Thursday, 21.10.2021

Johan Schioldann: History of the Introduction of Lithium into Medicine and Psychiatry

Birth of modern psychopharmacology 1949




        My interest in the history of the introduction of lithium into medicine and psychiatry goes back to the early 1990s, when I translated from Danish the treatise On Periodical Depressions and their Pathogenesis by the famous Danish neuropathologist, Carl Lange (1834-1900).[1] He believed that these conditions were caused by the so-called uric acid diathesis and manifested as recurrent uratic depressions.

        Particularly inspired by Neil Johnson’s[2] and Amdi Amdisen’s[3] works on the history of lithium therapy, and my own subsequent studies within this fascinating, controversial field, I concluded that Carl Lange’s treatise, in itself a unique nosography of the milder forms of endogenous depression, was a landmark in the history of lithium therapy.[4]

        Carl Lange’s brother, Frederik (Fritz) Lange (1842–1907),[5] Superintendent Psychiatrist of a large mental asylum at Middelfart in Fuenen, Denmark, took up his brother’s treatment method. Where Carl Lange gave lithium to generally depressed patients, some of those of Fritz Lange—judging by his published records of them—can be diagnosed, retrospectively, as having suffered from bipolar mood swings.

        The Lange brothers were the first to use lithium therapy systematically in mood disorders.[6] Thus, they must be considered founding fathers of lithium therapy. However, as their use of this regime was based on the fallacious but die-hard uric acid diathesis, their contemporary countrymen, e.g. Ferdinand Levison, Viggo Christiansen and Erik Faber, virtually ridiculed them and as good as accused them of quackery;[7] Kraepelin,[8] with explicit reference to Lange’s depression treatise, dismissed his aetiological views outright. In consequence, the Langes’ observations and their use of lithium were not taken up and investigated further, despite their exhortations this be done. Eventually, lithium’s thymoleptic effects fell into oblivion.

        Fascinatingly, it was not until half a century later, in 1949, that an antipodean, the Australian psychiatrist, John F. Cade (1912–80),[9] rediscovered lithium’s antimanic properties—a revolutionary event that changed the face of psychiatry[10] and gave birth to modern psychopharmacology.

        As Goodwin and Ghaemi[11] wrote fifty years later, ‘the discovery of lithium, and the recognition that it could specifically treat seriously ill individuals, redirected the focus of the field to the sick individual, and thus helped to re-establish psychiatry as the medical specialty it is’. They went on to say that ‘by launching the psychopharmacology revolution, lithium forced psychiatrists to become adept at diagnosis’, and that eventually it became an important driving force behind the redefinition of current psychiatric classification (DSM-IV and ICD-10). As Akiskal[12] expressed it, ‘lithium medicalised psychiatry in bringing significant attention to the course of bipolar disorder’.

        As Johnson put it, intriguingly, Cade did not regard his experimental works on guinea pigs, which led him to his ingenious discovery of the specific antimanic effect of the lithium ion, as a natural extension of the uric acid diathesis.[13]

        In fact, first Amdisen[14] - and then, in a joint paper in 1983, Johnson and Amdisen[15]- expressed the view that ‘before Cade considered using lithium as a therapeutic substance there had been others [e.g. Alexander Haig and Carl Lange and other uric acid authorities] who, unknown to Cade, had already done so, and, indeed, for exactly the same purpose—the control of manic excitement’. It was the following year that Amdisen[16] elaborated on this view, stating that it had escaped Cade’s ‘historical research’ that ‘for as long time as 80–90 years before he published his results a presumably not seldom used treatment of mania existed, i.e. a therapeutic or, more often, prophylactic treatment of rheumatism [by Alfred Garrod], and that Garrod [e.g. in his 1859 textbook] regarded a daily intake of 5–25 mmol of lithium salts as one of the most important, if not the very decisive, part of this treatment, even during completely symptom-free intervals’.

        In his ensuing important book on the history of lithium therapy, in 1984, Johnson,[17] who considered himself ‘fortunate’ to have been ‘numbered amongst [Cade’s] friends’,[18] even co-authoring a paper on lithium with Cade,[19] discussed the issue in greater detail, pointing out that ‘when Cade undertook the work which was to lead to the rediscovery of lithium therapy, uric acid again entered the story’. Johnson placed emphasis on the fact that ‘in considering the most likely candidate for his hypothetical enhancer of urea toxicity, [Cade] went immediately to uric acid and thence to the most soluble of the uric acid salts—lithium urate’. And although, he went on, ‘Cade did not see his work as a progression from the ideas of Haig, and Lange and the rest of the proponents of the uric acid diathesis’, he concluded importantly that ‘no research worker is ever truly free of the influences of his scientific forebears’. Moreover, Johnson had no doubt that Cade had been ‘clearly aware of Garrod’s writings and quoted Garrod’s authority for supposing lithium urate to be the most soluble of the urates’.

        Johnson then asked, ‘is it possible that Cade’s immediate choice of uric acid as the putative modifier of urea toxicity owed its spontaneity to the still current (or, at least, very recently deceased) uric acid diathesis concept’? As Cade had found that not only lithium urate, ‘but lithium carbonate too’, produced effects on his guinea pigs, he ‘unhesitatingly transferred his attention to hospitalised patients’. Johnson therefore had to decide why Cade was ‘so positive in taking such a decision’; the crux of the matter being whether he had ‘any reason, other than the results of his guinea pig studies, for believing that a successful outcome in his patients was likely’. Johnson’s somewhat equivocal answer was:

        Probably not—at least not in a formal, explicit way; but it seems hardly likely that the various claims which had been put forward for over a hundred years for the therapeutic benefits of lithium in a wide range of disorders, including mental affections, were either totally unknown to Cade or failed to influence his thought, at least in a general way.

        Frank Ayd,[20] an authority on the history of modern psychopharmacology, and who formed ‘an enduring, rewarding friendship’ with Cade, wrote in 1991 that in his ‘original report on lithium’ Cade reviewed the history of lithium ‘as he knew it then’, but ‘in time it became evident that [he] had, in fact, rediscovered the use of lithium to control manic excitement’. However, Ayd added, ‘when Cade learned more of the early history of lithium he acknowledged its earlier uses for mania’.

        In the present work, which includes a revised, amended version of my 2001 book on the early history of lithium therapy, I intend, in the interests of the history of medicine and psychiatry, to test the opinions put forward by Johnson, Amdisen and Ayd, as to whether Cade, when he carried out his ground-breaking work in 1947–1949, had penetrated into lithium’s pre-history[21] ‘the first era of lithium in medicine’.[22] Had Cade gained knowledge of, and was he inspired by, the earlier uses of lithium salts in the treatment of mood disorders, that had occurred since approximately 1859? Amdisen[23] was of the opinion that ‘in the years around 1950 neither of the terms “rheumatism” [nor] “gout” would possibly suggest to anyone anything associated with psychiatry’.

        Thus, the most important aim of this book is to establish a more correct history of Cade’s ‘discovery’ of lithium treatment. Therefore, other than to Johnson, Amdisen and Ayd, reference must also be made to a 2005 work by Callahan and Berrios,[24] the latter being one of the world’s experts on the epistemology and historiography of psychiatry.[25] In that work the authors include a brief account of ‘the story of lithium’,[26] expressing the view that ‘although unknown to him, Cade was retracing the steps of a Danish psychiatrist, Carl Lange, who had reached the same conclusions [as Cade] 50 years earlier and who had successfully given lithium to patients with affective disorders.’ ‘Locked in the Danish language’, they went on, ‘Lange’s work was not available to Cade [thus causing] an incorrect history of the “discovery” of lithium treatment that historians are finding difficult to resolve’.

        To this it should be added that Vestergaard[27] not only cast doubt on my 2001 statement that Carl Lange was ‘a founding father’ of lithium treatment in psychiatry, but also argued intriguingly that ‘there is nothing to indicate that lithium pioneers of later times, Australian (John Cade) as well as Danish (Mogens Schou),[28] placed any importance on Carl Lange’s observations and writings, although these were probably known to them’.

        Joining the debate was Himmelhoch[29] who found that Lange’s ‘clinical observations and orderings […] are most original and remarkable’. It is surprising, therefore, he added, that Lange’s papers and clinical research ‘have not been given proper recognition for originality’, and finally, he ‘would guess that Cade himself was well aware of Lange’s ideas’.

        Subsequently, Goldney,[30] having acquainted himself with the early history of lithium therapy, pertinently wrote: ‘Dr John Cade has held a special place in the history of Australasian psychiatry, but the assumptions of history, as with science, can be challenged’.

        I wish to emphasise that my interpretation and, at times reinterpretation, of the vast range of source materials presented here, some of them not previously known, do not, nor are meant to, in any way or extent, detract from the epochal contributions of either Cade or Mogens Schou,[31] who in 1954 in one of the first double-blind studies in psychiatry scientifically confirmed Cade’s findings.

        To this it should be added that the conclusions reached in this work may not be final: they are naturally subject to the scrutiny of other medical historians who may read the presented material differently, or further relevant sources and evidence may emerge before the bar of the history of medicine.

        It was during the 1960s that sporadic observations by Hartigan[32] and Baastrup respectively,[33] and systematic but open investigations by Baastrup and Schou,[34] suggested that lithium had prophylactic properties against recurrent affective disorders (bipolar and unipolar). This was considered ‘a medical landmark’,[35] causing though the infamous Battle of Lithium, spearheaded by Michael Shepherd and Barry Blackwell[36] (and in more recent years rekindled by Joanna Moncrieff)[37] In 1970 Baastrup and Schou[38] published their controlled, double-blind studies of discontinuation design, ‘unparalleled in psychiatry’,[39] that confirmed lithium prophylaxis; this would be hailed by Goodwin and Kay Jamison[40] as ‘one of the most important advances in modern psychiatry’.[41] This era of lithium therapy falls outside the scope of the current work, but it is richly documented by Johnson.—The two works, the present one and Johnson’s, together support Fawcett’s generally expressed notion,[42] that the history of lithium carbonate is ‘a striking example of the fundamental unity of psychiatry and medicine’.

        The History of the Introduction of Lithium into Medicine and Psychiatry is a narrative-analytical work. The arrangement of the rich source material will necessarily cause a certain amount of redundancies in the text; that is, the repeating of information that is fitted into different time sequences. However, this cannot be avoided in a historiographical work where the same event may be relevant on more than one occasion and in different contexts. They are presented thus in order to weave, as far as the source material allows, an in-depth, comprehensive and scholarly fabric that extricates, even if not fully possible,[43] the actual events and sequence of the intricate, checkered[44] and quixotic[45] story of lithium. This is at the cost of a somewhat repetitive stamp to the work. But whether the story of lithium, an expression that Cade[46] used, contains ‘a number of surprises’, as Nathan Kline[47] once put it, remains to be seen.



[1] Lange C.: ‘Om periodiske Depressionstilstande og deres Patogenese’. Copenhagen: Lunds Forlag, 1886. The English translation published in Schioldann J.: ‘In commemoration of the centenary of the death of Carl Lange. ‘The Lange theory of ‘periodical depressions’. A landmark in the history of lithium therapy’. Adelaide Academic Press, 2001:23–49. For Lange’s biography see ibid. pp.11–22.—Appendix I.

[2] Johnson FN.: ‘The history of lithium therapy’. London: MacMillan, 1984 (Book reviews: Shepherd M, Med. Hist. 1985;29:223–224. Blackwell B, Psychol. Med. 1985;15:695–713. Jobe TH, Bull. Hist. Med. 1987;61:135–136). Johnson issued a minimally rephrased edition, ‘The origins of lithium therapy’, in Rev. Contemp. Pharmacother. 1999;10:193–265. Johnson FN, Amdisen, A.: ‘The first era of lithium in medicine’ Pharmacopsychiatr. 1983;16:61–63.

[3] Johnson FN, Amdisen A.: ‘The first era of lithium in medicine’. Pharmacopsychiatr. 1983;16:61–63. Amdisen A.: ‘Lithium treatment of mania and depression over one hundred years’, in Corsini GU. (ed.): ‘Current trends in lithium and rubidium therapy’. Lancaster: MTP Press, 1984:11–26. Amdisen A.: ‘Carl Lange på fransk visit i psykiatrien’ [Engl. summary: ‘C. Lange’s flying call to psychiatry’]. Dan. Medicinhist. Aarb. 1985;14:9–40 (25). Amdisen A.: ‘The history of lithium’. Biol. Psychiatr. 1987;22:522–523. Amdisen A.: ‘Historical origins’, in F. Neil Johnson (ed.): Depression & mania. Modern lithium therapy. Oxford: IRL Press, 1987:24–28. Amdisen A.: ‘Lithium as a pharmacological agent. Historical aspects. Topical aspects in monitoring of psychiatric lithium therapy’. (Thesis. Danish text with English abstract). Aarhus: Psykiatrisk Hospital i Aarhus, 1985.

[4] Schioldann J.: ‘In commemoration of the centenary of the death of Carl Lange. The Lange theory of ‘periodical depressions’. A landmark in the history of lithium therapy’. Adelaide Academic Press, 2001. (Book reviews: Vestergaard P, Ugeskr. Læg. (Cph.) 2001;163:7063. Berrios G, Hist. Psychiatr. 2002;4:482–483. Retterstøl N, Tidsskr. Nor. Lægeforen. (Oslo) 2002;122:2481. Munk-Jørgensen P., Acta Psychiatr. Scand. 2002;105:158. Himmelhoch JM., Bipol. Disord. 2005;7:477. Goldney RD., Aust. NZ. J. Psychiatr. 2006;40:377.)

[5] Schmidt J.: ‘Hospitalets første overlæge Frederik Lange’, in Jens Schmidt (ed): 100 år Middelfart Sygehus psykiatrisk afdeling 14. Juli 1988. Middelfart: mv-tryk, 1988. pp.19–26.

[6] The time sequence created by Per Bech (‘The full story of lithium. A tribute to Mogens Schou (1918-2005)’. Psychother. Psychosom. 2006;75:265–269) is somewhat peculiar. This work was cited by Goodwin FK, Jamison KR.: Manic-depressive illness. Bipolar disorders and recurrent depression. 2nd Edn. Oxford University Press, 2007. (‘Treatment’, p.798).

[7] It is not correct when Schäfer writes that ‘after a brief period of acclaim’, though he correctly added: ‘however, their ideas were unjustly ignored in the psychiatric literature’. Schäfer U.: ‘Past and present conceptions concerning the use of lithium in medicine’. J. Trace Microprobe Techn. 1998;16:535–556 (536).

[8] Kraepelin E.: ‘Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. Achte, vollständig umgearbeitete Auflage. III. Band.’ Klinische Psychiatrie. II. Teil. Leipzig: J. A. Barth, 1913. p.1371. Kraepelin E.: ‘Manic-depressive insanity and paranoia’. Translated by R. M. Barclay, from the eighth German edition of Text-book of Psychiatry, [1913] vols. iii. and iv. Edited by G. M. Robertson. Edinburgh: Livingstone, 1921. p.182.

[9] Cade JF.: ‘Lithium salts in the treatment of psychotic excitement’. Med. J. Aust. 1949;2:349–352.

[10] Fieve RR.: ‘Moodswing. The third revolution in psychiatry’. New York: Morrow, 1975; cf. 1997 edition (Bantam Books).

[11] Goodwin FK, Ghaemi SN.: ‘The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe’, in: Mitchell PB, Hadzi-Pavlovic D, Manji HK. (eds.): ‘Fifty years of treatments for bipolar disorder. A celebration of John Cade’s discovery’. Aust. NZ. J. Psychiatr. 1999;33 (supplement.):S54–S64. cf. Goodwin FK.: ‘Introduction’, in: Goodwin FK. (ed.): ‘The lithium ion. Impact on treatment and research’. Arch. Gen. Psychiatr. 1979;36:833–834. Goodwin FK., Jamison KR.: ‘Manic-depressive illness. Bipolar disorders and recurrent depression’. 2nd Edn. Oxford University Press, 2007. (‘Fundamentals of Treatment’, p.699).

[12] Akiskal HS.: ‘The scope of bipolar disorders’, in: Akiskal HS., Tohen M. (eds.): ‘Bipolar psychopharmacotherapy. Caring for the patient’. Chister: Wiley, 2006. pp.1–8.

[13] Johnson, 1984, op. cit., pp.43–44 (‘Cade and the uric acid diathesis’).

[14] Amdisen A.: ‘Lithiumbehandling af mani og depression i forrige århundrede’. Med Forum (Cph.) 1983: 110–119.

[15] Johnson FN, Amdisen, A.: ‘The first era of lithium in medicine. An historical note’.Pharmacopsychiatr. 1983;16:61–63.

[16] Amdisen, 1983, op. cit. Amdisen A.: ‘Lithium treatment of mania and depression over one hundred years’, in: Corsini GU. (ed.): ‘Current trends in lithium and rubidium therapy’. Lancaster: MTP Press, 1984:11–26.

[17] Johnson, 1984, op. cit., pp. ix, 43–44.

[18] Johnson FN.: ‘John F. J. Cade, 1912 to 1980: a reminiscence’. Pharmacopsychiatr. 1981;14:148–149.

[19] Johnson FN, Cade JF.: ‘The historical background to lithium research and therapy’, in Johnson FN. (ed.): ‘Lithium research and therapy’. London: Academic Press, 1975. pp.9–22.

[20] Ayd FJ.: ‘The early history of modern psychopharmacology’. Neuropsychopharmacol. 1991;5:71–84 (81–82).

[21] Amdisen, 1984, op. cit.

[22] This term was coined by Amdisen (cf. Johnson, 1984. op. cit., p.x. Johnson, Amdisen, 1983, op. cit.).

[23] Amdisen, 1984, op. cit.

[24] Callahan CM, Berrios GE.: ‘Reinventing depression: a history of the treatment of depression in primary care 1940–2004’. Oxford University Press: Oxford, 2005.

[25] cf. Berrios GE: ‘History and philosophy. Editorial overview’. Curr. Opin. Psychiatr. 1992;699–700. Berrios GE: ‘Historiography of mental systems and diseases’. Hist. Psychiatr. 1994;5:175–190. Mulder RT: ‘Why study the history of psychiatry?’ Aust. NZ. J. Psychiatr. 1993;27:556–557. Engstrom E.: ‘Beyond dogma and discipline: new directions in the history of psychiatry’. Curr. Opin. Psychiatry 2006;19:595–599.

[26] Callahan, Berrios, op. cit., pp.95–96

[27] Vestergaard P.: ‘Book review: Schioldann J.: The Lange theory of “Periodical depressions”. etc. 2001, op. cit’. Ugeskr. Læg. 2001;163:7063.

[28] cf. Retterstøl N.: ‘Book review: Schioldann, 2001’, op. cit. Tidsskr. Nor. Lægeforen. (Oslo) 2002;122:2481.

[29] Himmelhoch JM.: ‘Book review: Schioldann, 2001’, op. cit. Bipol. Disord. 2005;7:477–478.

[30] Goldney RD.: ‘Book review: Schioldann, 2001’, op. cit. Aust. NZ. J. Psychiatr. 2006;40:377.

[31] Schou M, Juel-Nielsen N, Strömgren E, Voldby H.: ‘The treatment of manic psychoses by the administration of lithium salts’. J. Neurol. Neurosurg. 1954;17:250–260.

[32] Hartigan GP.: ‘Experiences of treatment with lithium salts’, Appendix in Johnson FN.: ‘The history of lithium therapy’. Macmillan Press, 1984. pp.183–187. Abbreviated version of same in J. Ment. Sci. 1961;Suppl:49. Hartigan GP.: ‘The use of lithium salts in affective disorders’. Br. J. Psychiatr. 1963;109:810–814.

[33] Baastrup PC.: ‘The use of lithium in manic-depressive psychosis’. Compr. Psychiatr. 1964;5:396–408.

[34] Baastrup PC, Schou M.: ‘Lithium as a prophylactic agent. Its effect against recurrent depressions and manic- depressive psychosis’. Arch. Gen. Psychiatr. 1967;16:162–172.

[35] Goodwin FK, Jamison KR.: ‘Manic-depressive illness. Bipolar disorders and recurrent depression’. 2nd Edn. Oxford University Press: Oxford, 2007. (‘Maintenance Medical Treatment’, pp.819–820).

[36] Blackwell B., Shepherd M.: ‘Prophylactic lithium: another therapeutic myth? An examination of the evidence to date’. Lancet 1968;i:968–971. Blackwell B: ‘Need for careful evaluation of lithium’. Am. J. Psychiatr. 1969;125:1131. Blackwell B.: ‘Lithium prophylactic or panacea?’ Med. Counterpoint. 1969;Nov:52–59. Shepherd M.: ‘A prophylactic myth’. Int. J. Psychiatr. 1970–71;9:423–425. Blackwell B.: ‘Prophylactic lithium: science or science fiction?’ Am. Heart J. 1972;83:139–141. Shepherd M: ‘Discussion’, in: Bohacek N., Mihovilovic M., (eds.): ‘Psihofarmakologila 3: Proc. 3rd Yugoslav Symp’, Opatija, 1973. Zagreb: Medicinska Noklada, 1974:329–330.

[37] Moncrieff J.: ‘Lithium: evidence reconsidered’. Br. J. Psychiatr. 1997;171:113–119. Moncrieff J: ‘Forty years of lithium treatment’. Arch. Gen. Psychiatr. 1998;55:92–93.

[38] Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A.: ‘Prophylactic lithium: double-blind discontinuation in manic-depressive and recurrent depressive disorders’. Lancet 1970;ii:326–330. Schou M: ‘Prophylactic lithium maintenance treatment in recurrent endogenous affective disorders’, in Gershon S, Shopsin B (eds.): Lithium. Its role in psychiatric research and treatment. Plenum Press: New York, 1973:369–393.

[39] Grof P.: ‘Has the effectiveness of lithium changed?’ Neuropsychopharmacol. 1998;19:183–188.

[40] Goodwin FK, Jamison KR.: ‘Manic-depressive illness’. Oxford University Press: New York, 1990. Grof P: 1998, op. cit.

[41] Schioldann J.: ‘John Cade’s seminal paper turns fifty. (Editorial)’. Acta Psychiatr. Scand. 1999;100:403–405.

[42] Fawcett J.: ‘Lithium carbonate in medicine and psychiatry’. Adv. Exp. Med. Biol. 1980;127:1–13.

[43] cf. Bech P.: ‘The full story of lithium. A tribute to Mogens Schou (1918-2005)’. Psychother. Psychosom. 2006;75:265–269.

[44] Prien RF., Caffey EM., Klett CJ.: ‘Lithium carbonate. A survey of the history and current status of lithium in treating mood disorders’. Dis. Nerv. Syst. 1971;32:521–531. Strobusch AD, Jefferson JW: ‘The checkered history of lithium in medicine’. Pharm. Hist. 1980;22:72–76.

[45] Gershon S., Shopsin B. (eds.): ‘Lithium. Its role in psychiatric research and treatment’. Plenum Press: New York, 1973 (loc. cit. in ‘Introduction’ pp.1–3).

[46] Cade JF.: ‘The story of lithium’, in Ayd FJ., Blackwell, B. (eds.). ‘Discoveries in biological psychiatry’. Lippincott: Philadelphia, 1970. pp.218–229. Johnson FN, Cade JF: ‘The historical background to lithium research and therapy’, in Johnson, FN. (ed.): ‘Lithium research and therapy’. Academic Press:London, 1975. pp.9–22.

[47] Kline NS.: ‘Lithium: The history of its use in psychiatry’. Mod. Probl. Pharmacopychiatr. 1969;3:76–87.


August 12, 2021