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Saturday, 08.08.2020

Samuel Gershon: Lithium history
Janusz K. Rybakowski’s comment


          To address an attempt to demythologize Dr. John Cade’s introduction of lithium in contemporary psychiatry, I would start by pointing out that since his 1947 paper 71 years have elapsed, and 69 years from his 1949 one. Therefore, this period should be named as the “70-year history. ”In my comment, I would like to raise the issue of the so-called "uric acid connection" in two aspects: 1) how this concept added to the Cade's introduction of lithium for psychiatric treatment; and 2) how the "uric acid connection" has contributed to a current purinergic hypothesis of psychiatric disorders, especially that of bipolar disorders.  

          The recorded facts show that the first to introduce lithium for the treatment of mood disorders was the most distinguished 19th century Danish physician and scientist Carl Lange. Besides introducing lithium to psychiatric therapy, he is also well-known as the co-founder of the first biological concept of emotions, known as the James-Lange theory. In addition to William James, who was a philosopher and psychologist, Carl Lange, as a neurologist, proposed a brain circuit of emotion, including the vasomotor center.

          In 1886, Carl Lange published in Denmark his treatise on the periodic depressive states Om Periodiske Depressionstilstande ogderes Patogenese (About Periodic Depression Conditions and Their Pathogenesis) (Lange 1886). This was reproduced nine years later in German as Periodische Depressionzustände und ihre Pathogenesis auf dem Boden der harnsaurenDiathese (On periodical depressions and their pathogenesis in the context of uric acid abnormality) (Lange 1895). The English translation of this monograph by Johan Schioldann appeared more than 100 years later, only in the beginning of the 21st century (Schioldann 2001). Precise clinical description of depression in the Lange’s work amazingly complies with the diagnostic criteria for depression in effect in the 21st century. However, the most important issue of his monograph is a pathogenic concept of depression as a condition connected with an excess of uric acid.Thus, depression being a “gout of the brain.”

          Lithium urate had been known during this time as a most soluble urate, and Alfred Baring Garrod recommended lithium for the treatment of gout and rheumatic gout (Garrod 1859). This prompted Lange to administer lithium as lithium carbonate in order to eliminate a possible uric acid excess by forming the lithium urate in depressive patients. To this end he also used the dose recommended by Garrod, i.e., around 25 mmol lithium (equaling about 1000 mg of lithium carbonate) per day. While Carl Lange was giving lithium to ambulatory patients in his private practice, this treatment was taken up by his brother, Fritz, the superintendent of Middelfart psychiatric hospital, who administered it to psychiatric inpatients.

          It can also be stated that the first to use lithium for the treatment of acute mania was American physician, William Alexander Hammond in New York, and it was the bromide salt of lithium (Hammond 1871). However, there was no mention of possible involvement of uric acid and it is probable that the sedative effect he mostly ascribed to bromide. Anticonvulsant properties of potassium bromide were previously noted by Sir Charles Locock at a meeting of the Royal Medical and Chirurgical Society in 1857.

          Because Lange's papers were published only in Danish and German, there is no possibility of Cade knowing them. Also, it is not probable that Cade knew of Hammond’s work. In my opinion, both Cade's experiments with uric acid and the dose of lithium he proposed may have their origin in Alfred Garrod’s work on gout; Garrod’s book is mentioned in Cade’s 1949 paper (Cade 1949).

          Therefore, it was the concept of uric acid diathesis of depression elaborated by Carl Langethat prompted him to use lithium as a therapeutic drug. Cade's experiments with uric acid were in some way connected with re-introducing lithium into psychiatric treatment. However, 100 years after the seminal publication of Lange, Felber (1987) named the connection between uric acid and lithiumeingenialem Irrtum (an ingenious error).

          The situation changed in the 21st century when it was found that both uric acid, as the final metabolite of purine bases, and some purines (e.g., adenosine) may play a role in the regulation of psychological processes, including mood and activity. Concomitantly, new evidence has been accumulated concerning a role of uric acid in the pathogenesis and treatment of bipolar disorder (BD). In patients with BD, higher prevalence of gout and increased concentration of uric acid have been found, and the therapeutic activity of allopurinol, used as an adjunct to mood stabilizers, has been demonstrated in mania. In recent years, research on the role of the purinergic system in the pathogenesis and treatment of mood disorders and also schizophrenia has focused on the role of adenosine (P1) receptors and nucleotide (P2) receptors. Activation of adenosine receptors is related to an antidepressant activity. Alterations of P2 receptors (mostly P2X7 receptors) has been found significant for the pathogenesis of mood disorders, especially BD. Therefore, a direct connection between uric acid and BD, and indirectly with lithium, as the main therapeutic modality in this disorder can no longer be denied. A review article on the disturbances of purinergic system in mood disorders and schizophrenia is going to be shortly published in Psychiatria Polska (Malewska-Kasprzak, Permoda-Osip, Rybakowski 2018).



Cade JFK. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2; 612-23.

Felber W. Die Lithiumprophylaxe der Depression vor 100 Jahren - eingenialemIrrtum. Fortschr Neurol Psychiatr 1987; 55: 141-4.

Garrod AB. The Nature and Treatment of Gout and Rheumatic Gout. London: Walton and Maberly; 1859.

HammondWA. Treatise on diseases of the nervous system. Appleton, New York, 1871.

Lange C. Om PeriodiskeDepressionstilstandeogderesPatogenese. Copenhagen, Lund, 1886.

Lange C. PeriodischeDepressionzustände und ihre Pathogenesis auf dem Boden der harnsäurenDiathese. Hamburg / Leipzig: Verlag von Leopold Voss; 1895.

Malewska-Kasprzak M, Permoda-Osip A, Rybakowski J. Disturbances of purinergic system in affective disorders and schizophrenia. Psychiatr Pol 2018; 52

Schioldann J. In commemoration of the century of the death of Carl Lange. The Lange theory of ‘periodical depressions’. A landmark in the history of lithium therapy. Adelaide:Academic Press; 2001.

Schioldann J. History of the Introduction of Lithium into Medicine and Psychiatry. Adelaide: Academic Press; 2009.


December 6, 2018