Tuesday, 18.05.2021

Carl Lange: On Periodical Depressions and their pathogenesis Speech delivered to the Medical Society of Copenhagen, January 19, 1886.Translated from the Original Danish into English by Johan Schioldann*
Janusz K. Rybakowski’s comment


            Johan Schioldann should be congratulated for an excellent translation of Carl Lange's speech delivered in 1886, the year that his treatise Om Periodiske Depressionstilstande og deres Patogenese  was published in the form of a monograph in Danish (Lange 1886). The monograph was translated and published in German nine years later, in 1895, with the title Periodische Depressionzustände und ihre Pathogenesis auf dem Boden der harnsauren Diathese,. Its English translation by Johan Schioldann appeared more than 100 years later, in the beginning of the 21st century (Lange 1895; Schioldann 2001).

            Carl Lange appears to have been an extremely astute researcher and clinician, and his very perceptive clinical observations and pathogenic hypotheses were reflected in his speech and further in his book. My comment will be divided into two parts: one about clinical peculiarities of a phenomenon named by Lange “periodical depression” and the second about his pathogenetic considerations pertaining to this psychiatric anomaly.

            To the first part: Is there a possible counterpart to Lange's “periodic depression” in contemporary diagnostic classifications? I would suggest a mild to moderate form of the major depressive disorder (DSM-5) or recurrent depression (ICD-10). The severe forms, with psychotic symptoms, definitely do not belong here.  I would like to point out that the precise clinical characterization of this kind of depression by Lange amazingly complies with many, but not all, diagnostic criteria and descriptions in effect in the 21st century.

            Two issues deserve comment here. First, is a possible relationship between depression and melancholia as perceived by Lange. Melancholia is probably the oldest psychiatric ailment known; the term derives from the humoral theory of the fifth century BC Hippocrates' school as the excess of black bile (melaena chole). The term “depression” in the present meaning was probably used for the first time by Robert Whytt (1714–1766), a court doctor of the Scottish king George III and an excellent researcher of the nervous system. In his treatise Observations on the Nature, Causes, and Cure of Those Disorders which have been Commonly Called Nervous, Hypochondriac, or Hysteric, Whytt introduced the name “depression of mind” (Whytt 1765).

            The popularity of the term “depression” was on the rise throughout the 19th and 20th centuries, reaching a peak at the end of the 20th century and continuing to date. In his textbook of 1899, Kraepelin used the term “depression” within the concept of manisch-depressives Irresein, including alternating manic and depressive states, as well as periodic depressive states (Kraepelin 1899). At first, Kraepelin only excluded “involutional melancholia,” i.e. depression starting in the climacteric period. But when further clinical observations showed that involutional melancholia does not constitute a separate entity from other disorders of manic-depressive kind, it was added to the category manisch-depressives Irresein in the next issue of Kraepelin’s textbook.

            In the most recent version of American Diagnostic and Statistical Manual (DSM-5), a depressive episode with melancholic features occurring both within bipolar and major depressive disorder is defined. Among the symptoms, generally showing higher severity than in other kinds of depression, the mood being regularly worse in the morning is listed. Such symptom is also mentioned by Lange as that of periodic depression. According to DSM-5, melancholic features are seen more frequently in patients hospitalized and can be accompanied by psychotic symptoms. Apparently, in the understanding of melancholia by Carl Lange, there was a severe depression with psychotic symptoms.

            The second issue is a lack of mention by Lange of the opposite psychopathological pole, such as mania or hypomania in his patients. The occurrence of such a phenomenon could place their depression in the context of bipolar mood disorder. As we now know, about a half of bipolar illness starts with a depressive episode. The lack of mention of (hypo)mania by Lange may be because he was seeing ambulatory patients and such patients never want to come to a doctor on account of their manic or hypomanic symptoms. It could also be speculated that long-term lithium administration performed by Lange might have suppressed an appearance of hypo(manic) episodes in these patients.

            Near the beginning of his lecture, Lange states that the condition of periodic depression is very frequent. This is in agreement with contemporary epidemiological studies suggesting that depression is the most common psychopathological reaction. Also, the most frequent kind of depression is that of mild to moderate intensity, the equivalent of Lange's "periodic depression." The symptomatic picture of the kind of depression described by Lange is to a great extent similar to the contemporary description of a mild and moderate form of the major depressive disorder. It should be indicated, however, that some symptoms are thought to be more frequent in the melancholic type of depression or a depression in the course of bipolar disorder.

            Mental symptoms of depression described by Lange include mental stiffness or paralysis, lack of spirits and joie de vivre, as well as an inability to initiate motor and/or mental activity. This may correspond with such "diagnostic" symptoms of depression as psychomotor retardation, indecisiveness and anhedonia.  In his patients, Lange also finds a pronounced admixture of anxiety, sometimes reaching the stage of "agony," which could be an equivalent of agitated depression. Depression may have predominant apathy or anxiety which may constitute a continuum. This concurs with the contemporary anxiety dimension as the specifier of depression.

            According to Lange, disturbances of sleep in periodic depression are frequent, with early morning awakenings with anxiety and frequently worse mood in the morning. He also points to daytime sleepiness (“I could sleep forever”). This is a frequent symptom of atypical depression, which is probably more frequent in bipolar mood disorder. Somatic symptoms of depression include variable painful symptoms (a headache, low back pain) or abdominal discomfort without any objective basis. Such symptoms, if they dominate the clinical picture, are contemporarily called "masked (somatic) depression."

            Lange’s observations on the periodicity and natural course of illness are also in line with contemporary views. The mean duration of 3-6 months is now commonly accepted as an average length of a depressive episode in major depressive disorder.

            In Lange’s speech, a pathogenic concept of periodic depression as a condition connected with an excess of uric acid was put forward. Thus, depression is a “gout of the brain.”  Therefore, the concept of uric acid diathesis of depression elaborated by Carl Lange is what prompted him to use lithium as a therapeutic drug.  Previously, the use of lithium in rheumatic gout had been initiated by a British physician, Archibald Garrod, based on the good solubility of lithium urate (Garrod 1859). However, in a paper celebrating the 100th anniversary of Lange’s publication, a German psychiatrist, Werner Felber, named the connection between uric acid and lithium ein genialer Irrtum (an ingenious error) (Felber 1987).

            However, in the 21st century, 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 the role of uric acid in the pathogenesis and treatment of mood disorders. In patients with bipolar disorder, higher prevalence of gout and increased concentration of uric acid have been found; the therapeutic activity of allopurinol, used as an adjunct to mood stabilizers, has also 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 been 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 bipolar disorder. (Malewska-Kasprzak Permoda Osip and Rybakowski 2018). Therefore, a direct connection between uric acid and mood disorders, and indirectly with lithium, as the main therapeutic modality in these disorders can no longer be denied.



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.

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6 Auflage.Leipzig:  Barth; 1899.

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 und 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: Adelaide Academic Press; 2001.

Whytt R. Observations on the Nature, Causes, and Cure of Those Disorders which have been Commonly Called Nervous, Hypochondriac, or Hysteric, to which are Prefixed Some Remarks on the Sympathy of the Nerves. London: T. Becket, and P. DuHondt, and Edinburgh:  J. Balfour; 1765.


February 28, 2019