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Wednesday, 19.06.2019

Leonardo Tondo: Interviews with Pioneers in Psychiatry

Mogens Schou On Lithium 

Janusz K. Rybakowski’s comment

 

            My comment on Leonardo Tondo’s biographical sketch of Mogens Schou comes at an opportune time as we recently celebrated the 100th anniversary of the birthday of this great Danish clinician and scientist -- a true giant of lithium research and treatment.  For the establishment of contemporary lithium therapy, Schou did probably more than anyone in the world. The celebration took place in Copenhagen on November 23, 2018, the day before he was born in 1918. During the symposium I highlighted Mogens Schou’s scientific achievements and spoke about his care of patients.

            From the beginning of his research on lithium in 1952 until his death in 2005, Schou devoted more than a half of a century to indefatigable lithium activity which he performed with great and exceptional scientific scrutiny. Among lithium researchers, Schou can be named Primus Inter Pares as he with his co-workers was the first to perform pivotal studies and to make important clinical observations on lithium therapy. Concomitant with this, Mogens Schou was also extremely engaged in the care of patients receiving lithium.

            In 1952 for the first time Schou gave lithium to a manic patient, i.e., three years after John Cade had reported an antimanic effect of lithium (Cade 1949). In 1954 he and his co-workers published the first controlled study on lithium’s effectiveness among patients in a manic state (Schou, Juel-Nielsen, Strömgren and Voldby 1954).  When it was performed more than half a century ago, the study was unusual because the researchers used a neutral preparation (placebo) for comparative purposes to show the real effect of lithium, which was not well known at that time. The study included 38 patients in a manic state among whom 30 had “clear” affective symptoms. Among these patients, a spectacular improvement was noted in 12, improvement in 15 and a lack of effect in three. During the therapy, the measurements of the concentration of the drug in blood serum were systematically made and in six of them in the cerebrospinal fluid. It was found that concentrations of lithium ion in the serum remained within 0.5 to 2 mmol/l, which was an important element for further research on relations between the concentration of lithium in serum and its clinical effectiveness and toxic symptoms (Schou, Juel-Nielsen, Strömgren and Voldby 1954). Three years later Schou summed up, in his extensive article published in "Pharmacological Reviews," the contemporary knowledge concerning pharmacology, biochemistry and clinical effects of lithium (Schou 1957).

            In the early 1960s the first reports appeared pointing to a possible prophylactic effect of lithium therapy on manic and depressive recurrences; these came from England (Hartigan 1963) and Denmark (Baastrup 1964). Following this Schou, together with Baastrup performed a mirror-image study of lithium prophylaxis on 88 patients with unipolar and bipolar affective disorder (Baastrup and Schou 1967). They found that the average duration of disordered mood (mania or depression) within a year before lithium was 13 weeks while during a year on lithium it was shortened to an average of two weeks.

            The year 1968, exactly a half of century ago, was marked by Schou’s important clinical observations and studies. For the first time the adverse effect of lithium on thyroid function (goiter) was described, based on findings in a big group of 330 lithium-treated patients (Schou, Amdisen, Eskjaer Jensen and Olsen 1968a). Further, a study on renal handling of lithium elucidated the mechanism of renal lithium reabsorption (occurring in the proximal tubule) and its relationship to sodium reabsorption (Thomsen and Schou 1968). This discovery provided a plausible explanation of lithium toxicity with sometimes fatal outcome in subjects receiving lithium as a salt substitute which occurred in the 1940/1950s. Also, based on eight cases, the first comprehensive description of lithium poisoning was published, with a characterization of prodromes, clinical picture and outcomes, as well as suggested management (Schou, Amdisen and Trap-Jensen 1968b).

            However, in the same year, we witnessed a strong backlash against lithium prophylaxis provided by British psychiatrists Barry Blackwell and Michael Shepherd in a Lancet piece titled  “Prophylactic lithium. Another therapeutic myth?”. The article questioned the validity of findings on lithium’s effectiveness and requested double-blind trials on this issue (Blackwell and Shepherd 1968). Fifty years after this publication Barry Blackwell, who initiated INHN discussion on the topic with "The Lithium Controversy. A Historical Autopsy" (Blackwell 2014) seems to be confident that lithium remains the best first choice for mood stabilization in bipolar disorder.

            Eight placebo-controlled trials in which Schou exercised a significant initiative were performed in Europe (Denmark and the UK) and in the USA from 1970 to 1973; the patients included were to have at least two recurrences of illness in the two years preceding lithium treatment. Most of these studies employed a method comparing the course of illness in a group in which lithium was discontinued and replaced with placebo with a group which continued to receive lithium (discontinuation design). “Recurrence of illness” was defined as a deterioration that would require psychiatric hospitalization or commencing regular antidepressive or antimanic treatment. Analysis of all research showed that the percentage of patients in whom recurrences of depression or mania occurred was significantly lower while receiving lithium (on average 30%) than while receiving placebo (on average 70%) (Schou and Thomson 1976).

            Because lithium therapy can be administered during pregnancy, Schou initiated the Register of Lithium Babies 45 years ago (Schou, Goldfield, Weinstein and Villeneuve 1973). The clinical observations to date have shown that use of lithium by pregnant women with a mood disorder, especially by those previously treated with this drug, results in a favorable risk/benefit ratio in favor of lithium (Poels, Bijma, Galbally and Bergink 2018).

            In his promulgation of lithium therapy, Schou was very interested in how such a therapy influences the various aspects of the patient’s life. As bipolar disorder is overrepresented among the artists, he was the first to examine the issue of the effect of lithium prophylaxis on artistic creativity.  Of 24 artists treated with lithium due to bipolar disorder, 12 reported an increase in their artistic productivity, six a slight decrease and six noted no change at all (Schou 1979).         

            Mogens was extremely dedicated to the best clinical practice of lithium therapy. Since 1980 successive issues of Schou’s book Lithium Treatment of Manic-Depressive Illness have appeared. This was a practical guide to lithium therapy for doctors, patients and their families. The successive revised editions appeared in 1983, 1986, 1988 and 1993. The 6th edition was titled Lithium Treatment of Mood Disorders (Schou 2004).

            Schou, together with Bruno Müller-Oerlingausen from Berlin and Paul Grof from Ottawa, were the Founding Fathers of the International Group for the Study of Lithium-Treated Patients (IGSLI) created in 1988. In the 1990s the group published seminal papers showing a favorable influence of lithium on the decrease of mortality and prevention of suicidal behaviors (Müller-Oerlinghausen, Ahrens, Volk  et al. 1991; Müller-Oerlinghausen, Wolf, Ahrens et al. 1994; Müller-Oerlinghausen, Wolf, Ahrens et al.1996). Recently, the IGSLI publication confirmed the neuroprotective effect of lithium (Hajek, Bauer, Simhandl et al. 2014). Since its conception, the group has had yearly meetings; the most recent, the 32nd IGSLI conference, took place in Santiago, Chile, where attendees had the opportunity to visit the Acatama Dessert where a significant part of the world’s lithium resource production is located.

            During the years 1990-1994 the journal Lithium was published; Schou was on the editorial board and was the author of the first scientific article in the journal on lithium and treatment-resistant depression (Schou 1990). After many years, lithium augmentation of antidepressants is the best evidenced pharmacological strategy in treatment-resistant depression (Bauer, Adli, Ricken et al. 2014). For some researchers, this diagnosis is regarded as the second main indication for lithium use (after preventing mood recurrences) in mood disorders.

            With the foundation in 1999 of the International Society of Bipolar Disorders (ISBD), Mogens was nominated as its honorable president. Since 2001, during the society’s annual international conferences, Schou awards have been given for exceptional achievements in the field of research, educational activity and organizational and media activity concerning bipolar affective disorder.

            On 23–25 September 2005, Mogens Schou participated in the 19th IGSLI conference in Poznań, Poland. In spite of the limitations connected with his advanced age, he was very glad that he could actively participate in this conference and during which he presented one of his new research proposals. It concerned the issue of lithium prophylaxis of unipolar depression where he suspected significant efficacy, especially among so-called "hidden bipolars." Over the years, a growing number of controlled studies have been published confirming that lithium has prophylactic effectiveness in unipolar depression. It was recently reported in Finland that, on the basis of an observational study, lithium monotherapy was shown to be the pharmacological treatment associated with the lowest risk of psychiatric hospitalization in patients with severe unipolar depression (Tiihonen, Tanskanen, Hoti et al. 2017). There was no sign then that several days after the Poznan IGSLI conference Mogens Schou’s busy lithium-oriented life would end.

            My personal account of Mogens Schou spans from 1971 when I wrote a letter to him until the IGSLI conference in Poznan in 2005 when Mogens brought me a copy of my letter as a token of our long-term acquaintance. This was a very emotional event for both of us. I had been Mogens’s student, visiting him on several occasions in Risskov, Denmark, and gradually became his partner in lithium research. The crowning achievement of our relationship was the Mogens Schou Research award I received during the 20th Annual Conference of the International Society of Bipolar Disorder conference held in Mexico City in March 2018.

 

References:

 

Baastrup PC. The use of lithium in manic-depressive psychosis. Compr Psychiatry 1964; 5, 396-408.

Baastrup PC, Schou M. Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry 1967; 16: 162-172.

Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs 2014; 28: 331-342.

Blackwell B, Shepherd M. Prophylactic lithium: another therapeutic myth? An examination of the evidence to date. Lancet 1968; 7549: 968-971.

Blackwell B. The lithium controversy: A historical autopsy. inhn.org.controversies. June 19, 2014.

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

Hajek T, Bauer M, Simhandl C, Rybakowski J, O'Donovan C, Pfennig A et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med 2014; 44: 507-517.

Hartigan GP. The use of lithium salts in affective disorder. Br J Psychiatry 1963; 109, 810-814.

Müller-Oerlinghausen B, Ahrens B, Volk J, Grof P, Grof E, Schou M et al. Reduced mortality of manic-depressive patients in long-term lithium treatment:
an international collaborative study by IGSLI. Psychiatry Res 1991; 36: 329-331

Müller-Oerlinghausen B, Wolf T, Ahrens B, Glaenz T, Schou M, Grof E et al. Mortality of patients who dropped out from regular lithium prophylaxis: a collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI). Acta Psychiatr Scand 1996; 94: 344-347

Müller-Oerlinghausen B, Wolf T, Ahrens B, Schou M, Grof E, Grof P et al. Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients. Acta Psychiatr Scand 1994; 90: 295-297.

Poels EMP, Bijma HH, Galbally M, Bergink V. Lithium during pregnancy and after delivery: a review. Int J Bipolar Disord 2018; 6: 26.

Schou M, Amdisen A, Eskjaer Jensen S, Olsen T. Occurrence of goitre during lithium treatment. Br Med J. 1968a; 3: 710-713.

Schou M, Amdisen A, Trap-Jensen J. Lithium poisoning Am J Psychiatry 1968b; 125: 520-527.

Schou M, Goldfield MD, Weinstein MR, Villeneuve A. Lithium and pregnancy. I. Report from the Register of Lithium Babies. Br Med J 1973; 2: 135-136.

Schou M, Thompsen K. Lithium prophylaxis of recurrent endogenous affective disorders. In: Johnson FN, ed. Lithium Research and Therapy. Academic Press, London, 1976: 63-84.

Schou M. Artistic productivity and lithium prophylaxis in manic-depressive illness. Br J Psychiatry 1979; 135: 97-103.

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

Schou M. Lithium and treatment-resistant depression. A review. Lithium 1990; 1: 3-8.

Schou M. Lithium Treatment of Mood Disorders. A Practical Guide. Karger, Basel, 2004.

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

Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968; 215: 823-827.

Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J et al. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry 2017; 4: 547-553.

 

May 2, 2019