Monday, 12.04.2021

Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry 


Hector Warnes’ comment


       This is a comprehensive and erudite compendium of 176 pages, a bibliography of 470 references, including more than 50 research and clinical papers published by the author himself, and countless most revealing illustrations. In 1973 Prof. Rybakowski defended his doctoral dissertation on water and electrolyte metabolism in patients with affective disorders treated with lithium carbonate and the following year in a meeting of the psychopharmacology academy in Copenhagen where he met Mogens Schou, whose publications on the use of Lithium in bipolar disorders started in 1954. The first book on the subject was published by Mogens Schou under the title Lithium Treatment of Manic-Depressive Illness (Schou 1980).

       Both authors had a close relationship and invariably they both paid tribute to J.F.K. Cade whose 1949 publication on the use of lithium salts in the treatment of psychotic excitement launched the Lithium revolution along with Samuel Gershon who was a researcher of Lithium in the ‘50s, also in Australia, and in the ‘60s in the USA. In 2008 Professor Rybakowski published a book entitled The Faces of Manic-Depressive Illness, translated into English in 2009, which was re-edited in a second edition 10 years later.

       The book under review comprises 25 chapters. I shall only underline that each of the chapters are imbued with clarity, depthness and originality particularly the chapters on the bipolar patients who are "excellent lithium responders”; on lithium as a suicide prevention drug; on the molecular neuroscientific studies on lithium; its antiviral and immunomodulatory effects; its effects on cognitive functions by stimulating neuroprotective and brain centers that facilitates CREB induced neuroplasticity (stimulating the cAMP which activates PKA, leading to a cascade of molecular events including CREB transcription signalling ) and finally its effects on the creative process. Kay Redfield Jamison is a psychologist who had bipolar illness and wrote several splendid books on the subject and on the beneficial effects of Lithium.

       The subtitle of the Rybakowski’ book (The Amazing Drug in Psychiatry) may prompt the reader to expect a tendency of one-sidedness. However, a whole chapter (Chapter 11) is written about the "excellent lithium responders" since Paul Grof's 1999 research. Grof, in a paper written in 2010, stated that the patients (about 1/3 of cases) that respond best to lithium had an episodic clinical course of the disease with periods of full remission and lack of psychiatric comorbidity. In a follow-up study, for 10 years Rybakowski confirmed Grof's study and added that in more than 40% of patients who were not "excellent lithium responders" the severity and number of episodes were significantly reduced. He further stated that the combination of lithium with another mood-stabilizing drug may increase the percentage of efficacy. On page 88 Prof. Rybakowski added: "there is also a group of 20-30% of people in whom lithium monotherapy is completely ineffective and the number and severity of recurrences are similar to those before the introduction of treatment." Further, on the same page, Rybakowski mentioned a research carried out at his Department of Psychiatry in a group of 111 patients (76 females and 35 males treated with lithium for an average of 18 years). They found that better prophylaxis was achieved in patients with later onset of the disease, without the family history of affective disorder, with other family members responding well to lithium, in women with anxiety disorders and in men who do not abuse alcohol.

       Genetic studies with Joanna Hauser et al. at the University of Poznan showed that the prophylactic efficacy of lithium is correlated with the polymorphism of various genes in particular the BDNF gene, the DRDI gene and stress axis genes (p.166). The effects of lithium on biological processes include intracellular signalling processes, especially an effect on the phosphatidylinositol system (PI), and inhibition of the glycogen synthase kinase-3beta enzyme (GSK-3beta) (p.65). The inhibition of inositol monophosphatase-1 by lithium improves mitochondrial dysfunction connected to inositol depletion (p.65). Another enzyme, a serine/threonine kinase (GSK-3beta), is inhibited by lithium as shown by Peter Klein and Douglas Melton (1996) from the University of Pennsylvania (where the author spent one year) and Stambolic, Ruel and Woodgett (1996) from the University of Toronto (p. 66). In addition to the inositol system another intracellular signalling system is the adenyl cyclase system which transforms adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) (pp. 66-67). In this system the CREB protein (cAMP response element-binding protein) is the specific transcription factor and gene expression regulator (p. 67). On page 68 the author writes that the prophylactic effect of lithium is connected to Val66Met polymorphism of the BDNF gene and the interaction of the BDNF gene and the 5HTTLPR polymorphism of the serotonin transporter gene. Purinergic or nucleotide receptors are activated by adenosine triphosphate (ATP). On page 70 the author cited an epidemiological study from Taiwan (Chung 2010) which showed that 16.4 % of bipolar patients had gout compared with 13.6% of the control group. In 1886 Carl Lange published a book in his native language Danish on "Periodic depressive states and their pathogenesis in the context of uric acid abnormalities" involving 750 patients, translated in 2001 by an Australian Psychiatrist of Danish origin Johan Schioldann.

       Very impressive is the clinical acumen of Carl Lange in describing the symptoms of depression (as cited by Rybakowski): "sad facial expression, a feeling of sluggishness, fatigue, emotional numbness (petrification) and difficulties with taking initiative and performing mental and physical work. He stated that patients reported a loss of interest, an inability to enjoy life, aversion and fear of contact with people, and a sense of apathy and spiritual emptiness often accompanied by a vague fear. Among the somatic symptoms he listed: loss of appetite and weight, various pains (most often headaches and low back pains), hot and cold flushes, excessive sweating. Lange talked about restless sleep, unpleasant dreams and early waking up and the worst hours are those right after waking up. He paid special attention to circadian mood swings in patients with depression-deterioration of mood in the morning and improvement in the evening hours" (Rybakowski 2014, p.22). Carl Lange’s brother, Frederik Lange, was also a psychiatrist who agreed that an excess of uric acid was responsible for the mood (cerebral gout) and clinical symptoms of gout which responded to lithium (Schioldann 2009) (quoted by the author in his bibliography number 393).

       Janusz Rybakowski, with a scientific and humanistic spirit, has carefully written chapters on the adverse effects of lithium; on its drug interactions; on the use of other mood stabilizers; on its use in pregnancy and the postnatal period; in suicide prevention; on its antiviral and immunomodulatory effects; and on lithium and literature and art. He also offers a tentative suggestion that lithium could be used in neurodegenerative diseases; in clozapine-induced neutropenia; in cluster headaches and in trigeminal neuralgia associated with headaches; in inflammatory skin disorders; in infection-related-related neutropenia; in the control of thyrotoxic storm symptoms, as an antiviral and ant-inflammatory; and in the control of oral herpes (recurrence and very frequent herpes were cured after 2-7 days of treatment (cited in reference 343 a research headed by Rybakowski). The author based these assumptions on research or clinical data cited in his extensive bibliography.

       Each chapter is very stimulating and has a plethora of research material not easily available to psychiatrists. Prof. Rybakowski has vast experience in the field, particularly in the use of lithium in bipolar disorders.

       I am pleased to recommend this book for its precision, richness, research accuracy and impartiality.




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

Chung KH, Huang CC, Lin HC. Increased risk of gout among patients with bipolar disorder: a nationwide population-based study Psychiatry Res. 2010; 180:147-50. 

Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis. In: Birch NJ, Gallicchio VS, Becker VS, Becker RW, editors. Lithium 50 Years of Psychopharmacology. New Perspectives in Biomedical and Clinical Research. Cheshire:  Weidner Publishing  Group, 1999; pp. 36-51. 

Grof P. Sixty years of lithium responders. Neuropsychobiology. 2010; 62 :8-16.

Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA, 1996; 93:8455-9. 

Rybakowski J. The Faces of Manic-Depressive Illness. Poznan: Termedia; 2009. 

Rybakowski JK, Dmitrzak-Weglarz M, Kliwicki S, Hauser J. Polymorphism of circadian clock genes and prophylactic lithium response. Bipolar Disord 2014; 16:151-8. 

Schioldann J. 'On periodical depressions and their pathogenesis' by Carl Lange (1886). Hist Psychiatry. 2011; 22:108-30. 

Schioldann. J. History of the Introduction of Lithium into medicine and Psychiatry: Birth of Modern Psychopharmacology. Adelaide: Academic Press; 2009. 

Schou M. Lithium Treatment of Manic-Depressive Illness. Basel: Karger; 1980. 

Stambolic V, Ruel L,  Woodgett JR.  Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 1996; 6:1664-8.


January 14, 2021