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Monday, 27.05.2019

Thomas A. Ban: Vignette on the history of lithium in psychiatry.


         The content of this vignette was extracted and adopted, with some modification, from my essay entitled “The role of serendipity in drug discovery,” published in 2006 in Dialogues in Clinical Neuroscience (2006; 8: 335 -44), a journal, supported by an unrestricted grant  from the FrenchInstitut La Conference  Hippocrate - Servier Group.  


Vignette on the history of lithium in psychiatry


            The discovery and rediscovery of the therapeutic effects of Lithium in psychiatry were the result of false theories about the etiology of mood disorders (Ban 2006).

            Lithium is an alkali metal discovered by J.A. Arfvedson in 1817 while analyzing the mineral petalite (Ban 1969). The name Lithium comes from the Greek lithos: stone; it was coined by Jons Jacob Berzelius (1779-1848) who was involved in classifying minerals (Ban 2004; Schou 1957).The substance was first isolated in sufficient quantity for medical use by R. Bunssen and A. Mathiessen in 1855 (Healy 2002; Kline 1969). Four years later, after the demonstration that Lithium carbonate could dissolve urate stones, it was introduced into medicine for the treatment of gout by Alfred Barring Garrod (Garrod 1859; Johnson 1984).Gout is a disease characterized by urate deposits in the cartilage and increased uric acid, a breakdown product of urea, in the blood.

            During the second half of the 19th century many physicians believed in a uric acid “diathesis,” a predisposition for the accumulation of urea in the body that could cause a variety of disorders, from gout and rheumatism to cardiac disease and mental illness (Yeragani and Gershon 1986). Since acute symptoms of gout develop suddenly and persist untreated for days or weeks before they remit, William Hammond, at the Bellevue Hospital in New York, assumed that some forms of “mania,” a term used in those years for “universal – total madness,” might be a form of cerebral gout and employed Lithium in their treatment (Hammond 1871).On the basis of the same assumption, Carl Lange, a Danish neurologist, treated hundreds of patients with Lithium and in 1886 reported on its prophylactic effect in “periodical” depressive disorders (Lange 1886). Yet, without the availability of the necessary technology for monitoring blood levels, Lithium was too toxic a substance to be clinically employed.

            In the late 1940s the possible therapeutic effect of Lithium in “mania,” by that time perceived as a “mood disorder,” one of two “poles” of Emil Kraepelin’s “manic depressive insanity,” was recognized by John Cade, an Australian psychiatrist (Cade 1949; Kraepelin 1899; Neele 1949).Arguably influenced by RolvGjessing’s diagnostic concept of ”periodic catatonia,” introduced in the 1930s,  Cade assumedthat manic-depressive illness is analogous to thyrotoxicosis and myxedema and speculated that “mania” is a state of intoxication by a normal product of the body in excess and “melancholia” is a state of deficiency of the same substance (Cade 1970; Gjessing1938). To pursue his speculation he compared the effects of intraperitoneally injected concentrated urine from manic patients with urine from normal subjects in guinea pigs and found the former far more toxic (the animals died) than the latter.  Cade identified urea as the culprit that killed the animals and established that creatinine decreased  (“protected”), whereas uric acid increased  (“enhanced”), the toxicity of urine. Since the urine of manic patients was more toxic than could be neutralized by the protective action of creatinine, he decided to determine the toxicity-enhancing effect of uric acid. Since uric acid was virtually insoluble in water, he used the most soluble of the urates, Lithium urate, in his experiments. To his surprise, instead of enhancing toxicity, Lithium urate protected the animals from urea’s toxic effects. He attributed the protection of animals from the toxic effect of “manic urine” to Lithium and demonstrated that injection of an 8% urea solution killed five of 10 guinea pigs whereas a similar solution with Lithium added killed none (Cade 1970).

            To determine whether Lithium salts alone have any discernable effects Cade injected large doses of 0.5% aqueous solution of Lithium carbonate into guinea pigs and found that after a latent period the animals became extremely lethargic and unresponsive to stimuli for about two hours. This may seem a long way from the lethargy of guinea pigs to the control of manic excitement, but since Cade’s investigations had commenced in an attempt to demonstrate the presence of a toxic substance excreted in the urine of manic patients, he decided to compare the effect of Lithium in 10 manic, six schizophrenic and five depressed patients (Ban 2006). The substance seemed to be effective in controlling psychotic excitement and, especially, if it occurred in manic patients (Cade 1949, 1970).

            Prerequisites to the introduction (arguably re-introduction) of Lithium into the armamentarium of drugs in the treatment of mental pathology were:

1. Noack and Trautner’s establishment of blood levels at which lithium can be safely administered to patients with the employment of “flame photometry,” developed by Victor Wynn at the at the Florey Institute in Melbourne(Noack and Trautner 1951),and

2. the determination by Trautner and his team,which included Gershon, Noack and Morris, that the excretion and retention of ingested  Lithium had its effect on ionic balance in man  (Trautner, Morris, Noack and Gershon 1955).

            Instrumental to the introduction of Lithium into the assemblage of drugs employed to treat mental pathology were Schou and associates’ (Jüel-Nielsen, Strömgren and Voldby) demonstration in 1954 of its therapeutic efficacy in treating “mania,” verifying Cade’s 1949 observationsand Noackand Trautner’s 1951findings.

            Ultimately, it was Baastrup and Schou, in 1967,who demonstrated Lithium’s therapeutic efficacy in the treatment (including prophylaxis) of “periodical” (recurrent)  depressive psychoses, verifying  Carl Lange’s observations  in1886 (Baastrup and Schou 1967; Lange 1886;  Schioldann2011). It was also Baastrup and Schou who discovered and demonstrated Lithium’s therapeutic efficacy in the treatment (including prophylaxis) of Kraepelin’s “manic-depressive psychosis” (Baastrup and Schou 1967). Since then Lithium has remained one of the standard treatments of “manic depressive psychosis.” By the time the original version of this “vignette” was  written in 2006, the 4th edition (with text revised) of the Diagnostic and Statistical Manual of the American Psychiatric Association hadsubsumed“manic depressive psychosis” under “bipolar disorder,” a term (but not concept) adopted from Karl Leonhard’sClassification of Endogenous Psychoses(American Psychiatric Association 2000; Leonhard 1957).




American Psychiatric Association. DSM-IVTRDiagnostic and Statistical Manual of Mental Disorders. Fourth Edition Text Revised. Washington; American Psychiatric Association; 2000.

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Ban TA. Psychopharmacology. Baltimore: Williams and Wilkins;1969, p.410.

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D,   Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology. Budapest, Hungary; Animula; 2004; 697-720.

Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust.  1949; 2: 349-52. 

Cade JFJ. The story of lithium. In: Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia/Toronto; J.B. Lippincott Company; 1970; 218-29.

Garrod AB. Gout and Rheumatic Gout. London; Walton and Maberly; 1859; 438.

Gjessing R. Disturbances of somatic functions in catatonia with periodic course, and their compensation. J Ment Sci, 1938; 84: 608-21.

Hammond WA. A Treatise on Diseases of the Nervous System. New York; Appleton; 1871.

Healy D. The Creation of Psychopharmacology. Cambridge, Massachusetts/ London, England; Harvard University Press; 2002; 47-50.

Johnson FN. The History of Lithium. Basingstoke, England; MacMillan Press; 1984.

Kline NS. Lithium: The history of its use in psychiatry. In: Kline NS, ed. Modern Problems

of Pharmacopsychiatry. Volume 3. Basel/New York: S. Karger; 1969, p. 75-92.

Kraepelin E. Psyhiatrie, Ein Lehrbuch fuer Studierende und Aerzte. 6 Auflage. Leipzig: Barth; 1899. 

Lange C. Om periodiske  Depressionstilstande og deres Patagonese. Copenhagen; Jacob Lunds Forlag; 1886.

Leonhard K. Aufteilung der endogenen Psychosen. Berlin: Akademie – Verlag; 1957.

Neele E. Die Phasischen Psychosen. Leipzig: Barth; 1949.

Noack CH, Trautner EM. The Lithium treatment of maniacalpsychosis. MedJAust 1951; 2: 219- 22.

Schioldann J. Periodical depressions and their pathogenesis. History of Psychiatry 2011; 22:116-30.

Schou M. Biology and pharmacology of the Lithium Ion. Pharmacol Rev 1957; 9: 17 -58. 

Schou M, Jüel-Nielsen N, Strömgren E, Voldby H. The treatment of manic psychosis by the administration of lithium salts. J Neurol Neurosurg Psychiatry   1954; 17: 250-260.

Yeragani VK, Gershon S. Hammond and lithium: historical update. Biological  Psychiatry1986; 21:1101-1102.


January 24, 2019