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Magda Malewska-Kasprzak, Agnieszka Permode-Osip and Janusz K. Rybakowski: Disturbance of the purinergic system in affective disorders and schizophrenia
Janusz K. Rybakowski’s additional information
A commentary on Walter Felber’s paper on Lithium prevention of depression 100 years ago -- an ingenious misconception, published in 1987


           Werner Felber’s paper, Die Lithiumprophylaxe der Depression vor 100 Jahren - ein genialem Irrtum, was published a year after the 100th anniversary of Carl Lange’s treatise on the periodic depressive states:  Om Periodiske Depressionstilstande og deres Patogenese (Lange 1886). Lange’s monograph was reproduced nine years later in German, translated by Hans Kurella, as Periodische Depressionzustände und ihre Pathogenesis auf dem Boden der harnsauren Diathese (On periodical depressions and their pathogenesis in the context of uric acid abnormality) (Lange 1895). Johan Schioldann’s English translation appeared more than a 100 years later, in the beginning of the 21st century (Schioldann 2001). 

           Felber’s paper consists of six parts: 1) Preface; 2) Short biography of Carl Lange and the German translator of his book, Hans Kurella; 3) Remarks on Lange’s description of periodic depression; 4) Practical aspects of lithium therapy as performed by Carl Lange;  5) The reasons for the oblivion of epochal achievement; and 6) The pathway to lithium re-discovery.

           In the preface, Felber underlined the significance of the Carl Lange’s treatise of 1886 which became known to the wider public several years later thanks to German translation by Hans Kurella. The “uric acid diathesis” concept put forward in Lange’s treatise provided the basis for long-term lithium administration in periodic depression. Felber estimates that during the 20 years of his psychiatric ambulatory practice Lange treated about 2,000 of such patients with lithium.

           In the second part, the short biographies of Carl Lange (1834-1900) and Hans Kurella (1858-1916) were provided. The latter, a German psychiatrist promoted by Karl Kahlbaum, was a keen translator of neurological, psychiatric, anthropological and sociopolitical works of foreign authors, among them Scandinavian and Italian.

           The remarks on Lange’s description of periodic depression pay great tribute to the clinical astuteness of the Danish physician. Mental and somatic symptoms of depression were delineated, most of which comply with contemporary diagnostic criteria of depression. Among the first are, among others, mental stiffness or paralysis, inability to initiate motor or mental activity, lack of spirits and concomitant anxiety.  Within the second group, variable painful symptoms, vegetative disturbances, loss of weight and abnormalities of sleep are listed. In his treatise, Lange also points at circadian mood changes, with the worse mood in the morning in a majority of patients. Felber also mentions Lange’s observations on the periodicity and natural course of the illness which are to a great extent similar to contemporary views on the major depressive disorder of mild to moderate intensity.

           In the fourth part, Felber describes lithium administration outlined by Carl Lange, regarding dose and method of administration. The drug was given as lithium carbonate powder, 8-40 mmol lithium per day, in 3-4 doses. The daily amount of lithium is therefore comparable to what is used today. Lithium carbonate was dissolved in water or lemonade. In the end, Felber quotes Lange’s statement that long-term treatment with lithium caused a disappearance or decrease of depressive episodes with significant prolongation of remission, although in most cases, the illness was not fully cured.

           In the fifth part of the paper, Felber argues that the forgotten reason for introducing lithium into treatment of mood disorders by Lange was that the idea of uric acid diathesis behind it was false and was refuted by both psychiatrists and practitioners of general medicine where this kind of diathesis was a basis for using lithium in the treatment of rheumatic diseases.

           In his final part (6), Felber mentions John Cade who related to Garrod’s work on using lithium in gout on account of the suspected excess of uric acid in this condition (Garrod 1859). However, he did not mention the full story of Cade’s experiments which gave rise to the introduction of lithium into contemporary psychiatry. One of Cade’s premises was based on the excess of uric acid in manic patients. In the last paragraph of the paper, in relation to Carl Lange’s work, Felber speculates about the discrepancy between theory and practice, showing how a false theory could sometimes result in a spectacular clinical achievement.

           However, as far as pathogenesis of psychiatric disorders is concerned, the situation nowadays is entirely different from that of 30 years ago when Falber was writing his paper.  In the recent two decades it has been 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, a higher prevalence of gout and increased concentration of uric acid have been found, and the therapeutic efficacy 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 antidepressant activity. Alterations of P2 receptors (mostly P2X7 receptors) has been found significant for the pathogenesis of mood disorders, especially bipolar disorder (Malewska-Kasprzak, Permoda-Osip, Rybakowski 2018). Therefore, a direct connection between uric acid and bipolar disorder, and indirectly with lithium, as the main therapeutic modality in this disorder can no longer be denied.



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 - ein genialem Irrtum. Fortschr Neurol Psychiatr 1987; 55: 141-4.

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

Lange C. Om Periodiske Depressionstilstande og deres Patogenese. Copenhagen: Lund; 1886.

Lange C. Periodische Depressionzustände und ihre Pathogenesis auf dem Boden der harnsäuren Diathese. Hamburg/Leipzig: Verlag von Leopold Voss; 1895.

Malewska-Kasprzak M, Permoda-Osip A, Rybakowski J. Disturbances of the 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.


February 21, 2019