Johan Schioldann: Carl Lange, 1834-1900. A founding father of neurology, psychophysiology and lithium therapy: a biographical portrait.
Janusz K. Rybakowski’s comment

            Johan Schioldann’s biography of Carl Lange brings us closer to the most distinguished 19^th century Danish physician and scientist. Besides Lange's great achievements in neurology, he was the first who introduced lithium for the treatment of mood disorders based on the concept of "uric acid diathesis" and was the co-founder of the first neurobiological theory of emotions, known as the James-Lange theory

            In my comment, divided into three parts, I will consider how the concepts and achievements of Carl Lange related to psychiatry have survived into the 21^st century; in other words, what is the contemporary psychiatric legacy of Carl Lange?

Lange’s description of periodic depression

            In 1886, Carl Lange published in Denmark his treatise on the periodic depressive states: Om Periodiske Depressionstilstande og deres Patogenese (Lange 1886). This was produced nine years later in German 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).

            The symptomatic picture of periodic depression as described by Lange is, to a great extent, similar to the contemporary description of the mild and moderate form of the major depressive disorder. Mental symptoms of depression described by Lange include mental stiffness or paralysis, lack of spirits and joie de vivre, as well as the inability to initiate motor and/or mental activity. These may correspond with such "diagnostic" symptoms of depression as psychomotor retardation, indecisiveness and anhedonia.  In his patients, Lange also observed a pronounced admixture of anxiety, sometimes reaching the stage of "agony," which could be an equivalent of agitated depression. According to him, depression may be a continuum between predominant apathy and anxiety. This concurs with contemporary (DSM-5 2013) anxiety dimension as the specifier of depression. Lange also pointed out that disturbances of sleep in periodic depression are frequent, with early morning awakenings with anxiety and frequently worse mood in the morning; he also mentioned daytime sleepiness. Among somatic symptoms of depression, Lange listed variable painful symptoms, headache, low back pain or abdominal discomfort, without any objective basis. Such symptoms, if dominating 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 given by Lange is now commonly accepted as an average length of a depressive episode in major depressive disorder.

The introduction of lithium for the treatment of mood disorders and the purinergic hypothesis of these disorders

            The important part of Lange's treatise is a pathogenic concept of depression as a condition connected with an excess of uric acid. Thus, depression is 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 suspected uric acid excess in depressive patients. Lange gave lithium on a long-term basis as prophylaxis against recurrences of periodic depression. He noticed that such long-term treatment with lithium resulted in a disappearance or decrease of depressive episodes with a significant prolongation of remission, although in most cases the illness was not fully cured. 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 Denmark’s Middelfart psychiatric hospital, who administered it to psychiatric inpatients.

            The re-introduction of lithium into contemporary psychiatry took place a half century later due to the clinical observations of an Australian psychiatrist, John Cade. In his experiments, some "uric acid connection" was also observed since he suspected an excess of uric acid in manic patients (Cade 1949). However, a novel history of lithium use began in the early 1960s when it was demonstrated that a long-term treatment with lithium could prevent the recurrence of manic and depressive episodes in mood disorders (Hartigan 1964; Baastrup and Schou 1967). Nowadays, long-term treatment with lithium is the first choice procedure for the prevention of recurrences in mood disorder, mostly in bipolar disorder, and concurs with Lange's long-term lithium administration for the management of periodic depression.

            Celebrating the 100^th anniversary of the seminal publication of Lange, a German psychiatrist, Werner Felber (1987), called the connection between uric acid and lithium ein genialem Irrtum (an ingenious error). He speculated about the discrepancy between theory and practice, showing how a false theory could sometimes result in a spectacular clinical achievement. However, from the 21^st century perspective it seems that this Lange’s concept had some merit. 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. New evidence has been accumulated concerning the role of uric acid in the pathogenesis and treatment of bipolar disorder. In such patients, 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. Research on the role of the purinergic system in the pathogenesis and treatment of mood, focusing on the role of adenosine (P1) receptors and nucleotide (P2) receptors, demonstrated an activation of adenosine receptors related to an antidepressant activity and alterations of P2 receptors (mostly P2X7 receptors) as 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 bipolar disorder, and indirectly with lithium as the main therapeutic modality in this disorder, can no longer be denied.

Neurobiological theory of emotions 

            In 1885 Lange published a treatise, Om Sindsbevägeleser. Et Psyko-Fysiologisk Studie (About emotions. Psychophysiologic study), which consisted of research on vasomotor changes and conditional reflexes during emotional stress (Lange 1885). Two years later it was translated into German as Über Gemüthsbewegungen. Eine psychophysiologische Studie (Lange 1887) and after 10 years, into French as Les émotions: Étude psycho-physiologique (Lange 1895). This treatise provided a basis for Lange's biological (psychophysiological) theory of emotions. According to him, a perception of emotional states reflects an experience of "peripheral" somatic changes in reaction to stimuli having emotional salience. These somatic changes are mostly expressed as vasomotor reactions, i.e., contraction and relaxing of blood vessels of skin, muscles and other organs. These reactions are regulated by the vasomotor center in the brain stem.

            At the same time, a similar concept was put forward by a prominent American philosopher and psychologist, William James. According to him, a perception of a fact or a phenomenon results in somatic expression establishing a base for raising an emotion (James 1884). This emotion is brought to awareness since information concerning both emotion and somatic reaction comes to the brain. However, contrary to Lange, who was a physician and neurologist and proposed the vasomotor center as the structure for emotions, James, being more a philosopher, did not define brain structures connected with emotions. 

            Among significant 20^th century American researchers seeking the brain centers of emotion, the work of James Papez should be included based on his proposal of the so-called Papez circuit (Papez 1937); Paul Maclean, who postulated the association of emotional processes with the structures of the limbic system (MacLean 1955); and, more recently, Joseph LeDoux demonstrated that the brain structure mostly associated with the processing of emotional stimuli is the amygdala, belonging to the limbic system and described it in his book "The Emotional Brain" (Le Doux 1996).

            The main message shared by both creators of the James-Lange theory is that psychological (cerebral) and physiological processes are to a great extent coupled. More than 100 years later, a prominent American researcher of Portuguese origin, Antonio Damasio, in his book "Descartes' Error," defined such coupling as the "body loop" (Damasio 1994). Damasio is, among others, a founder of the concept of the somatic marker, postulating a contribution of somatic experiences (so-called "gut feelings") to the processes of decision making. In this case, somatic experiences influence the activity of the ventromedial prefrontal cortex (Damasio, Everitt and Bishop 1999). In one of his recent papers, he writes: "Feelings are mental experiences of body states” (Damasio and Carvalho 2013). This statement could be a direct corroboration of  the James-Lange theory.

References:

Baastrup PC, Schou M. Lithium as a prophylactic agent. Its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry 1967; 16: 162-72.

Cade JFK. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2; 612-623.

Damasio A, Carvalho GB. The nature of feelings: evolutionary and neurobiological origins. Nature Rev Neurosci 2013; 14: 143-152.

Damasio AR, Everitt BJ, Bishop D. The somatic marker hypothesis and the possible functions of prefrontal cortex. Philosoph Trans Royal Soc London, Series B. 1999; 351: 1413-1420.

Damasio AR. Descartes' Error: Emotion, Reason and the Human Brain. Putnam Publishing, New York, 1994.

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5, Arlington, VA, American Psychiatric Association, 2013.

Felber W. Die Lithiumprophylaxe der Depression vor 100 Jahren - ein genialem Irrtum. Fortschr Neurol Psychiatr 1987; 55: 141-144.

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

Hartigan G. The use of lithium salts in affective disorders. Br J Psychiatry 1963; 109: 810-814.

James W. What is emotion? Mind 1884; 9: 188-205.

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

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

Lange CG. Les émotions. Étude psychophysiologique. Paris. Alcan, 1895.

Lange CG. Om Sindsbevägelser. Et Psyko-Fysiologisk Studie. Copenhagen, Lund, 1885.

Lange CG. Über Gemüthsbewegungen. Eine psychophysiologische Studie. Leipzig, Theodor Thomas, 1887.

LeDoux JE. The Emotional Brain. New York, Simon and Schuster, 1996.

MacLean PD. The limbic system (‘‘visceral brain’’) and emotional behavior. Arch Neurol Psychiatry 1955; 73: 130-134.

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

Papez J.W. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937; 38: 725-743.

March 14, 2109