’s experiments with lithium salts in guinea pigs.

Cade now swiftly transitioned from these rodent animals to a pilot study, prescribing lithium to a cohort of psychotically excited patients, including manic as well as depressed patients. He observed a striking anti-manic effect. Therefore, in this swift transition had he been guided by a prior knowledge of the use of lithium in affective disorders: gouty mania, maniacal symptoms (Garrod 1859), by the “old authors” presumed caused by, but by 1947-1949 long since discredited, uric acid diathesis, and not revealed by him? Or was he guided by other reasons? Why has Cade’s “story of lithium” remained so enigmatic? Can the puzzle be solved? Was it an expected or unexpected discovery, to him, to us historians? Sheer luck? Serendipity? Cade, for his part, maintained that it was the inevitable outcome of the testing of his hypothesis (Cade 1949, 1970, 1975, 1979) whereas, subsequently, first Gershon (1968) and most authors after him have argued that his discovery is serendipitous, among them Blackwell (1972), who now considers it to be both serendipitous and deductive (Blackwell 2017).

The only extant source that can shed sharper light on Cade’s swift transitioning and choice of lithium is found in his case card regarding his first lithium patient, W.B. But this opinion does not appear to be shared by Blackwell, who writes:

“The final piece of tendentious deductive reasoning was derived from the case card of Cade’s first patient with mania which records the prescription of lithium with the added comment that he had “an extremely high blood uric acid.” The author states, “This case card is highly indicative of the fact, if not proof, that Cade was fully acquainted with the views of his scientific forbears [sic] of a presumed connection between mania (gouty mania) and uric acid”, a belief never expressed in any of Cade’s writings about his discovery and totally inconsistent with the views about lithium [Cade] expressed before.”

Blackwell had already presented a brief summary of Cade’s papers with which he intends to document that, in fact, Cade had never expressed a belief of a presumed connection between gouty mania and uric acid and, moreover, that this was totally inconsistent with the views Cade had expressed about lithium:

In his 1949 paper, Cade’s only reference to earlier medical use of lithium was in gout when he mentions Garrod’s text (Garrod, 1859). About gout’s many “manifestations,” he makes no reference to depression or mania mentioned by earlier authors. His conclusion about the historical use [of] lithium was unequivocal: “…the uselessness of lithium in most of the conditions for which it was prescribed, and the fact there was other, more efficacious, treatment in the only disease in which it [had] been shown to be of some value, [and so] it is not surprising that lithium salts have fallen into desuetude.” Long after his own discovery he was able to write: “So the introduction of the lithium ion into medicine was all a silly mistake. It was perfectly useless for the conditions for which it was prescribed” (Cade, 1978) [sic Cade 1977]. He did, however, note that, “The water[s] of certain wells were considered to have special virtue in the treatment of mental illness…it is very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters.”

In other words, Blackwell accepts Cade’s statements at face value as correct and sufficient, at the latest in 1949, but reiterated by Cade, for instance, in his 1977 paper (with some modification in his 1978 paper), finally followed by, as if in way of some concession, but Blackwell failed to provide author, title and when first published: “The water[s] of certain wells […] it is very likely…” etc., etc. Cade had first paraphrased and commented on the wells in his 1949 paper, its provenance: Henderson and Gillespie’s Textbook of Psychiatry, published in 1944 and not included in Blackwell’s literature list. However, “it is very likely that their supposed efficacy…” etc., etc., was Cade’s comment, thus Cade contradicting himself in the same 1949 paper!

My critical analysis of the source materials to which Cade refers in his 1947 and 1949 papers (Schioldann 2009) drew no comment from Blackwell, nor are the authors and/or publications concerning this period of time (nor most of the prior ones) included in his list of references, except Garrod’s work, of which he includes the second edition, 1863, not the 1859 edition. Especially, Blackwell does not seem to think that it begs the question why Cade, in his paraphrasing of Garrod (1859), does not mention gouty mania and maniacal symptoms and their association with uric acid diathesis and consequent treatment with lithium salts.

In Sam Gershon’s (1968) opinion, “the introduction of lithium […] would seem to have been quite serendipitous, as we do not have any significant basis for its reinvestigation,” and with Soares (2000) he noted: “Looking at the origin of this story we find a fortuitous is path is traveled.” Further, Gershon (2000, 1971; Gershon and Daversa 2006) argued that one cannot extrapolate from lithium dosages in animal studies to dosages in humans. Mogens Schou (1992, 1996, 1998, 1999, 2001), for his part, found Cade’s work “indeed strange – the hypothesis which started his work was crude. His experimental design was not particularly clear. And his interpretation of the animal data may have been wrong.” Also, Schou’s attempts to replicate them failed. And critically he asked, “why would a compound counteracting the effect of intraperitoneal urea be of psychiatric interest?”

In accordance with these “expert” opinions, I concluded that Cade’s observations cannot be considered to be documentation of scientific fact. Did Cade, therefore, have knowledge that he did not reveal, that made his hypothesis and the outcome of his subsequent clinical not so unlikely? – a question also posed by Neil Johnson (1984; Schioldann 2009). In other words, did Cade have knowledge of the claims of, and was he influenced by, the “old authors” as to a possible therapeutic effect of lithium in a variety of conditions comprising mental disorders, e.g., “gouty mania,” “maniacal symptoms,” to be caused by the uric acid diathesis, as mentioned before? Further, I argued that Cade cannot not have acquired a broad knowledge of the literature on the relevant subjects (Note 3) and that this broad knowledge would have underpinned his work. Furthermore, that rather than based on erroneous, irreproducible observations in guinea pigs, he made an inductive leap in medias res, with prior knowledge into the undertaking of a pilot study of lithium in psychotically excited patients, but precipitated or sparked by his observations recorded in the W.B case card (Schioldann 2009):

“Date: 6/3/48. – Time: 12.15pm. – Test: Blood uric acid. – Result: 17.5 mg/%. – Mental State: Chronic mania. This extremely high blood uric acid result is suspect. – 18/3/48 – Blood creatinine 2.4 mg/% - 13/4/48. [Blood creatinine] 2.0 mg/% - [Same day, WB] Has been on large doses of lithium citrate for a fortnight.”

Knowledge of the relevant literature, presented in my book, can leave no doubt that W.B.’s case card has all the fingerprints of the old, but erroneous and thus long since discarded concept of uric acid diathesis and its treatment with lithium salts in mental disorders, e.g. ‘gouty mania’, ‘maniacal symptoms’ (Garrod 1859), erroneously then assumed and consistently with this I concluded:

“This case card is highly indicative of the fact, if not proof, that Cade was fully acquainted with the views of his scientific forebears of a presumed connection between mania (gouty mania) and uric acid” (Note 4).

The epithet suspect is the pivot that provides the final evidential weight in this “clinical equation” that the card contains, but which, for some reason, escaped proper attention by Blackwell. Not only the fact that he misquotes and misinterprets the card, but on wrong premises he resorts to cast serious blemish on my work – “the final piece of tendentious reasoning”! In fact, I put it that the W. B. card is the centerpiece or master card along Cade’s trajectory that holds the key with which to unlock Cade’s enigmatic story. Further, I argued that it was between 6th and 29th March that Cade had self-administered (Note 5) lithium in order to ascertain the right dosage to prescribe from various pharmacopoeias and other published sources (Note 6).

Cade resurrected the uric acid diathesis (Note 7), though only briefly (Note 8). His discovery, or finding, was not accidental, as he himself persistently claimed: “the inevitable though unforeseen product of a hypothesis and of a series of experiments to test that hypothesis,” and thus, in his opinion, not serendipitous. I agree with Cade, but for another obvious reason: Cade had traveled a path or overlapping paths, erroneously though, with a paradoxical outcome, but which, for some reason, he did not reveal or acknowledge. Although consistent with this, his premises erroneous, Cade, retracing the “old authors” (some of whom had observed therapeutic effect of lithium in mental disorders), arguably his seminal (re)discovery was not an unexpected, fortuitous, thus serendipitous outcome, as mentioned before and lastly by Blackwell (2017), but perhaps more fittingly describable as pseudoserendipitous, a derivative term of Walpole’s. By the same token, I must refute Blackwell’s absurd claim that “In the second part of John [sic] Schioldann’s book we can see how Cade’s Hero status is preserved and protected” in that “the voluminous database [sic] is somewhat subjectively and selectively mined to favor Cade and Schou’s view that the discovery of lithium was not serendipitous […].”

In this respect, Schou’s opinion (1977, 1982, 1984) could appear equivocal, but he did hold an extended opinion of Walpole’s concept (Note 9). All other things being equal, a couple of months before Schou died, in September 2005, when I was in the final stages of my studies on Cade’s “story of lithium,” which he read, and due to Cade’s curious change of subject: from the background for his discovery in 1949 to strontium – to be presented at a lecture at Risskov in 1970 – I queried with Schou, whom I knew well and became friends with, whether he thought that Cade did know about the past, i.e., the old authors and lithium therapy. He replied (2005):

“I have now perused all the approx. 40 letters Cade and I exchanged between 1963 and 1978 [and also perused by me] […] I did not hide my admiration and gratitude for the contribution he made with the 1949 article. At no time have I had any skepticism towards his work. I do not know whether there was something behind Cade’s choice of lecture when he was at Risskov. I had exhorted him to give an account of the background for his discovery of lithium’s antimanic effect, however, against all expectations he spoke about his investigations with strontium. On the basis of your work it could be that he was concerned that I as biochemically and physiologically more knowledgeable was going to ask him delicate questions. This thought never occurred to me. I believed his [1949] account blindly, although I had difficulty in following his logic.”

Schou’s reply certainly adds support to my interpretation of Cade’s “story.”

Blackwell, in no uncertain terms, rules out any influence on Cade by “the early Danish work decades earlier,” i.e., that of Carl Lange (1834-1900), namely his work on “periodical depression and uric acid diathesis” and its treatment with lithium (Schioldann 2001, 2009, 2011). It was not well received by contemporary psychiatry, either at home or abroad, due to his apparently rigid distinction between melancholy and depression and the fact that he had not been aware of the hypomanic/manic phases (Note 10) – not to mention his associating depression with the disreputed uric acid diathesis, hence the treatment with lithium salts. It was given its final coup de grace in 1927 by no less than Kraepelin, referred to by Blackwell (Note 11).

Given his research interests into manic-depressive illness and schizophrenia (“dementia praecox”), Cade would have read Kraepelin’s work, at least in English: Manic-Depressive Insanity And Paranoia (1921), which describes, in overview, some of the topics of interest and relevance to Cade’s own hypothesis about manic–depressive illness, and in addition Kraepelin’s dismissive comments on Lange’s depression thesis:

“Lange has arrived at the opinion, that increased formation of uric acid may be regarded as the essential cause of states of depression”; “Lange has assumed as the foundation of periodic depressive states with psychic inhibition, which indubitably belong to the domain of the malady [‘manic-depressive insanity’] here described, a gouty mode of development, a view which, however, till now cannot be regarded as proved or even as probable.”

Blackwell mentions Kraepelin’s dismissal of Lange’s work in general, but not in any context with Cade, and he was possibly influenced by the opinion espoused by Callahan and Berrios (2005), who did not refer to Kraepelin:

“Although unknown to him, Cade was retracing the steps of a Danish [neuropathologist], Carl Lange, who had reached the same conclusions 50 years earlier and who had successfully given lithium to patients with affective disorders. Locked in the Danish language, Lange’s work was not available to Cade. This caused an incorrect history of the ‘discovery’ of lithium treatment that historians are finding difficult to resolve.”

Cade’s reading of Kraepelin’s 1921 edition would have informed him that Lange’s depression thesis (1886) had been translated into German by Kurella (1896). But even if he had been sufficiently proficient in German, it would not have been available to him (it is not contained in “Libraries Australia Database”), so it would have remained “locked” in both Danish and German, but he would surely have become aware of the gist of it from Kraepelin’s text and thus also linking him in with the “old authors” on the subject, including, as mentioned before, various hypotheses concerning the pathogenesis of manic-depressive illness:

“[…] in manic-depressive insanity marked disorders of metabolism must take place”; “the endogenous excretion of uric acid […] remains in depressive patients at the lower limits of the normal, whereas in manics it is reduced”, querying “abnormally rapid breaking down of the purin bodies to still lower stages of disintegration”; “periodic neurasthenia which certainly belongs to manic-depressive insanity [with] diminution of uric acid excretion at the time of moodiness”; “intoxication by metabolic products of intestinal bacteria”; “insufficiency of thyroid gland activity”; “the relations between Basedow’s disease and manic-depressive morbid phenomena and […] auto-intoxication by glandular products”; “the remarkable changes of state often beginning so suddenly [in the form of] the clinical pictures recalling many intoxications (alcohol, products of fatigue)”; “internal poisons.”

Cade might also have been acquainted with Carl Lange’s thesis via the work of Haig (1891, 1900), who after Garrod was “a leading authority on uric acid.” He not only mentions the work, but they had also corresponded about it. For that matter, the German edition of Lange’s thesis was reviewed in “Journal of Mental Science” in 1897.

It is not correct, as Blackwell opines, that according to my work both Strömgren and Schou “disavowed” any influence of the Lange brothers in their decision to study lithium. In his letter to Neil Johnson (Johnson 1984), Strömgren would not rule out

“the old Danish lithium treatment may have prepared me unconsciously and made me sensitive to any new information concerning lithium.” But “to the conscious parts of my brain, however, it looks as if I was convinced by the first report from Australia that here was really a thing to be taken seriously” (Note 12).

In an interview of Strömgren by Schou in 1986 (Schioldann 2002), Schou put it to him: “It was surely Trautner’s work you read first, and then later Cade’s, and then you showed them to me.” “Yes,” Strömgren replied. Schou, for his part, denied any knowledge of Lange’s work initially, although one would find it hard to believe, had Strömgren not mentioned it to him, and he was adamant that he had never discussed lithium with his father, H. I. Schou, who died in the spring of 1952.

Blackwell again claims, more indirectly though, that in my book “Cade’s Hero status is preserved and protected,” Blackwell arguing that my failure to mention some blemishes in Cade’s story “does serve the purpose of embellishing a perfect Hero image”: 1) ”why did John Cade never speak of the work of Noack, Gershon and Trautner” (1951), “which made lithium safe to use” – “perhaps the greatest enigma of them all”; 2) “doubts about Cade’s ban on lithium”; and 3) “concealment of his first patient’s death due to lithium toxicity.”

I was not driven by any wish to protect or embellish “a perfect Hero image.” Interestingly, several of my Australian colleagues expressed their worry that my writing about Cade’s “story of lithium” would dent his reputation. As one of them said, remarkably: “You are cutting down one of our tall poppies.” I simply riposted: “I am an historian.”

The issues raised by Blackwell are recounted in my book, including the Cade-Trautner-Noack-Gershon question; a complete picture cannot be established on the available sources. However, Gershon recounted that Trautner and himself were never asked to present their data in Australia, “only overseas where there was great interest” (Gershon, 2007). Trautner (1954) wrote to Schou: “We are very glad to see, that you were able to confirm our results, particularly in view of a lot of opposition we meet” and the following year (Trautner, 1955): “During the first trials of lithium quite a few incidents occurred. Clinicians discarded the drug as unpredictable.”

In 1974 Schou met up with Gershon in New York and they discussed how it all began, including Trautner’s great contribution, reiterated by Schou directly to Trautner (1974):

“I still remember clearly the correspondence we had in the early fifties […] Much has happened to lithium since then, but we are still taking advantage of your contributions. I hope it gives you pleasure to think back on that work.”

But, understandably, Trautner not so pleased, replied (1975):

“It seems that lithium therapy gets slowly accepted, anyway some doctors [not named by Trautner] who violently opposed its use on humans, now scramble to get a share of the credit of its introduction [sic].”

After the death of W.B. in 1950, Cade banned the use of lithium in his own hospital. However, many Australian psychiatrists continued to prescribe lithium, some of them heeding Noack’s and Trautner’s 1951 report about serum monitoring of lithium, making the treatment safe, others not, e.g., Ashburner (1981) and Glesinger (1954), who found that serum monitoring was not required, leaving this to the academic departments. Intriguingly, although everybody knew about it, Cade remained uncommunicative about W.B.’s cause of death. I refrained from offering any deliberation of possible underlying personal motives, or for that matter, grudges Cade might have harbored, or regarding his manner, style, cognitive or personality-wise, as Blackwell sees fit to do.

Unfortunately, I could not shed any light on whether Trautner, the physiologist (Johnson 1984, Schioldann 2009), and Cade had met at any stage before or during his lithium experiments on guinea pigs, i.e., 1947-1948, and/or whether Trautner himself might have undertaken such or other studies. According to a personal communication to Johnson from D. Wright (1981), Head of the Howard Florey Institute of Experimental Physiology and Medicine, where Trautner worked, he was carrying out investigations on “nervous tissue metabolism” (Johnson 1984).

Blackwell claims that my “assessment of the importance of Cade’s discovery of lithium in 1949 and its impact on the early development of psychopharmacology tilts strongly in a positive direction in a manner not supported by the data”:

“It was in 1963 that Schou first wrote to Cade informing him of an interest in prophylaxis […] It is from this point on that Cade’s interest in lithium was vigorously renewed and from this point forward that comments begin to appear in the literature about the positive influence of events in 1949 on the entire history of the field. The flood of positive attributions stems largely from authors with a special interest in lithium, writing 20-30 years after Cade’s discovery and at a time when innovation in the field had slowed to a crawl. - Cade’s discovery of lithium’s value in mania is combined and conflated with Schou’s later discovery of serendipity [sic] to claim that this body of work formed a foundation for the whole of psychopharmacology as a discipline, an assumption not supported by close scrutiny of the relevant literature.”

I find Blackwell’s opinion one-sided and prejudiced, if not polemical, but of course difficult to disentangle, not least for the reason that Blackwell has himself, as he puts it emphatically, “played a personal and significant role in the controversies swirling around lithium.”

With Schou’s placebo-controlled double blind trial (together with Strömgren, N. Juel-Nielsen and H. Voldby) in 1954, the anti-manic effect of lithium became evidence-based. It was in 1963 Schou first wrote to Cade that his 1949 publication had “[…] meant a good deal to my professional life.” He also wanted to inform him of his attendance at the Third Conference of the Collegium Internationale Neuropsychopharmacologium (CINP) in Munich 1962, where he had emphasized that “the new era of psychopharmacology did not start in 1952 with reserpine and chlorpromazine, but in 1949 with your discovery of the effect of lithium.”

During the 1960s Schou indefatigably agitated internationally for the introduction of lithium in the treatment of mania – an uphill battle – assisted in this endeavor by Alec Coppen, Nathan Kline and Sam Gershon. By 1964, independently of one another, Hartigan (1963), Baastrup (1964) and Schou had made sporadic observations which were suggestive of lithium also having prophylactic properties in manic-depressive illness. Subsequently, Baastrup and Schou tested this in a non-blind, systematic lithium trial. Obviously, it was not in 1963, as Blackwell recounted, that Schou first wrote to Cade “informing him of an interest in prophylaxis” (Blackwell’s wording); it was three years later, on 19 July 1966, to be exact, that Schou expressed himself in very different, exuberant terms – he had attached a copy of the manuscript to be published the following year (Baastrup and Schou 1967):

“It is indeed a most interesting drug you have introduced into psychiatry. The more I learn about it, the more am I intrigued by it, and I should not be astonished if studies based on the observations with lithium would eventually lead to a real break-through in the control of manic-depressive psychosis.”

Cade replied, two weeks later:

“What is most impressive is your demonstration that lithium is so effective in preventing relapses of depressive as well as manic phases. This was something about which I had never been sure until I read your paper.”

Finally, Cade felt vindicated, attested to by his editorial to the inaugural issue of “The Australian and New Zealand Journal of Psychiatry,” 1967, entitled Lithium in psychiatry: historical origins and present position.

The 1967 paper, a non-blind systematic study by Baastrup and Schou, “Lithium as a prophylactic agent. Its effect against recurrent depressions and manic-depressive psychosis,” sparked fierce controversy, the infamous Battle of Lithium (Schioldann, 2006, 2009), waged in the international medical press, 1968-1972, and spearheaded by Shepherd and Blackwell, for and against “the beleaguered Danes.” Shepherd and Blackwell (1968), labeled the claims of the prophylactic efficacy “another therapeutic myth” based on “serious methodological shortcomings” and “spurious claims.” The ethical issue weighed heavily on Schou and Baastrup, conscious that to deprive their patients of lithium prophylactic therapy would expose those with depression to increased safety risk and thus, in accordance with the Helsinki Declaration, be ethically indefensible (Schioldann 2006). As Schou wrote (Schioldann 2009), “the controversy created uncertainty among British and American psychiatrists, and they hesitated to start prophylactic lithium treatment.” However, after painful consideration of the ethical dilemma, in 1970 Baastrup, Schou, Amdisen, Thomsen and Poulsen published a prospective-discontinuation double blind design trial: “Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent depressive disorders.” Considered “unparalleled in psychiatry” (Grof 1998), they reaffirmed lithium’s prophylactic efficacy; their findings were supported by concurrent works from Ireland, England and North America, using open, discontinuation and prospective trial designs (Schioldann 2009). Thus, not only did prophylactic lithium become evidence-based, lithium was to become the first-choice mood stabilizer in manic-depressive illness.

Shepherd did not comment on the trial directly, whereas Blackwell (1970) opined that it had “methodological inadequacies thus rendering the evidence unreliable”; Shepherd (1970-71), in “A prophylactic myth” even used terms such as unethical and unscientific. Deplorably, the controversy was to assume ad hominem proportions, leaving bad memories, if not scars (Schioldann 1999). It has been recounted by Johnson (1984) and by David Healy (2008), and in some detail by Schou himself in his My journey with lithium (Schioldann 2009), but not commented on by Blackwell in his review. It was 20 years later that Goodwin and Jamison (1990), world authorities on manic-depressive illness, hailed this trail-blazing discovery of lithium prophylaxis as “one of the most important advances in modern psychiatry.”

In the wake of the battle of lithium, in 1984 Felix Post (Wilkinson 1993) related that to Aubrey Lewis and Shepherd lithium was “dangerous nonsense” (Note 13). Further, Strömgren (1992; Schioldann 1999) had queried Shepherd, whom he knew well (Shepherd 1982), why the controversy against lithium prophylaxis had been continued. In the words of Strömgren, Shepherd had “quite openly” replied that it was:

“simply due to the fact that English psychiatry under the reign of Aubrey Lewis did not distinguish between psychogenic and endogenous depression (Schioldann 2003) (Note 14) and if lithium were to be recommended against depression, all doctors in England would use it against all types of depression, with the result that many patients not in need of it would only suffer damage from it – therefore lithium must be ravaged with fire and sword.”

In the interview of Strömgren by Schou in 1986 (Schioldann 2002), Schou asked him this delicate question: “Why do you believe that there was so much hesitation towards lithium both internationally, but also here in this hospital [Risskov]?” Strömgren’s reply was unequivocal:

“Yes, in the course of time, one has seen many drug trials give promising results, only afterwards to show that after all it was nothing. So the general skepticism had to be overcome, and there were also then people, as there always are, who meant that it was never a solution to prescribe medication to the patients. There were several of the influential colleagues who meant that this was not the avenue, and therefore they were not interested in carrying out such a treatment in systematic manner, and which they probably thought sooner or later might be abandoned and perhaps had some side-effects of which the patients should be spared. So, obviously, it took thumb-thick [“tommetykke”] proofs before it became clear to all and sundry that lithium was an essential plus in our armamentarium.”

Indubitably, Strömgren is referring to the Lewis-Shepherd-Blackwell prohibitive edict against prophylactic lithium. However, now 45 years on, with Blackwell’s statements included in de Moore’s and Westmore’s (2016) interesting book on Cade and his discovery in 1949, the controversial prophylactic issue can finally be laid to rest. Blackwell to the authors: “It turned out that we were wrong. Lithium was really the start of a revolution in psychiatry.” Blackwell must be lauded for placing this on the historical record!

This historical correction also addresses Blackwell’s last concern in his review whether lithium has formed “a foundation for the whole of psychopharmacology as a discipline,” an assumption, he emphasizes, that was “not supported by close scrutiny of the relevant literature.”

Most succinctly it has been expressed by Gershon (Schioldann, 2009), who has played a leading role in the lithium “travelog” right from the start in the early 1950s until the present day: “The introduction of lithium in 1949 makes it the first agent in the modern era of psychopharmacology, in that it preceded the introduction of chlorpromazine and reserpine” and with Daversa (Gershon and Daversa 2006) he wrote: “Lithium sparked a psychopharmacological revolution in psychiatry, or could be considered to be the breeder core.”

 

Notes:

Note 1) Blackwell: “A distinction is made between the first and second parts of the book. The massive database of lithium’s pre-1949 history [Part I] is impressive and valuable to all clinicians and research workers interested in lithium. I have only one caveat to assert that however compelling it might be, there is not a shred of evidence, real or circumstantial, from his own or the writings of others, that John Cade knew anything about that”; “despite the total lack of evidence in Cade’s own writings that he knew of lithium’s prior use in affective disorders, the author advances slender evidence that it might have been otherwise”; ”another slender thread in the rumor mill was […]”; “the final piece of tendentious deductive reasoning was derived from the case card of Cade’s first patient with mania […].”

Note 2) Da Costa (1888) is the first author that I was able to retrieve in the medical literature where a lithium salt (the citrate) other than lithium bromide (Mitchell 1870; Hammond 1871) was used to relieve or “remove” exclusively nervous symptoms. Intriguingly, it would appear that Da Costa thought that the remedies should be taken on a more or less permanent basis, for “until the state is permanently remedied,” the nervous symptoms “may appear for years.”

Note 3) Detailed reading lists of the requirements in the course of Diploma of Psychological Medicine and for the examination for the degree of Doctor of Medicine: The Melbourne University Calendar 1938 (Schioldann 2009).

Note 4) Neil Johnson (1984): “This observation is interesting in the light of the uric acid diathesis which had held sway in medicine prior to this [1948].”

Note 5) Chiu E. and Hegarty RM. (1999): Cade took “lithium carbonate for 2 weeks to test whether it was toxic or had unpleasant side-effect,” and they recounted that his wife, Jean, recalled that “I looked at him the next day, and the weeks that followed and wondered what I would do if he was changed by the lithium.”

Note 6) Cade FN. (1970, 1978). “The original therapeutic dose, decided on fortuitously, proved to be the optimum, that is 1.200 mg of the citrate thrice daily or 600 mg of the carbonate.”

Note 7) Cade did not use the term or concept of uric acid diathesis in his single-author articles, but in his paper with Neil Johnson (1975), where they made reference to “four papers by [Carl] Lange, published in 1897, in which the use of lithium salts in the treatment of ‘uric acid diathesis’ was described: this condition apparently involved both gout and mental depression and some improvement was noted in the latter.”

Note 8) A relative of Cade’s lithium patient, R.T. had written to him asking whether a poison in the blood could be established as the underlying cause and thus some form of treatment. Cade replied: “Please let me reassure you on several points that [R.T.’s] mental condition is not due to ‘poison in the blood’ so that no treatment directed to neutralize such a poison would be of the slightest use” (Schioldann 2009).

Note 9) Schou M. Correspondence with G. Kaufmann (1984), who also characterized Cade’s discovery as serendipitous. Schou’s reply: “It is not quite clear to me what you mean by ‘serendipity’ […] John Cade himself disliked that word, and I agree with him if it is used with the meaning ‘fortuitous’ or ‘random.’ I believe that discoveries often are made if an observation meets the prepared mind, and fortuitous circumstances may decide this, but other factors are at work to decide when a mind is prepared and when the time for the making the relevant observations and drawing the relevant conclusions is ripe.”

Note 10) Lange himself was not convinced that “uric acid diathesis” was the cause of periodical depression. In his classic work: Om Sindsbevægelser. Et Psyko-Fysiologisk Studie (1885, On Emotions. A Psycho-Physiological Study, 1922) (cf. The James-Lange theory of emotions), he had virtually formulated alternating periods of mania (as an illness of mood) and depression as a nosological entity, 14 years before Kraepelin (1899) formulated the concept das manisch-depressive Irresein (manic-depressive insanity), Lange commenting that “every psychiatrist knows the strongly developed forms which occur as ‘melancholia’ or ‘mania.” He emphasized that “the study of ’the emotional illnesses’ becomes particularly important […] once it has become more systematized than hitherto has been the case.” It was the following year, in 1886, he presented just such a study of “the emotional illnesses,” namely his depression pamphlet! (Schioldann 2009; Lange and Schioldann 2011).

Note 11) Blackwell (1985): “Much is made of earlier hints that vague mental symptoms associated with uric acid diathesis might benefit from lithium”. “Of more compelling interest is that the Danish internist, Carl Lange, published a monograph in 1886 Concerning Periodic Depression and its Pathogenesis which included the use of a lithium-containing mixture for preventative treatment.” Blackwell made reference to Schou’s father, H. I. Schou, for having denied Lange’s claims for lithium (based on Amdi Amdisen’s reading of Lange). This is not correct. What he did was to discard the uric acid diathesis as spurious. Had he been as curious, as was Cade, he might have undertaken a pilot study similar to what Cade was to do. Kraepelin had dismissed it in several editions of his work, last in 1927. Co-incidentally, it was the same year that it was resurrected by H. I. Schou due to its nosographical and nosological views. (Schioldann 2001, 2009; Lange and Schioldann 2011).

Note 12) In the same letter, Strömgren wrote that he found it “extremely fascinating if lithium salts which are chemically so simple could have a therapeutic effect in psychiatry, especially so if they were active against just one disease, which could tell us much more about that disease than lots of information concerning the therapeutic effects of complicated compounds which had no clear preference with regard to the different disorders they were used for. This was the reason why I asked my brilliant younger colleague Mogens Schou to devote himself to lithium studies.” In Schou’s interview of Strömgren in 1986 (Schioldann 2002), he recounted that he had always thought that the biological genesis of the manic-depressive psychosis was relatively simple, and given the illness’s ability to swing momentarily, perhaps it was caused by equally simple electrolyte mechanisms, and perhaps analogous to the interaction of electrolyte and hormones, as for instance had been shown by the Zondek brothers (Hermann and Bernhard) and which subject he years earlier had considered for his doctoral thesis. And therefore, he said: “It came like a revelation to me when I first heard about lithium,” this being a simple “chemical element.”

Note 13) Felix Post: “[Aubrey Lewis] was a therapeutic nihilist. He didn’t believe much in treatment, and it is true, that in those days, treatments were not terribly effective. He was not enamored of ECT and certainly not insulin coma. Lithium he, Shepherd too, thought dangerous nonsense.”

Note 14) Since his MD thesis (A clinical and historical survey of depressive states based on the study of sixty-one cases. [ibid. ‘Reaction, psychogenesis’, pp. 301-316]. University of Adelaide, 1931), Lewis held firm opinions about the dichotomy: endogenous and exogenous (1971), and in 1972, in scathing manner, he advocated for the relegation of the concept ‘psychogenic’, among whose ‘orthodox believers’ he grouped Wimmer, Strömgren and Faergeman, thus ultimately Wimmer’s concept of psychogenic psychosis (Schioldann 1996, 2003). Lewis died in 1975.

 

 

 

 

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February 15, 2018