Lithium Controversy

I would call myself a representative of the second generation of lithium researchers and my response to the “Lithium controversy” will be related to my personal “lithium” career, which started two years after publishing the famous Lancet paper of Blackwell and Shepherd “Prophylactic lithium: another therapeutic myth?” Forty-five years of such a career have strongly supported in my mind the recognition that lithium is a powerful and beneficial reality (and not myth) for long-term treatment of mood disorder.

In 1970, after finishing my internship, I started working in the Department of Psychiatry, Medical Academy in Poznan (presently Poznan University of Medical Sciences). One of my first activities was to adopt the methods of measuring lithium level in serum and urine (and also in red blood cells) in order to monitor patients on lithium therapy. Among my first patients, a female physician with previous three depressive episodes, who started lithium in 1970, is  still an active lithium patient. The period of her lithium monotherapy has amounted now to 45 years, with excellent results, no recurrences and perfect health status. In 1973, I defended my doctoral thesis on water and electrolyte metabolism in patients with affective disorders treated with lithium carbonate. In 1974, I was attending the WHO Training Course in Psychopharmacology for Medical School Teachers which was held in Copenhagen and Aarhus. It was at that time when I first met Mogens Schou, and we have stayed close friends for the next 31 years.

In 1976-77, I was a NIH Fogarty Fellow at the University of Pennsylvania, Philadelphia. Together with Alan Frazer, current Editor-in-Chief of the International Journal of Neuropsychopharmacology, and other people working at the Depression Research Unit, we were one of the first group discovering pathways of lithium transport across membranes, based on an erythrocyte model. We confirmed that the main mechanism determining erythrocyte-serum lithium ratio was the lithium-sodium countertransport system. This issue became the  topic of my habilitation thesis, which I defended in Poland in 1980. In the same year, my first publication on lithium prophylaxis appeared in Psychiatria Polska. A group of 61 patientswho had received lithium treatment for an average of 5 years was included in the analysis. To assess the effect of lithium, a “mirror image” method was used. The analysis showed that during the period of using lithium compared with “pre-lithium” period of identical duration, the number of recurrences decreased by 71% and the number of hospitalizations decreased by 72%. Among 44% of patients, no recurrences of illness were observed while using lithium [1].  

During my stay in Philadelphia, I made friends with William “Dutch” Dyson, a surgeon by background and a great enthusiast of lithium treatment, who was running a lithium clinic for several hundred patients, and with Jay Amsterdam, the subsequent director of the Depression Research Unit at the University of Pennsylvania. Several years later, Jay and I published the results of our research showing antiviral effect of lithium on herpes infections. The main paper was presented in the international journal “Lithium”, in publication during 1990-94, of which I was on the Editorial Board [2]. In this paper, a retrospective research of the effect of prophylactic lithium on labial herpes recurrences was performed in Polish and American patients. The Polish population comprised 69 patients receiving lithium for an average of 8 years. Among 28 patients from this group who had recurrent labial herpes, in 13 (46%) there was full cessation of recurrence of this condition during lithium therapy. The American population comprised two groups, 52 persons in each, matched with regard to sex, age and 5-year duration of systematic pharmacological treatment. In the first group, bipolar patients received lithium and in the second group, major depressive patients received antidepressants. The frequency of labial herpes recurrence in comparison with the 5-year period before treatment decreased in the group receiving lithium by 73% whereas no significant difference was observed in the group receiving antidepressants.   

On the 50^th anniversary of Cade’s paper, during the lithium congress held in Lexington, Paul Grof introduced the concept of “excellent lithium responders” as the subjects in whom, during lithium monotherapy the illness ceased to exist and suggested that, such group comprise approximately 1/3 of lithium-treated patients [3]. Since doubts were expressed at that time about whether the prophylactic effect of lithium was similar in the 1960/1970s as at the time of lithium’s introduction ,we carried out a research comparing a group of patients from Poznan among whom lithium treatment was started in the 1970, with a group in which lithium was introduced in the 1980s. In each group, there were 79 patients who were observed for 10 years. The percentage of excellent lithium responders among persons who completed a 10-year observation period was similar in both groups (34 and 28%, respectively) [4]. The excellent lithium responders are characterized by the “Kraepelinian” type of manic-depressive condition with moderate number of episodes, separated by clear periods of asymptomatic remission. We subsequently found that this group, despite of long term duration of illness, had normal cognitive functions and normal levels of brain derived neurotrophic factor (BDNF), the decrease of which was postulated as a marker of late stage of bipolar illness [5].

In the last two decades I have been also involved in the activity of the International Group for the Study of Lithium-Treated Patients (IGSLI) which was founded in 1988 by  Mogens Schou, Paul Grof and Bruno Mueller-Oerlinghausen. The 19^th IGSLI conference took place in Poznan with participation of Mogens Schou who, in spite of the limitations connected with his advanced age, was very glad to actively take part and presented one of his new research proposal. There was no sign then that several days after the conference Mogens Schou would finish his busy life.

In 2010, I became the editor of the special issue of Neuropsychobiology devoted to lithium and wrote an accompanying editorial [6]. In this issue, the International Consortium on Lithium Genetics (ConLiGen) was also presented, an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment [7]. The initiative, led by Thomas Schulze originated in 2009, and I was one of the founders. Recently, the first results of genome-wide association study of lithium response in bipolar illness were obtained, based on the analysis of 2,563 patients collected by 22 participating sites all over the world. The paper was submitted to Lancet on the 47 anniversary of the Blackwell and Shepard’s article in this journal [8]. So the term ”lithium controversy” in reference to Lancet publications - from 1968 until today – has historically come full circle.

1. Rybakowski J, Chlopocka-Wozniak M, Kapelski Z. Clinical evaluation of the effectiveness of long-term preventive use of lithium carbonate in endogenous depressive syndromes. Article in Polish. Psychiatr Pol 1980; 14: 357-361.
2. Rybakowski JK, Amsterdam JD. Lithium prophylaxis and recurrent labial herpes infections. Lithium 1991; 2: 43-47.
3. Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis. In: Birch NJ, Gallicchio VS, Becker RW, eds. Lithium: 50 Years of Psychopharmacology, New Perspectives in Biomedical and Clinical Research. Cheshire, Connecticut, Weidner Publishing Group 1999; 36-51

4.   Rybakowski JK, Chlopocka-Wozniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disorders 2001, 3, 63-67.

5. Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol 2010; 13: 617-622.
6. Rybakowski JK. Lithium: sixty years thereafter. Neuropsychobiology 2010; 62: 5-7.
7. Schulze TG, Alda M, Adli M et al. The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology 2010; 72-78.
8. Hou L, Heilbronner U, Degenhardt F et al. Common genetic markers for lithium response in bipolar disorder. Submitted to Lancet.

Janusz Rybakowski

May 14, 2015