Edward Trautner (1890–1978), a pioneer of psychopharmacology

ABSTRACT

This article examines the scientific career of Edward Trautner, who did pioneering research in the 1950s on lithium treatment for psychiatric disorders. Trautner was the first scientist to study the mechanism of action of lithium as a psychiatric medication. His research established that lithium could be used safely and rationally, and anticipated by a decade the large volume of research in the 1960s and 1970s that led to international acceptance of lithium treatment for mood disorders. Trautner was a pioneer of biological psychiatry who considered pharmacology to be a useful therapeutical tool rather than a permanent cure for putative chemical imbalances. His research involved cross-disciplinary collaborations that combined clinical and laboratory research in the disciplines of psychiatry, physiology, biochemistry, teratology, and even oncology. Trautner himself had a multidisciplinary background that included publications in literature and philosophy.

KEYWORDS:

• Biological psychiatry (history of)
• bipolar disorder
• John Cade
• lithium therapy (history of)
• Mogens Schou
• neuropharmacology (history of)
• psychopharmacology (history of)

Acknowledgments

The research published in this article was conducted within the larger horizon of the International Trautner Project, a collective effort to rediscover the life and work of Edward Trautner, which has brought together researchers in two language spheres and two continents, working without grant funding. Beside ourselves, the other core contributors to the project are Michael Messer (Trautner’s student at the University of Melbourne in the 1950s), Beverly Close (Hervey Bay Family History Association, Queensland, Australia), Aoife Naughton (Dublin, Ireland), and Christa Steinle (former director of the Neue Galerie Graz/Universalmuseum Joanneum).

For the present article, thanks are due in particular to Sam Gershon, F. Neil Johnson, Derek Denton, Walter A. Brown, Brandon Reines, and Barry Ninham for their advice and insight on scientific matters; and to Juliet Flesch (author of Life’s Logic) and Carol Bunyan (a coauthor of Dunera Lives) for advice and help with historical matters. We thank Tracy McDonald and Sandra Dayao (Cumberland Hospital Library) for help in locating scientific papers; Peter Gill for archival work in the face of Covid lockdowns; and Sophie Garrett (University of Melbourne Archives) for patient help in locating documents. Christian Fiedler (bamberger-bier.de) helped reconstruct Trautner’s schooling; and Thomas Kruckemeyer (German Language Services, Adelaide, Australia) provided valuable help with translation.

For their first-hand testimony, we again thank Sam and Lisl Gershon, F. Neil Johnson, and Derek Denton; we also thank Kit Noack-Corris, Barbara Noack-McNamara, Margaret Goding, and Meriel Wilmot-Wright.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

¹ Over the course of the 1960s, Schou became the world leader in lithium research; in 1984, F. Neil Johnson would call him “the driving force behind the modern use of lithium on a worldwide scale” (Johnson 1984b, p. xi).

² Trautner’s theorizing often remained unpublished, or confined to the briefest discussions in his published works. This was not to his liking, and he complained for instance that editors had forced him to cut whole paragraphs of speculative material from a paper (Trautner to Mogens Schou, September 28, 1955, in “Trautner-Schou correspondence 1953–1975”). In the present article, we have retrieved Trautner’s theoretical insights from unpublished records, and also attempted to reconstitute the thinking behind the logical development of his research.

³ Sam Gershon, interview with G. de M., October 20, 2010. R. D. Wright, letter to F. Neil Johnson, August 26, 1981, quoted in Johnson (1984b, p. 63). Wright’s original letter, and all the other documents collected by Johnson in preparation of his book, have unfortunately been lost, as Johnson related in an e-mail to W. W. of April 24, 2020.

⁴ Johnson (1984b, pp. 61–62 and footnote 17). Contacted recently by us, Johnson expanded: “When I started work on the History and, in the course of doing so, corresponded or met with Mogens Schou and others, my interest in Trautner’s work blossomed and I began to realize just how important his contribution had been to the early acceptance of lithium therapy. Indeed, if I recall correctly, I expressed the opinion that, in this respect, his 1951 and 1955 papers had probably been more influential than those published by John Cade—a view also voiced on a number of occasions by Mogens and others” (e-mail to W. W. of March 13, 2021).

⁵ See Trautner and Shaw (1945); Loftus-Hills, Trautner, and Rodwell (1945); Trautner and Neufeld (1946); Trautner (1946); Loftus-Hills, Trautner, and Rodwell (1946); Trautner and Neufeld (1947); Trautner (1947); Mitchell and Trautner (1947); Trautner and Polya (1948); Trautner, Neufeld, and Rodwell (1948); Trautner and Roberts (1948); Trautner and Neufeld (1949); Trautner (1949); Trautner and McCallum (1950).

⁶ See the sections titled “The game gets under way,” “The ionotropic mechanism,” “The metabotropic mechanism,” and “Lithium shock.”

⁷ These unpublished notes are cited and discussed below in the sections titled “The game gets under way,” “The ionotropic mechanism,” “The metabotropic mechanism,” and “Lithium shock.”

⁸ See the section “Lithium shock.”

⁹ See sections “Lithium shock” and “The ionotropic mechanism.”

¹⁰ The lecture was given on March 2, 1914, as noted in Bericht des Naturwissenschaftlichen Vereins für Schwaben [Report of the natural-science club for Swabia], vol. 42, p. IV.

¹¹ The evidence for Trautner’s career intentions at this stage are (a) his studies and first job, which were oriented toward a teaching career rather than a medical license or a doctorate; (b) the magazine piece published in 1914; (c) a description of him in 1919 as a “young teacher and writer” and an “idealist trained in the new pedagogical teachings” (Hiller 1919); and (d) the magazine Trautner edited in 1919, Der Weg, whose first publisher was an anthroposophist and whose ideological content leaned at times toward the ideas of that movement.

¹² On August Bier (1861–1949) see the biographical notice on the Deutsche Biographie website; also P. Freyschmidt-Paul, August Bier: das chirurgische Werk, thesis, Ruhr Universität Bochum (Germany), 1999. James or Johannes Fraenkel (b. 1879) was for many years the head of the orthopedic division of Bier’s surgical clinic (see K. Vogeler-Stettin, “Die Chirurgie unter Bier”, in Das Universitätsklinikum in Berlin, ed. P. Diepgen and P. Rostock. pp. 124 and 132. Leipzig: J. A. Barth, 1939).

¹³ Trautner described this research in an application for a temporary medical license, which he submitted to the Australian “Alien Doctors Board” on March 27, 1942 (Files of the Central office of the Australian Department of Health, National Archives of Australia: item ID 143378, digital pages 288–290). Fraenkel’s wartime research on choline is described in his papers, Über erweichende Behandlung [on emollient treatment], Muenchener Medizinische Wochenschrift vol. 62:2 (1915), no. 41/42, pp. 1401–03; and Zur Behandlung der Kontrakturen (Bedingungen der Cholin behandlung) [For the treatment of contractures (conditions of choline treatment)], Zentralblatt für Chirurgie 1917, Nr. 31 (both cited by Trautner 1920).

¹⁴ On Oscar A. Mendelsohn (1896–1978), see the notice by Ray Marginson in the Australian Dictionary of Biography. Trautner’s work at Mendelsohn & Co. is attested in a memo from the Chairman of the Commonwealth Alien Doctors’ Board, J. H. L. Cumpston, dated May 16, 1942, found in the correspondence files of the Australian government’s Department of Health (National Archives of Australia: item ID 143394, digital page 173).

¹⁵ University of Melbourne, Registrar’s Correspondence (University of Melbourne Archives, series UM 312 / accession no. 1999.0014), year 1942, file 498: “Physiology: Staff.”

¹⁶ See list of publications cited in note 5.

¹⁷ On Roy Douglas “Pansy” Wright, see the biography by McPhee (1999). On wartime phytochemistry research at the University of Melbourne, see Foley (2006), and Price, Lamberton, and Culvenor (1992). Trautner’s change of direction in 1947 is attested in “Trautner-Wright correspondence 1946–1948.” See also the University of Melbourne’s Research Reports for 1947–1949.

¹⁸ See Bradley et al. (1950), Trautner and McCallum (1950), Trautner and Bradley (1951), and Trautner (1951).

¹⁹ Lithium’s biophysical properties are discussed by Jakobsson et al. (2017), and Alfredsson et al. (2021).

²⁰ See Kent and McCance (1941); Radomski et al. (1950); Davenport (1950); Talso and Clarke (1951); Foulks, Mudge, and Gilman (1952). Trautner himself contributed to scientific knowledge on this subject (Trautner et al. 1955). Radomski’s research, conducted in dogs, was aimed at understanding the mechanism of lithium toxicity. As such it was an important precursor for Trautner’s study of the mechanism of action of lithium as a psychiatric drug.

²¹ See de Moore and Westmore (2016, p. 166) and Johnson (1984b, pp. 59–60). Within a year of Cade’s publication, more than 100 patients in the Melbourne area were being treated with lithium, and several dozen also in Sydney, Perth, and Tasmania. Cade’s findings were known in the Melbourne area before they were even published, according to later testimony by the psychiatrist J. V. Ashburner (quoted in Johnson 1984b, pp. 59–60). The enthusiasm for lithium spread rapidly within weeks of the publication, as attested by letters received by Cade (quoted by de Moore and Westmore 2016, p. 166, from originals in the Cade family archives and in the papers of Edmond Chiu). In September 1950, Ashburner, the superintendent of a Melbourne-area mental hospital, reported that his hospital had given lithium to 50 patients, in some cases for as long as 12 months (Ashburner 1950). In their August 1951 paper, Noack and Trautner reported giving lithium to 100 patients over the course of two years at a Melbourne-area hospital (Noack and Trautner 1951); and by 1953, Trautner’s group had treated more than 300 patients (Trautner to Schou, September 28, 1953, in “Trautner–Schou correspondence 1953–1975”; and Trautner et al. 1955, p. 288, col.1).

The spread of lithium treatment in Australia outside of Melbourne appears to have been based on contact with Cade. For example, F. J. Scanlan, the superintendent of Parramatta Mental Hospital in the Sydney area, wrote to Cade in October 1949 to ask where lithium supplies could be obtained (letter dated October 6, 1949, cited in de Moore and Westmore 2016, p. 166). Charles Brothers, the director of mental hygiene in the state of Tasmania, wrote to Cade in June 1950 that lithium was in such widespread use there that hospitals were having a hard time maintaining adequate supplies (unpublished letter, Cade family archives). Five years later, a Tasmanian psychiatrist reported that trials of lithium at his hospital “were started some years ago,” and that lithium treatment “has evidently become a routine procedure in several Australian mental hospitals since Cade’s paper was published in 1949” (Margulies 1955). In Western Australia, lithium was given to 104 patients between 1950 and 1954 at the Claremont Mental Hospital, where Cade’s friend Frank Prendergast was the superintendent (Glesinger 1954). However, lithium treatment was not the norm throughout Australia: John Cawte, the acting superintendent of a large mental hospital in South Australia, did not mention lithium in an account of how acute mania was being managed at his hospital in 1952 (Cawte 1952). Cawte would later remember that time period as being “before the advent of lithium, chlorpromazine, or haloperidol” (Cawte 1988, p. 82; see also p. 78).

²² The first death in Australia due to psychiatric lithium occurred in December 1949; this was followed by a second death in March 1950, and then the death of Cade’s patient in May 1950. The first death was published as a case report in the Medical Journal of Australia in August 1950 (Roberts 1950). The second was described within a larger case series published in 1954 (Glesinger 1954). Cade never published an account of the third death (Brown 2019; de Moore and Westmore 2016). In fact, no other Australian lithium death was ever published, either in medical journals or in the media, although at least four more did occur in the state of Victoria (Public Records Office of Victoria, inquest nos. 1952/941, 1952/1866, 1952/1884, and 1953/1925). Despite the lack of public disclosure, these lithium deaths were widely known within the medical community of the state of Victoria (see de Moore and Westmore 2016, pp. 183–184 and 170–171; and Westmore 2002, pp. 164–167).

²³ See de Moore and Westmore (2016, chap. 20); for a more detailed discussion, see Brown (2019, chap. 5). See also Johnson (1984b, chap. 4) and Schioldann (2009, chap. 23). The American lithium toxicity cases (including several deaths) were reported in Australian newspapers in February 1949 (e.g., see the Melbourne Herald of February 19, 1949, p. 1). Clinical details were summarized in the Medical Journal of Australia of July 30, 1949, i.e., about one month before Cade’s paper appeared there (Anonymous 1949).

Newspapers in Australia were silent about psychiatric lithium toxicity, and silent also about the benefits of psychiatric lithium. We conducted a search of the Trove database of Australian newspapers between January 1949 and December 1955, looking for mentions of psychiatric lithium: this returned only one hit, a 1950 piece on mental hospital management in Western Australia (The West Australian, April 6, 1950, p. 3). We have argued elsewhere that this silence in the press, as well as evidence from coroner’s depositions, suggests that a de facto clinical trial of lithium was occurring in Australia’s public mental hospitals, with unofficial support from regulatory authorities (de Moore and Westmore 2016, p. 186).

²⁴ John Cawte, mentioned in note 21, later befriended Cade, and he recalled that Cade had “become frightened” of lithium (Cawte 1988, pp. 21–22; 1999). R. D. Wright recalled that Cade regarded lithium as “too dangerous” (Wright 1981). Cade’s motives for withdrawing from lithium research have been discussed by de Moore and Westmore (2016, pp. 116, 119, 176–177, 235, 250, 279), Brown (2019, pp. 165–171), and Schioldann (2009, p. 246).

²⁵ According to Trautner himself, “The clinical use of the drug was started by Dr. Cade in 1949 [sic], the physiological and pharmacological investigation in the Department of Physiology in 1950” (E. Trautner, “Application for Grant from Mental Health Research Funds—1957,” typescript with cover letter dated December 11, 1956, in “Physiology MHRF file”).

²⁶ John Harold Talbott (1902–1990) was the chief of medicine at the Buffalo General Hospital in Buffalo, New York. He would later serve as editor of the Journal of the American Medical Association and of the Merck Manual.

²⁷ Cade (1949) recommended starting doses of 60 grains per day of lithium citrate or 30 grains per day of lithium carbonate (i.e., respectively, 42 mEq and 52.5 mEq per day of lithium ion). The lithium salt substitutes were typically consumed at well under 0.5 grams per day of lithium chloride (i.e., 12 mEq per day of lithium ion; Talbott 1950).

²⁸ Trautner to Mogens Schou, September 28, 1955, in “Trautner–Schou correspondence 1953–1975.”

²⁹ See Wright (1981). Wright’s recollection came 30 years after the fact, but his chronology is confirmed by Trautner’s writeup of his work in the Research Report for 1950, and in his 1951 paper with Noack (Noack and Trautner 1951).

³⁰ Physiology department rosters named Trautner as “research staff” as opposed to “teaching staff” (University of Melbourne Archives; see also the Research Reports). It is unlikely he would have taught a full lecture course. The diploma in psychological medicine (DPM) was a postgraduate degree awarded after completion of residency training in psychiatry. This diploma did require six lecture classes given over a two-year period, but physiology was just one of the six required classes. If Trautner gave lectures, his role was probably confined to teaching a module on brain metabolism within the larger physiology lecture course. (For the dates and subjects of lectures in the DPM program, see the Faculty of Medicine Handbook published by the University of Melbourne.)

³¹ Charles Hugh Noack (1917–1969) grew up in Adelaide, obtaining his bachelor of medicine degree in 1941 at the University of Adelaide. He served in the Royal Australian Air Force from 1942 to 1946, then opened a general practice in Longford, Tasmania. In January 1949, Noack sold his practice and moved to Beechworth, Victoria, to work as a resident at the mental hospital there. His career in psychiatry took him through the following appointments: Beechworth (January to c. August 1949), Mont Park (c. September 1949 to c. June 1953), Bundoora (c. June 1953 to c. January 1955), Sunbury (1955–1956), Observatory Clinic (1956–1963), and private practice (1964–1969). This chronology was assembled from documents and testimony provided by Noack’s eldest daughter, Kit Noack-Corris; institutional affiliations given in Noack’s scientific papers; newspaper stories; and Australian government files (National Archives of Australia item ID nos. 5251653, 5251654, and 1804806).

Against Wright’s recollection that Trautner first met Noack as a student in his class, student records kept by the University of Melbourne Archives show that Noack did not matriculate at the university until May 18, 1950, and that he was dispensed from first-year lectures in physiology on the grounds of his experience as an Air Force doctor. But Noack and Trautner began their lithium research in 1950, as attested by Trautner in a 1956 grant application (cited above, note 25). Thus, the likelihood is that R. D. Wright himself brokered the partnership with Trautner, as he would later broker Trautner’s partnerships with his two other chief collaborators in lithium research, Michael Messer and Sam Gershon. (This was attested by Messer and Gershon in interviews with G. de M. of November 12 and October 20, 2010, respectively.) However, neither of these collaborations was limited to lithium. Noack, for example, would work with Trautner concurrently on tigloidine (for reference, see note 48 below) and later also on succinate (see note 62).

³² R. D. Wright’s interest in promoting lithium research is attested by a noteworthy piece of circumstantial evidence. Noack and Trautner’s 1951 lithium paper was the lead research paper in the August 18, 1951, edition of the Medical Journal of Australia, and it was immediately preceded in the journal’s pages by the text of an important public lecture given by John Cade, suggesting an editorial intent to link them (Cade 1951; Noack and Trautner 1951). Cade’s lecture was a general review of the state of psychiatry in 1951, which ended with the prediction that biochemistry was about to revolutionize the field. The very next page carried Noack and Trautner’s pioneering study of psychiatric lithium treatment, which relied on biochemical measurements in tissue samples. Cade’s lecture had been chaired by Wright, so this meaningful juxtaposition in the journal may well have been Wright’s own doing. (Westmore 2002, p. 154.)

³³ See Hewat (1990, chap. 2), McPhee (1999, pp. 104–106), and Flesch (2012, p. 104).

³⁴ Flesch, ibid. The funding came from the Australian government’s National Health and Medical Research Council.

³⁵ Ray Bradley, interview with Peter McPhee, cited in McPhee (1999, p. 222, note 91). Trautner’s quip was a pun on the double meaning of “ionic,” because “doric” and “ionic” are also names for ancient Greek architectural styles.

³⁶ This connection was established by F. Neil Johnson, who interviewed Wynn for his book The History of Lithium Therapy. Johnson noted: “Trautner thus found himself in an environment in which notions of ionic regulation were being actively discussed, and in which the means for studying quantitative aspects of electrolytes were readily available” (Johnson 1984b, p. 61).

³⁷ See Cade (1949), Noack and Trautner (1951), and Trautner et al. (1955). Derek Denton’s habit of expressing concentrations in milliequivalents per liter was a sore point with older doctors in Melbourne (Hewat 1990, p. 31).

³⁸ Spectrophotometers (Figure 3) were invented in the 1930s and first commercialized in the 1940s, after which they proceeded to revolutionize all fields of chemistry. (An early example of their use to measure lithium levels in clinical tissue samples is Kent and McCance 1941.) Before the advent of the spectrophotometer, clinical chemistry had been cumbersome, and it took a long time to get from a clinical sample to a measured value. Moreover, standard laboratory tests did not actually produce a measured value for electrolytes. Instead, they reported “predicted values” based on chemical reactions of the blood with standard reactants (Morris and Travis 2002; Rosenfeld 2002).

The “flame attachment” to the spectrophotometer (Figure 4) enabled the sample to be vaporized and heated instantly, meaning that measurements could be taken from smaller and more freshly prepared biological samples, such as a blood sample taken directly from a hospital patient. The flame attachment was first used during secret wartime research on the manufacture of penicillin, for which it proved crucial. The first published accounts of its use with clinical samples date to the immediate postwar period (e.g., Fox and Bauer 1947; Hald 1947).

³⁹ Wynn et al. (1950) provided a visual illustration of the instrument (Figure 4). Wynn’s spectrophotometer was also described to us by Sam Gershon (interview with G. de M., October 22, 2010), and the room housing it was described by Michael Messer (e-mails to W. W. dated May 10, 2020, January 5, 2021, and July 7, 2021). According to Wynn, the spectrophotometer used by his group cost £500 (equivalent to about US $25,000 today), but the shipping cost another £500; R. D. Wright paid for the instrument using funds from a Rockefeller Foundation grant, and Wynn himself personally paid for the shipping. (Wynn, cited by Hewat 1990, 24; the Rockefeller Foundation funding is also acknowledged by Wynn et al. 1950.)

⁴⁰ Noack and Trautner (1951, p. 221, col. 2) indicated that Cade had communicated with them about his clinical experience regarding the deaths of two psychiatric patients from lithium toxicity: one was Cade’s own patient, and the other was a patient in Western Australia, probably at Claremont Mental Hospital in Perth, where Cade’s friend Frank Prendergast was the superintendent (Western Australian Death Index, reg. no. 526, 1950).

Trautner recorded that he and Noack began their lithium research in 1950 (cited above, note 25). However, two cases reported in their 1951 paper have treatment dates beginning in September 1949 (Noack and Trautner 1951, p. 221, case reports for Cases I and II). This suggests that Noack may have included data from lithium patients already under his care prior to meeting Trautner. This may have been done under supervision from John Cade, as Noack and Cade worked across the street from each other in 1949, at Mont Park and Bundoora hospitals. In fact, the Noacks and Cades were family friends in the early 1950s, and the Noack family were invited to parties at the Cade household (Kit Noack-Corris, interview with W. W., September 10, 2020).

⁴¹ R. J. H. Morris, letter to F. N. Johnson dated September 11, 1981 (quoted in Johnson 1984b, p. 160). Surprisingly, Morris was not credited on Noack and Trautner’s 1951 paper, though his collaboration with them had begun in 1950, as attested by that year’s edition of the Research Report. The fault would later be remedied somewhat by giving Morris coauthorship on the 1955 paper (Trautner et al. 1955).

⁴² In his letters, Trautner was always highly conversant with the details of lithium treatments carried out under his supervision (e.g., see “Trautner-Schou correspondence 1953–1975”). Sam Gershon recalls of a slightly later time that he used to drive out to outlying mental hospitals to help Gershon with patient interviews. They would conduct the interviews together, to assess the suitability of patients for a lithium trial or to check on the patients’ progress (Sam Gershon, interviews with G. de M., October 22, 2010, and with W. W., February 23, 2021).

⁴³ Under the terms of a program for refugee doctors,Trautner received a temporary medical license issued on May 2, 1942 and valid until December 31, 1943 (Security Service, New South Wales [sic], Book of Licenses for Alien Doctors, 1942, National Archives of Australia: item ID 448841). A 1943 letter Trautner wrote to the Australian Minister of the Interior in support of his application for citizenship, shows how his medical license added to his status and desirability as an immigrant; it is preserved in the Correspondence files of the Department of Immigration’s Central Office (National Archives of Australia: item ID 1924692, digital page 88). After being awarded Australian citizenship in November 1947, Trautner applied for a permanent medical license, even though by then he was stably employed as a researcher. The license was clearly intended to support his claim to citizenship, as attested by many remarks in Trautner’s correspondence with R. D. Wright (“Trautner–Wright correspondence 1946–1948,” letters dated December 4, 1946; January 24, 1947; August 25, 1947; October 21, 1948). Trautner received his permanent license in June 1948, and he is listed after that time in the Victoria Government Gazette’s annual inventory of physicians (e.g., January 8, 1949; January 31, 1950; and subsequent editions). (N.B.: Trautner’s name does not appear in the main alphabetical list, but on the last page, on a separate list of “persons registered under the provisions of the Medical Practitioners Registration Act 1946.”)

⁴⁴ The subject matter of the 1955 paper was described as early as 1950 in the Research Report for that year, which lists a project titled “Action of lithium on the healthy and the maniacal patient.” This indicates that the 1951 and 1955 papers really stem from a single continuous research project. Likewise, the 1951 paper includes a preview of the findings of the 1955 paper, and states that “a detailed investigation of the changes caused in the ionic composition of blood, plasma and urine in the healthy as well as in the maniacal patient is being carried out and will be reported in a following publication” (Noack and Trautner 1951, p. 220).

⁴⁵ For an example of the procedure, see Darnell and Walker (1940). For context, see Arden (1938).

⁴⁶ The investigation of lithium’s effect on healthy volunteers is mentioned in the Research Reports for 1950, 1952, and 1953. This was based on self-administration, as discussed in Noack and Trautner (1951) and Trautner et al. (1955).

⁴⁷ See “Interim Research Report 1951.”

⁴⁸ On the discovery of tigloidine and its use in experimental neurology, see Williams (2013, p. 396). Williams does not mention Trautner’s name, but most of the research she profiles was done by him. Tigloidine was first characterized by William Mitchell during the course of doctoral research at the University of Edinburgh (see, e.g., Barger, Martin, and Mitchell 1937). Trautner became aware of it during his wartime work on alkaloids of Duboisia, and during a stint at Oxford in 1947 he collaborated with Mitchell on a publication (Mitchell and Trautner 1947). Upon his return to Melbourne, Trautner then tested tigloidine and other substances to discover candidate drugs active at the neuromuscular junction (Trautner and McCallum 1950). This work identified tigloidine and procaine as candidate anti-Parkinsonian drugs, and Trautner then performed clinical tests of each substance with the help of Noack (Trautner and Noack 1951; Trautner 1951).

There ensued a seven-year hiatus in Trautner’s publications on tigloidine, mainly because he could not obtain it in sufficient quantity to perform clinical studies. After attempting to synthesize it himself, he was able to persuade T & H Smith and Co. of Edinburgh to do so, and in 1953 he resumed testing it on patients with Parkinson’s disease and Huntington’s chorea (Research Reports for 1952 and 1953). However, by 1954 his supply was still very limited, and he was saving it to treat a few cases of Huntington’s chorea (unpublished interim research report dated July 15, 1954, in University of Melbourne Archives, R. D. Wright Papers (accession no. 1968.0003), item no. 6/12: “Succinic Acid Committee,” p. 18 of 45). Finally, in November 1958, Trautner published a case series of 12 Huntington’s patients (Trautner and Gershon 1958). In subsequent years he published two further papers on related topics (O’Rourke et al. 1960; Trautner and Gershon 1959).

⁴⁹ “Interim Research Report 1951” (emphasis in the original).

⁵⁰ Trautner had observed that the different salts of lithium (chloride, carbonate, citrate) produced different patterns of effect on the acidity or alkalinity of urine, and also had different therapeutic activities against mania. He experimented with this effect by administering extra chloride ion in the form of ammonium chloride or calcium chloride. His preliminary conclusion was that lithium must be acting on a “system extrinsic to the chlorine: cation ratio,” and that this must be located upstream from the kidney in the body’s electrolyte regulation cascade. The hypothalamus and adrenal glands were suggested as possibilities. (“Interim Research Report 1951”)

⁵¹ “Interim Research Report 1951.” Trautner anecdotally reported to Mogens Schou in 1957: “We have, with very promising results, used lithium in a few cases of premenstrual tension with tendencies to psychotic, violent or criminal behavior, giving three tablets per day from about ten days before the onset of menstruation and stopping it as soon as menstruation starts” (Trautner to Schou, March 20, 1957, in “Trautner–Schou correspondence 1953–1975”).

⁵² “Interim Research Report 1951”; Research Report for 1951, pp. 143–144.

⁵³ Lithium treatment for premenstrual tension proved unsuccessful when investigated by I. W. Sletten and Sam Gershon (1966), or no better than a placebo when investigated by Mogens Schou’s group (Singer, Chen, and Schou 1974). Lithium administration as a diagnostic tool was explored by Maurice Serry, working under John Cade at Royal Park Hospital in 1969 (Serry and Andrews 1969).

⁵⁴ Research Report for 1952.

⁵⁵ Noack’s frustration with the medical establishment is attested by a set of documents shared with us by his daughter Barbara Noack-McNamara. They consist of a typewritten “Critique of the Medical Curriculum” and two sets of handwritten notes for further development of the typescript. Internal references indicate these documents were composed in late 1951 to early 1952. They show that Noack was critical of a conservative attitude to new research among established clinicians. His arguments demonstrate a thorough knowledge of Marxist theory. Noack had been a Communist sympathizer since his student days in Adelaide, and his daughter Kit remembers that in the early 1950s he owned a significant collection of Communist literature (Kit Noack-Corris, interviews with W. W., September 10, 2020, and with G. de M., September 25, 2020). His Communist activism increased after 1951, and by the 1960s, he was a full member of the Communist Party.

⁵⁶ To safeguard privacy, we are not reporting Trautner’s stepson’s name or the details of his inquest. However, we have examined the inquest file and derive our account of the death from that source.

⁵⁷ Meriel Wilmot Wright, interview with W. W., March 24, 2020; Michael Messer, interview with G. de M., November 12, 2010; Frank Hird, e-mail to G. de M., November 29, 2010; Ray Marginson, interview with G. de M., January 19, 2011. Sam Gershon was not aware of the suicide.

⁵⁸ Sam Gershon, interview with W. W., February 7, 2019; Lisl Gershon, interview with G. de M., November 2, 2010; Michael Messer, interview with G .de M., November 12, 2010, and e-mails to W. W. of January 26–29, 2019.

⁵⁹ In 1954, Gershon told the reporter Charles Hellier that he first met Trautner in the early months of 1953 and began a scientific collaboration with him soon afterward (Hellier 1954). Gershon’s first publication with Trautner was in September 1953, when they cosigned a letter to the editor of The Lancet (Richardson et al. 1953).

According to the eminent historian of psychiatry Edward Shorter, the seminal event in stimulating American interest in lithium was Gershon’s arrival in 1960 in Ypsilanti, Michigan, where he joined the Schizophrenia and Psycho-pharmacology Joint Research Project of the University of Michigan (Shorter 2009). According to the University of Melbourne Archives, Gershon left for the United States in March 1959, and returned again in May 1960. He then left Australia permanently for the United States in January 1963. Trautner’s last published paper was coauthored with Gershon and appeared in the January 16, 1960, edition of the Medical Journal of Australia (O’Rourke et al. 1960).

⁶⁰ On the chronology of Gershon’s professional appointments, see Mudge (1954, p. 2) and Hellier (1954). The chronology given in these newspaper stories is confirmed by available archival documents. For instance, inquest records indicate that Gershon was treating patients at the Ballarat Mental Hospital between October and December 1952 (Public Records Office of Victoria, inquest numbers 1952/1866 and 1952/1884). Patient data sheets from Royal Park Hospital record that Gershon was treating patients there between March and August 1953 (Public Records Office of Victoria, VPRS 6345/P0, unit 44, item 605: “Mental Hygiene – Treatment of Mental Disorders – Use of Drugs,” pp. 275–352 of 352). Gershon’s affiliation with Royal Park is also attested in his first scientific paper (Trautner, Trethewie, and Gershon 1953), which reported treatment dates between December 1952 and April 1953.

⁶¹ On Cade’s mistrust of lithium after the death of his patient in 1950, see note 24. But in 1953 he changed his mind and set up a clinical laboratory at Royal Park Hospital, which would be used to monitor blood lithium levels in psychiatric patients. He hired a biochemist to run the laboratory, Shirley Aldythea Andrews (1916–2001), who said that Cade equipped the laboratory with a flame spectrophotometer, and directed her to do “a wide variety of routine and unusual tests, including blood lithium levels on a daily basis” (Shirley Andrews, interview with Ann Westmore, November 25, 1999, quoted in Westmore 2002, pp. 182–183, footnote 151).

⁶² Succinate, or succinic acid, is a simple carboxylic acid abundant in all living organisms, a component of the system of cellular energy metabolism called the Krebs cycle. The Krebs cycle was cutting-edge science in the 1940s, and many researchers around the world were interested in its components: molecules such as glucose and fumarate and succinate, as well as the enzymes that facilitate their biochemical interconversions. Succinate had elicited particular interest among scientists working on brain metabolism, and contemporary reports were divided as to whether it stimulated or depressed the brain. It was being tested in psychiatric patients as a treatment for depression, and also as an antidote to “model psychoses” induced by hallucinogens such as LSD or mescaline.

At the University of Melbourne, no fewer than 11 projects involving succinate or its dehydrogenase enzyme were carried out between 1947 and 1953 (Research Reports for 1947–1953), and three of these projects involved Trautner. His first contribution on the subject was published in 1951 (Harris, Trautner, and Messer 1951). In 1953, he and Gershon investigated succinate’s effect on a variety of psychiatric conditions, including depression and barbiturate overdose as well as schizophrenia and drug-induced hallucination. Patient data sheets from Royal Park Hospital (cited above) recorded that 18 patients were treated with succinate by Gershon between March and August 1953. Gershon’s first three scientific publications came out of that work: Trautner, Trethewie, and Gershon (1953); Trautner, Gershon, and Duerrheim (1954); and Gershon and Trautner (1954).

⁶³ Trautner to Mogens Schou, September 28, 1953, in “Trautner-Schou correspondence 1953–1975.”

⁶⁴ Both the treatment for lithium toxicity and the investigation of lithium in normal subjects are mentioned by Trautner in his letter to Mogens Schou, ibid. See also the Research Reports for 1952 and 1953.

⁶⁵ Research Reports for 1952 and 1953. Michael Messer’s work is discussed more fully below in the section titled “The metabolic subtext.”

⁶⁶ The French research on lithium is discussed by Johnson (1984b, pp. 61–62); a longer list of citations is provided by Schioldann (2009, pp. 254–255). Both authors also cite a lone Italian paper published in 1953. Each of the French case series involved about 10 patients, and the later papers cited and commented on the earlier ones. According to one of these papers (Deschamps and Denis 1952), lithium first became known in France in the spring of 1950, thanks to literature reviews in which Cade’s paper had been summarized.

⁶⁷ Trautner too would experiment with the combination of lithium and chlorpromazine, but he found that this led to toxic symptoms (Trautner to Schou, November 2, 1956, in “Trautner–Schou correspondence 1953–1975”).

Many of the French authors admitted to being skeptical of Cade at first, because of lithium’s reputation as an obsolete treatment for gout, and because of the high doses, but they came around to the view that lithium is a surprisingly effective and nonhypnotic treatment for mania, which shortens hospital stays while enabling staff to take people out of the restraints “which the overpopulation of our facilities made practically mandatory” (Duc and Maurel 1953).

Despinoy and de Romeuf (1951) commented pertinently that lithium may not so much cure mania as subdue it: “Sometimes the agitation doesn’t disappear completely, but is reduced as if the effect of lithium on motor functions did not permit manic behavior to become explicit.” Some of the French authors reported as well that lithium can be beneficial in calming patients with schizophrenia, melancholia, or congenital mental disabilities, when they are in states of agitation. There was universal agreement with Cade on the desirability of beginning treatment with a high dose and then moving toward a maintenance dose: Duc and Maurel (1953) even devised a three-phase approach, which they characterized as an “attack dose,” a “charge dose,” and a “maintenance dose.” Surprisingly, the French researchers were unanimous in saying that they had no problem with toxicity, and even felt that Cade’s concern about toxicity was excessive.

⁶⁸ The first lithium treatment date reported by Schou was September 1952 (Schou et al. 1954, p. 258, Case 6, and p. 260, Case 34).

⁶⁹ An “Addendum” to Schou et al. (1954) acknowledged the first four French publications on psychiatric lithium, saying that they came to the author’s attention only after the manuscript was submitted. The submission date is not recorded, but Schou’s paper was published in November 1954.

⁷⁰ In a 1998 interview with historian David Healy, Schou stated that he had been introduced to lithium by Noack and Trautner’s 1951 paper, which he became aware of before Cade’s 1949 one (Schou 1998, p. 261). Schou’s mentor Erik Strömgren likewise stated in an interview conducted by Schou himself, in 1986, that it was Noack and Trautner’s paper that initially attracted his attention to lithium, and that he immediately made Schou aware of that paper (Strömgren and Schou 1986; discussed in Schioldann 2018). Schou’s close collaborator Amdi Amdisen has corroborated this version of events (Amdisen 1984). The convergent testimony of Schou, Strömgren, and Amdisen is supported by an examination of the annual literature roundups published by Strömgren in the Nordic Journal of Psychiatry: Noack and Trautner’s 1951 paper was singled out for mention in the 1952 roundup, but Cade’s paper was not mentioned in the roundups for previous years (Strömgren, 1950–1952).

⁷¹ Trautner’s correspondence with Schou is held at the Museum Ovartaci in Aarhus, Denmark (“Trautner–Schou correspondence 1953–1975”). The file consists of 20 letters exchanged between 1953 and 1961, plus one letter dated February 1975. Four additional letters between 1953 and 1961, which have not been preserved, can be inferred based on context; and one additional letter dated November 27, 1974, was quoted by Johnson (1984b, p. 163), and by Schioldann (2009, pp. 259–260). The first extant letter in the Museum Ovartaci file is dated September 28, 1953. It is a reply by Trautner to an earlier letter from Schou. By October 1953, Schou felt able to write about lithium to a colleague in New York: “We have at least satisfied ourselves to the extent that we have decided to go into the matter more systematically, both the clinical and the metabolic side. I am taking part in the organisation of the clinical trial” (Schou to Heinrich Waelsch, October 27, 1953, quoted by Schioldann 2009, p. 258).

⁷² F. N. Johnson, e-mail to W. W. dated March 13, 2021; see also Gershon and Daversa (2013).

⁷³ See Goodwin and Ghaemi (1999). Blind controlled trials had been in use since the eighteenth century, but the first modern “randomized controlled trial” in a clinical setting was conducted in 1946 by Sir Geoffrey Marshall at the British Medical Research Council’s Tuberculosis Research Unit.

74 “We found on ourselves that after three days ingestion of a moderate dose [of lithium], between one half and two-thirds of the daily intake was found in the next fortnight’s urine, allowance being made for the last dose taken. [...] The highest [plasma] value observed on ourselves was 2.0 milliequivalents per liter after the intake of 50 milliequivalents (1.7 grammes) of lithium carbonate within two hours. Only slight gastric discomfort was felt” (Noack and Trautner 1951).

⁷⁵ On Cade’s self-administration of lithium, see de Moore and Westmore (2016, p. 124). Albert Hofmann contributed a fascinating reflection on his self-administration experiments with LSD, mescaline, and psilocybin, at the 2nd Taylor Manor Hospital scientific symposium (published in Ayd and Blackwell 1970, pp. 91–106). Werner A. Stoll—the son of Hofmann’s supervisor, Arthur Stoll—led the first controlled study of the psychopharmacology of LSD in 1947 (Stoll 1947). He self-administered LSD and compared his experience with the observed effect on staff and patients at the psychiatric clinic of the University of Zurich. His published paper includes a detailed description of his subjective experience.

⁷⁶ In the late 1960s, Schou’s work came under public criticism from a number of psychiatrists at the prestigious Maudsley Hospital in London, particularly Michael Shepherd and Barry Blackwell. The scientific and human aspects of this controversy were reviewed by Brown (2019, chap. 6).

⁷⁷ Derek Denton, interview with W. W., January 14, 2021.

⁷⁸ At that time, the medical staff at Sunbury consisted of five psychiatrists, with 1,300 patients under their care (“Report of the MHA,” 1956). Gershon seems to have taken up his new position at Sunbury in early March of 1954, as attested by a memo from W. L. Rowe to the Minister of Health titled “Dr. S. Gershon,” dated February 22, 1954, discussing his impending transfer; and a form filled out by Gershon on March 20 gives details of two succinate treatments at Sunbury Hospital (Public Records Office of Victoria, VPRS 6345/P0, unit 44, item 605: “Mental Hygiene – Treatment of Mental Disorders – Use of Drugs,” digital pages 215 and 229). Gershon had previously been working at a child and adolescent facility called the Travancore Clinic, as shown by the “Report of the MHA” for 1954 (p. 48).

⁷⁹ The Mental Hygiene Authority was a small government agency created in 1952 to oversee the public mental health system in the state of Victoria. Eric Cunningham Dax (1908–2008) was recruited from England in 1952 to be the first chairman of the newly formed Authority and institute much-needed reforms. On Dax’s career and personality, see Westmore (2008).

⁸⁰ Douglas Alan Coats (1924–2000) was no relation to the Melbourne surgeon Albert Coates. He was born and educated in Adelaide, and joined the Physiology Department at the University of Melbourne in 1952. He coauthored papers on electrolyte physiology with Derek Denton, R. D. Wright, and James R. Goding (Flesch 2012, pp. 146–148).

⁸¹ Geoffrey Arthur Goding (1917–1992) studied medicine at the University of Melbourne, where he earned a bachelor’s degree in medicine in 1940, followed by a Diploma in Psychological Medicine in 1948 (University of Melbourne Archives). He was appointed superintendent of the Beechworth Mental Hospital in 1952, then of the Sunbury Mental Hospital in February 1954 (Margaret Goding, interview with G .de M., May 26, 2021, and subsequent e-mail; “Report of the MHA” 1954, p. 39).

⁸² Everton Rowe Trethewie (1913–1984) was profiled by Flesch (2012, pp. 148–151). In 1951, Trethewie was enlisted to help with Trautner’s research on succinate (Research Reports for 1951 and 1952). After this he coauthored two papers on succinate with Trautner and Gershon (Trautner, Trethewie, and Gershon 1953; Trethewie, Trautner, and Gershon 1956).

⁸³ Sam Gershon, interview with W. W., February 23, 2021. Gershon gave further testimony about this laboratory in interviews with G. de M., October 22, 2026, and November 9, 2010.

Of the five psychiatrists on staff at Sunbury (see note 78), three were supporters and contributors to Trautner’s work: Geoff Goding, Sam Gershon, and Charles Noack. In addition, the physiologist Douglas Coats, who lived on the grounds of Sunbury Hospital, also contributed to Trautner’s research. Coats worked in the Ionic Research Unit at the University of Melbourne, alongside Goding’s brother James.

Geoff Goding and his family had just moved into their new house on the grounds at Sunbury when Sam Gershon arrived (Margaret Goding, interview with G. de M., May 26, 2021, and subsequent e-mail). After the Godings and Gershon, the Coats family were transferred to Sunbury in 1954, and early in 1955 it was the turn of the Noacks. The Coats’s transfer is attested by their change of address on electoral rolls accessed on Ancestry.com. Noack’s transfer occurred no earlier than the beginning of 1955, given that he was appointed deputy superintendent of Bundoora hospital in December 1954 (Victoria Government Gazette, January 26, 1955). He was working at Sunbury by the time he was credited as coauthor with Trautner of a paper published on August 20, 1955 (Trautner et al. 1955), which stated in its acknowledgments that the clinical work was done at Sunbury. Noack was also at Sunbury when he did clinical work on barbiturate sleep treatments published with Trautner (Trautner, Murray, and Noack 1957). Although published in 1957, this paper’s acknowledgments and its authors’ institutional affiliations attest that the research was conducted at Sunbury hospital prior to July 1956, when Geoff Goding was replaced as superintendent. (Goding’s transfer is discussed below in the section “After Sunbury”).

⁸⁴ Sam Gershon, interviews with G. de M., October 26, November 9, and December 22, 2010; and interview with W. W., February 23, 2021. The government of the state of Victoria was then in the hands of the Labor Party, for whom R. D. Wright was an important intellectual authority.

⁸⁵ Dax would spell out this vision in his book Asylum to Community (Dax 1961, esp. pp. 204–05). Sunbury’s new superintendent Geoff Goding had earned praise from Dax during his previous post as superintendent of the Beechworth Mental Hospital, when Goding had instituted reforms in line with Dax’s vision for transforming the older “custodial” type of psychiatric care into “community mental health.” Goding alluded to this in a 1979 interview (Goding and Lang 1979, pp. 1 and 15); and Goding’s wife Alison provided more detail in an unpublished memoir, excerpts of which were shared with us by their daughter, Margaret Goding. Margaret also shed further light on the matter in an interview with G. de M. of May 26, 2021.

⁸⁶ Trautner to Schou, September 28, 1955, in “Trautner–Schou correspondence 1953–1975.”

⁸⁷ Schou to Trautner, September 10, 1955; Trautner to Schou, September 28, 1955. Ibid.

⁸⁸ Trautner to Schou, September 28, 1955, ibid.

⁸⁹ Today, clinical guidelines generally state that lithium is safe at plasma levels of 0.4 to 0.8 mEq/L (e.g., Malhi et al. 2015; Nolen et al. 2019). But in 1951, Noack and Trautner had stated: “The plasma level observed does not reliably indicate the amount of retained lithium or the degree of ‘saturation’; it indicates merely the lithium in circulation. The relation between intracellular lithium content, plasma level and rate of urinary excretion appears to be variable. High plasma levels may precede massive excretion, but low levels do not necessarily exclude the imminence of toxic symptoms” (Noack and Trautner 1951, p. 220, col. 2).

This warning was sounded again in the 1955 paper: “Toxic symptoms were observed at basic plasma levels below 0.6 milliequivalents per liter, levels at which there was never any indication of ionic instability; and on the other hand, at distinctly dangerous levels over 3.0 milliequivalents per liter, amounting to the displacement of about 1.5% of the total monovalent inorganic ion content of the body, there were often no toxic symptoms. Obviously the early appearance and the intensity of toxic symptoms are individual reactions of the patient rather than measures of the toxic effect” (Trautner et al. 1955, p. 289, cols. 1–2).

⁹⁰ Trautner to Schou, September 28, 1955, answer to point (4) (in “Trautner–Schou correspondence 1953–1975”).

⁹¹ Trautner to Schou, September 28, 1955 (in “Trautner–Schou correspondence 1953–1975”).

⁹² Trautner to R. D. Wright, dated “9/4/57” (probably April 9, 1957), in “Physiology MHRF file.” The letter is unsigned, but the author can only be Trautner, based on the content.

⁹³ Michael Messer, e-mails to W. W. dated March 10 and April 21, 2020 (on his nonlithium work); and April 8, 2020, February 20, 2021, and August 12, 2021 (on his lithium work).

⁹⁴ Messer’s work on lithium is described in his Ph.D. thesis (Messer 1958b), in notices by Trautner and Messer in the Research Reports for 1954, 1956, and 1957, and in grant applications written by Messer in December 1955, and September, October, and December 1956 (in “Physiology MHRF file”). Trautner refers to the work in his 1955 paper (Trautner et al. 1955, p. 289, col. 2), and in his letter to Mogens Schou of September 28, 1955 (in “Trautner–Schou correspondence 1953–1975”).

⁹⁵ Trautner et al. (1955, p. 289, col. 2), citing Gosh and Quastel (1954), who in turn cited McIlwain (1953). The finding was that at low concentrations, narcotics have no effect on the energy metabolism of cerebral cortex, but when potassium or dinitrophenol are added to stimulate metabolism, the narcotics then have an inhibitory effect. This finding led to the discovery of a previously unknown potassium-dependent metabolic system which is inhibited by narcotics.

⁹⁶ See references given in note 94.

⁹⁷ Schou to Trautner, September 10, 1955, in “Trautner–Schou correspondence 1953–1975.” In fact, the experiments referred to were carried out in brain homogenates, not slices.

⁹⁸ Gershon commented somewhat enigmatically: “Essentially, no one ever paid any attention to that data.” (Interview with G. de M., November 9, 2010.) Five years later, he made the same point again in a similarly mysterious way: “This was an exciting finding but due to the usual ‘circumstances beyond our control’ we never continued with these experiments” (Gershon 2015).

⁹⁹ Messer e-mail to W. W., August 12, 2021.

¹⁰⁰ Prior to beginning his research on lithium, in 1948–1950 Trautner had worked on the enzymes that synthesize and degrade amine neurotransmitters such as acetylcholine (Bradley et al. 1950; Trautner and Bradley 1951).

¹⁰¹ See Schwartz (2000).

¹⁰² Sir Henry Dale (1875–1968) shared the Nobel Prize in 1936 for the discovery of cholinergic neurotransmission. In the years prior to World War I, he had distinguished two systems of cholinergic transmission, which he baptized “nicotinic” and “muscarinic.” These names are still used with regard to cholinergic neurotransmission, but for general purposes the names “ionotropic” and “metabotropic” are preferred (see Schild 1976).

¹⁰³ Noack and Trautner (1951) stated that they had treated 20 patients on a maintenance dose of lithium for 12 to 18 months. That paper was published in August 1951, so their experience with prophylactic lithium treatment must have dated back to late 1949 or early 1950. By 1955, Trautner said he had supervised “several hundred patients whose persistent psychotic condition was, for months or years, controlled by a constant daily dose of lithium” (Trautner et al. 1955, p. 284, col. 2). And in a letter to Mogens Schou, he said that he had been supervising some patients “under practically permanent lithium medication for five years” (Trautner to Schou, September 28, 1955, in “Trautner–Schou correspondence 1953–1975”).

¹⁰⁴ “Thus there would be two separate effects of lithium: (1) a specific effect on mineral (mainly sodium) balance, which with moderate doses is readily tolerated, but which on high doses may lead to serious depletion; (2) a general effect on a potassium sensitive functional metabolism of the cell, which may finally lead to a breakdown of cell metabolism” (Trautner et al. 1955, p. 289, col. 2).

¹⁰⁵ Pierre Deniker recalled that in the early 1950s in France, “there was a lot of interest in drug treatments that would mimic shock therapy” (Deniker 1970, p. 155–156). Trautner cited four publications by French researchers in his 1955 paper, one of which (Duc and Maurel 1953) investigated the EEGs of patients during lithium therapy and concluded that the drug may do something similar to convulsive therapy. Prior to this, two French teams had investigated the use of lithium in combination with ECT: Reyss-Brion and Grambert (1951) and Deschamps and Denis (1952).

¹⁰⁶ The effect of lithium on action potentials had previously been demonstrated by an in vitro study of neural impulse conduction (Gallego and Lorente de Nó 1951, cited by Trautner et al. 1955 p. 289 col. 2).

¹⁰⁷ “The main point in favor of an ionotrophic effect of lithium is the general observation that patients with acute mania reacted only to doses of lithium high enough to cause, at least initially, an acute disturbance of ionic equilibrium. … It may be suggested that lithium treatment acts to a certain extent by restoring to normal a disturbed electrolyte metabolism. This interpretation would explain the following observations: (i) the surprising variability of the therapeutic doses as determined by the varying magnitude of the basic disturbance; (ii) the change of lithium tolerance with the change of the psychotic condition; (iii) the observation that, early in the treatment, the patients promptly relapse if their lithium treatment is stopped” (Trautner et al. 1955, p. 289, col. 2).

¹⁰⁸ For example, the Maudsley Prescribing Guidelines in Psychiatry indicate that lithium treatment of acute mania should aim for plasma lithium levels of 0.8 to 1.0 mEq/L, whereas prophylactic treatment of bipolar disorder should aim for plasma levels of 0.6 to 0.8 mEq/L (Taylor, Barnes, and Young 2018, p. 205–206; see also Malhi et al. 2015; Nolen et al. 2019).

On the history of lithium’s acceptance and approval internationally, see Brown (2019, chap. 6) and Johnson (1984b, chap. 8).

¹⁰⁹ Roy Hullin, who in 1968 published one of the first British reports of lithium prophylaxis (Hullin et al. 1968), considered that Trautner’s 1955 paper “laid the foundations for later investigations of lithium-induced changes in ionic balance” (Hullin 1975). Hullin may have had in mind the confirmations of Trautner’s early findings on ionic disturbance by Coppen and Shaw (1963, 1966). Trautner’s findings about lithium retention were also confirmed by a number of other scientists, including Baer, Bunney, Epstein, Fieve, Greenspan, Goodwin, Hullin, Serry, Schou, and Platman, among others. See the citations given by Almy and Taylor (1973).

¹¹⁰ This was the conclusion of P. B. Mitchell (1999).

¹¹¹ See, for instance, Herken, Senft, and Wilutzky (1957), and Platman and Fieve (1969). Some of this had been foreseen by Radomski et al. (1950).

¹¹² F. N. Johnson, e-mail to W. W. dated March 13, 2021.

¹¹³ For a recollection of this in the Australian context, see Cawte (1988); in the French context, see Deniker (1970); in the English context, see Blackwell (1969). For a historical overview see Johnson (1984b, pp. 46–47), Shorter (1997, chap. 7, esp. pp. 246–262), and Healy (2002, pp. 96f).

¹¹⁴ Lithium is currently thought to act principally on the inositol signaling pathway, GSK-3, BDNF, the sodium/potassium ATPase, the cytokine cascade, TNF-alpha, and adenyl cyclase. Inositol phosphatase 3 (IP3) and GSK-3 are important intracellular signaling enzymes which have magnesium binding sites. However, there are estimated to be more than 3,000 human proteins with magnesium binding sites, rendering a classical causal understanding of lithium’s mechanism of action effectively impossible.

On lithium and the inositol pathway, GSK-3 and BDNF, see Jakobsson, Argüello-Miranda, and Chiu et al. (2017). On lithium and the sodium/potassium ATPase, the cytokine cascade, TNF-alpha, and adenyl cyclase, see the literature review by Masson et al. (2014).

¹¹⁵ In the mid-nineteenth century, the English physician Alfred Garrod (1819–1907) developed the “uric acid diathesis” theory of disease, which enjoyed widespread support in subsequent decades. The theory held that many ailments can be explained on the basis of a constitutional disposition or “diathesis” to building up excess uric acid. Uric acid was known to be the cause of gout, and because gout is a periodically recurring disease, Garrod proposed that a constitutional imbalance in the metabolism of uric acid could be the cause of other periodically recurring ailments, including mania. Garrod was, in fact, the first person to treat mania with lithium, because lithium had been shown in vitro to be an effective dissolver of uric acid crystals. John Cade cited Garrod in his 1949 lithium paper, and Cade seems to have been influenced by the uric acid diathesis theory in his investigation of lithium (see Schioldann 2009, chaps. 1–9 and 19; Johnson 1984b, chaps. 2–3).

A link between gout and premenstrual tension was suggested as early as 1853 by a young J.-M. Charcot, who reported in his doctoral thesis that some female sufferers of gout experience more severe symptoms during their menses (Charcot 1853, p. 36).

¹¹⁶ Lithium treatment for premenstrual tension was something Trautner had been interested in since 1951 (“Interim Research Report 1951”). In the Research Report for 1958, Trautner and Gershon wrote that the results of this research were “being prepared for publication,” which means the research was already complete. However, no publication resulted. The clinical trials must have taken place during the Sunbury period (1954–1956), because Gershon and Trautner lacked access to clinical facilities afterward. Gershon would publish on the same subject in 1966 (Sletten and Gershon 1966).

¹¹⁷ Trautner to Schou, September 28, 1954, answer to point 6 (in “Trautner–Schou correspondence 1953–1975”).

¹¹⁸ See Gershon and Trautner (1956). The treatment dates given in the paper indicate that the research was conducted between March and October 1954, although a figure legend alludes to three cases treated between June and August 1953.

¹¹⁹ Sam Gershon, interview with G. de M., October 26, 2010.

¹²⁰ Sam Gershon, interview with G. de M., October 22, 2010.

¹²¹ One of the cases reported in Gershon and Trautner’s 1956 paper concerned a 17-year-old juvenile delinquent who had been arrested for petty crimes, and was then subjected to frequent shock treatments at another hospital (Gershon and Trautner 1956, Case VI). In 1950, a ten-year-old boy was given shock treatment at Claremont Mental Hospital in Western Australia, leading to a public investigation of the hospital (de Moore and Westmore 2016, pp. 184–185).

¹²² Carrère and Pochard, who were cited by Gershon and Trautner (1956), stated: “The rapid therapeutic activity of lithium citrate is likely to make shock therapy unnecessary in many cases, and to reduce the indications for its use, which have perhaps been abusively extended in recent times, in the treatment of states of excitation as well as depressive states” (Carrère and Pochard 1954, p. 571, translation ours). Plichet suggested that “when convulsive therapy seems to have exhausted its effectiveness,” lithium might restore it (Plichet 1954, p. 870, col. 3, translation ours).

¹²³ Schou to Trautner, November 8, 1956, in “Trautner–Schou correspondence 1953–1975.”

¹²⁴ Trautner to Schou, September 15, 1954, in “Trautner–Schou correspondence 1953–1975.”

¹²⁵ See Coats, Trautner, and Gershon (1957). The research for this paper was mainly conducted at Sunbury in 1955, since the Research Report for 1955 discusses the laboratory work, and indicates the six clinical cases were already known. (The RR for 1954 does not mention this project.) The paper was submitted for publication on May 31, 1956, within the timeframe of the lab at Sunbury.

¹²⁶ On Douglas Coats see note 80 above. Coats and his family moved to Sunbury at the time when the psychopharmacology research lab was being set up there, as attested by their change of address on electoral rolls. Coats’s wife, Dr. Pamela Julie (Pam) Coats, worked on lithium and succinate research with James R. Goding and Sam Gershon, as attested by a grant proposal drafted by Trautner in October 1955 (“Research into Mental Disease,” hand-corrected typescript initialed by Edward Trautner, in “Physiology MHRF file”). Sam Gershon’s wife Lisl recalled that when she lived at Sunbury in early 1956, the Coatses were good friends who also lived on the hospital grounds (interview with G. de M. of November 2, 2010).

¹²⁷ Sam Gershon, interviews with G. de M., October 20 and 22, 2010.

¹²⁸ Trautner to Schou, September 28, 1953; September 28 [sic] 1955; March 20, 1957; April 6, 1957; July 12, 1959; see also Schou to Trautner, March 27, 1957 (in “Trautner-Schou correspondence 1953–1975”).

¹²⁹ Trautner stated in the Research Report for 1955 (p. 165) that the new treatment being developed for lithium toxicity was motivated by research he had just published in his 1955 paper. That paper drew on Michael Messer’s unpublished experiments to posit that under conditions of excess, lithium’s “general effect on a potassium-sensitive functional metabolism of the cell [could] finally lead to a breakdown of cell metabolism. If this was the case, then sodium medication alone would in toxic conditions merely replace the sodium loss without necessarily influencing the other effects of lithium” (Trautner et al. 1955, p. 289, col. 2).

¹³⁰ Trautner’s work in toads, done in collaboration with J. G. McKenzie, was described in the Research Report for 1953. It remained unpublished, and was not mentioned in the RR for 1954, perhaps because J. G. McKenzie had left the University of Melbourne. Gershon recalled the work with Coats in his interview with G. de M. of October 22, 2010, and the bath full of frogs in an e-mail to W. W. dated May 12, 2020.

¹³¹ Sam Gershon, interview with G. de M. October 22, 2010; Coats, Trautner, and Gershon (1957).

¹³² See Coats, Trautner, and Gershon (1957, p. 11, col. 2) and Noack and Trautner (1951, p. 220, col. 1). Intravenous saline solution with no additives was still being recommended as an antidote to lithium toxicity in the 1965 edition of Goodman and Gilman’s Pharmacological Basis of Therapeutics, suggesting that the Coats paper had not made an impact on American shores. Nevertheless, Schou’s group cited the Coats paper in their 1968 publication on lithium poisoning (Schou, Amdisen, and Trap-Jensen 1968). Goodman and Gilman’s 1965 edition also mentioned hemodialysis as a remedy for grave cases of lithium toxicity, although the first published articles on the subject date to several years later (letters to The Lancet by Hawkens and Dorken in April 1969, and by Schou’s colleagues Amdisen and Skjoldborg in August 1969). Early work on hemodialysis for lithium toxicity was reviewed by Okusa and Crystal (1994).

¹³³ Schou to Trautner, March 27, 1957, in “Trautner–Schou correspondence 1953–1975.”

¹³⁴ On February 6, 1956, Gershon was appointed senior lecturer in the Department of Pharmacology of the University of Melbourne.

¹³⁵ This is the story told in an unpublished memoir written by Goding’s wife, Alison Goding, excerpts of which were shared with us by their daughter, Margaret Goding. A 1979 interview with Geoff Goding and a 1993 obituary by Andrew Firestone confirm many points of the story (Goding and Lang 1979, pp. 1, 14–15).

¹³⁶ Noack’s daughter Kit recalls that her father was removed from Sunbury Hospital simultaneously to Goding, and the Noack and Goding families then moved to Melbourne, Goding to work at the Bouverie Clinic and Noack at the nearby Observatory Clinic (Kit Noack-Corris, interview with W. W., May 15, 2021).

¹³⁷ In a 1957 letter to R. D. Wright, Trautner wrote that the relevance of his work was diminishing, “owing to continuing lack of clinical facilities and of research funds” (Trautner to Wright, dated “9-4-57” [probably April 9, 1957], in “Physiology MHRF file”). In a 1961 note to Wright concerning grant funding, Trautner wrote: “Applications for fundamental (laboratory) research are o.k. (about same as last year). Applications for clinical research are useless unless facilities are granted.” (Handwritten annotation by Trautner on a memo from F. H. Johnson, University of Melbourne Registrar, to R. D. Wright, dated February 14, 1961; in University of Melbourne Archives, Department of Physiology papers (accession no. 1975.0005), Packet XXXV, File 9: “Mental Health Research Fund Committee.”)

¹³⁸ See Simon, Trautner, and Coats (1959) and Trautner and Gershon (1959).

¹³⁹ Trautner to Wright, dated “9-4-57,” cited above in note 138.

¹⁴⁰ Trautner to Wright, February 22, 1954, in University of Melbourne Archives, Department of Physiology papers (accession no. 1975.0005), Packet XXV, File 28: “Mental Hygiene Authority 1951–59)”; Trautner to Schou, September 15, 1954; September 28, 1955; March 20, 1957 (in “Trautner–Schou correspondence 1953–1975”).

¹⁴¹ “Mental Health Research Fund,” two-page typescript in “Physiology MHRF file,” attached to a cover letter by W. T. Agar dated October 11, 1955. Although this report is not signed by Trautner or directly credited to him, it appears to be written by him based on contextual evidence, including a list of references that includes three papers by Schou and four by French researchers.

¹⁴² E. Trautner, “Application for Grant from Mental Health Research Funds – 1957,” typescript with cover letter dated December 11, 1956, in “Physiology MHRF file.”

¹⁴³ See Coats, Trautner, and Gershon (1957); Trautner, Murray, and Noack (1957); and Trautner and Gershon (1958). Two papers published after 1958 still appear to be based on clinical work done at Sunbury: Trautner and Gershon (1959) and O’Rourke et al. (1960). The latter was Trautner’s last published paper.

¹⁴⁴ Research Reports for 1957–1960. Agents tested by Gershon included morphine, bemegride and barbiturates, imipramine (which Noack would also publish on in the early 1960s), chlorpromazine, reserpine, “JB 329” (a psychotomimetic compound), and organophosphorous compounds.

¹⁴⁵ In the 1950s, drug effects on fetal development were known to scientists, but standard clinical safety testing did not address them (see, e.g., Bass et al. 1951). Lithium salts were, in fact, one of the first chemical agents known to produce changes in embryonic development, as attested by Needham (1942). The first experiments on this topic date back to the 1890s (e.g., Herbst 1893).

¹⁴⁶ See Trautner et al. (1958). The idea had first occurred to Trautner prior to November 1954, as attested by a grant proposal drafted at that time which included the question of prolonged lithium treatment and reproductive health as an object of “Research into the effects of currently used rather toxic drugs.” This title, whose irony has a hint of R. D. Wright’s style, became the official one for the project (“Research into Mental Disease,” typescript hand-corrected and initialed by Trautner, together with a cover letter from R. D. Wright to G. W. Paton dated November 4, 1954, in “Physiology MHRF file”; see also a report of the same work published in the Melbourne University Gazette, June 1955, under the heading “Mental Health Research Fund”).

In the grant proposal, Trautner specified that he wanted to conduct research on “embryonal development” in order “to answer the already urgent question whether, for example, prolonged lithium or other drug ingestion would interfere with a pregnancy, or lactation, or, whether infants and children could safely be treated with the drugs.” He considered the question important enough to mention it in his 1955 paper (Trautner et al. 1958, p. 289, col. 2). In September 1956, Trautner wrote to Mogens Schou that the work was “ready to go to press,” but in October he submitted a new grant proposal for the project stating that “the experimental work is still in hand and will be continued if funds are available” (Trautner to Schou, September 12, 1956, in “Trautner–Schou correspondence 1953–1975”; R. D. Wright to R. Sunderland, October 2, 1956, in “Physiology MHRF file”).

¹⁴⁷ See Trautner et al. (1958). See also S. Gershon and D. W. Bruce, unpublished work summarized in the Research Report for 1957. On Keneth Hill Shankly (1921–1995), see Flesch (2012, pp. 120–121).

¹⁴⁸ See Simon, Trautner, and Coats (1959) and Trautner and Gershon (1959).

¹⁴⁹ See O’Rourke et al. (1960). Comprehensive references to Trautner’s work on tigloidine are given in note 48.

¹⁵⁰ Research Report for 1960.

¹⁵¹ Trautner’s retirement date was given by R. D. Wright in a letter to Neil Johnson (summarized in Johnson 1984b, p. 160, note 8); the date is confirmed by the University of Melbourne Archives, based on staff records. See also correspondence in University of Melbourne Archives, Department of Physiology papers (accession no. 1975.0005), Packet XXXV, File 9: “Mental Health Research Fund Committee.”

¹⁵² Kit Noack-Corris, interviews with W. W., September 10, 2020, and January 12, 2021, and interview with G. de M., September 25, 2020. Sam Gershon, e-mail to W. W., April 6, 2020, and interviews with W. W., January 26 and February 23, 2021.

¹⁵³ Schou to Trautner, November 27, 1974. This letter was not in the file scanned for us by the Museum Ovartaci in Denmark, but it was seen by Johnson and Schioldann, who quote this passage in their books (Johnson 1984b, p. 163; Schioldann 2009, pp. 259–260).

¹⁵⁴ Trautner to Schou, February 9, 1975, in “Trautner–Schou correspondence 1953–1975.”

¹⁵⁵ Queensland Government Registrar of Births, Deaths & Marriages.

¹⁵⁶ Trautner’s German writings from the 1920s attest to his deep interest in psychoanalysis as well as Nietzschean philosophy. He was particularly influenced by Otto Gross (1877–1920), a precursor to Wilhelm Reich and Erich Fromm. His debt to Gross was such that he would personify Gross as a character in his 1927 novel Gott, Gegenwart, und Kokain [God, the world of today, and cocaine]. Although this fictional portrait was critical of Gross, Trautner did struggle with Gross’s legacy in the book, a sign that he had been quite immersed in psychoanalytic thinking. In addition to Gross and Nietzsche, Trautner’s German writings show the influence of Freud, Wilhelm Stekel, and the anarchists Peter Kropotkin and Gustav Landauer. For further discussion, see Wallace and Steinle (2021).

¹⁵⁷ These relationships are discussed in Wallace and Steinle (2021).

¹⁵⁸ See Shorter (1997), Healy (2002), and Harrington (2019). A dedicated article by Shorter on the subject of lithium therapy does mention Trautner, but without doing justice to his originality (Shorter 2009).

¹⁵⁹ A special supplement on lithium of the Australia and New Zealand Journal of Psychiatry, which devoted impressive articles to “Early European Lithium Studies” and “Early North American research on lithium,” did not even cover “early Australian research”—other than to profile John Cade.

¹⁶⁰ See Johnson (1984b), Schioldann (2009), de Moore and Westmore (2016), and Brown (2019).

¹⁶¹ John Cade’s silence about Trautner and other subjects is discussed in Chapter 4 of Brown (2019). To this we can add, based on our interviews with Cade’s family and friends, that Cade did harbor feelings of animosity toward Sam Gershon, elicited by a falling out between them in 1953. However, Cade’s family were completely unaware of Trautner’s existence, suggesting that Cade did not feel animosity directed toward Trautner in particular.

¹⁶² Trautner’s publications from the 1950s included research on the retention and excretion kinetics of lithium, the effect of lithium on electrolyte balance, the physiology of lithium toxicity, the prophylactic effect of lithium against recurrent mood disorder, and the effects of lithium on pregnant mothers and fetal development. All of these questions would be pursued by Schou and his colleagues in their research of the 1960s and 1970s.

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