Janusz Rybakowski: Lithium therapy- a personal tale of the recent decade 


Hector Warnes’ comment


        Professor Rybakowski assembles in an encyclopaedic book of 445 pages around all the ground-breaking studies on lithium up to date. Rybakowski has himself carried out extensive research and clinical studies since 1970 and, followed closely and beyond the earliest studies of John Cade in 1949, Paul Baastrup and Mogens Schou in the early ‘50s, were those of G. Hartigan, Paul Grof, Samuel Gershon and many others. Rybakowski maintained a close relationship with Schou for more than 30 years until his death in 2005. Professor Rybakowski published 163 papers up to a decade ago but for the purpose of this book he selected out of 86 publications only 39 articles published in the last decade.  I shall only comment on the most salient ones.

        Rybakowski and Suwalska (2010) found that 13 out of 60 bipolar affective disorder patients were excellent responders to monotherapy. The remaining 47 patients experienced a variable number of episodic cycles and received other drugs along with lithium. The serum concentration of lithium ranged between 0.5 and 0.8 mmol/L. The mean period of lithium administration was 12.1 years. “Excellent lithium responders” constituted in this sample 22% of all lithium treated patients. They were compared with 60 healthy controls matched for age and gender who had no history of mental disorder. “Excellent lithium responders” had similar levels of BDNF than the healthy control group and performed better on all neuropsychological tests. “Excellent lithium responders”: people whose lives have been changed by lithium prophylaxis.  Paul Grof reported on “Excellent lithium responders” in 1999.

        On page 139 a Table on the “Clinical Factors Associated with the Prophylactic Efficacy of Lithium” is most didactic. Animal studies showed that development of cortical neuronal circuits was related to the expression of BDNF. Further studies have shown evidence of reductions in the volume of the hippocampus in subjects with chronic depression.

        On page 126 three factors contribute to the lithium non-responders: an episodic pattern in which depression precedes mania, a high number of previous hospitalizations and continuous (rapid) cycling. The excellent responders, on the other hand, had a course with periodic and distinct affective episodes and periods of complete remission (the “periodicity” described by Kraepelin). In addition, they have low psychiatric co-morbidity and frequently a family history of bipolar disorder. Further, using the Temperament Scale of the Memphis, Pisa, Paris and San Diego Auto-questionnaire which measures five temperaments: cyclothymic, dysthymic, irritable, hyperthymic, and anxious, the response to lithium correlated significantly positively with the hyperthymic temperament score and negatively with the anxiety, cyclothymic and depressive temperament scores (Rybakowski, Dembinska, Kliwicki et al. 2013). An important finding is the antidepressant and anti-suicidal effect of Lithium therapy in bipolar patients (Baldessarini, Tondo and Hennen 2003) confirmed by the author.

        Rybakowski in several studies reported on the genetic basis of bipolar illness and its response to mood stabilizers. On pages 87-88 he writes:

        "The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers such as the phospha-tidyl inositol (PI) (which improves inositol depletion-related mitochondrial dysfunction), the adenosine-monophosphate (cAMP) and protein kinase C (PKC) pathways, substances involved in neuroprotection (brain-derived neurotrophic factor (BDNF), and GSK-3p (glycogen synthase kinase) and a number of others miscellaneous genes.... Further studies suggest roles for the glutamatergic receptor. AMPA gene..."

        A prominent psychologist and researcher Kay Jamison, who was co-author with Frederick Goodwin on Manic-Depressive Illness published in 1990 and re-published in 2007, was closely associated with Rybakowski. She published several books on her own experience with lithium: An Unquiet Mind. A Memoir of Moods and Madness (1995); Touched with Fire. Manic depressive Illness and the artistic Temperament (1993); and The Night Falls Fast. Understanding Suicide (1999). After undergoing an eerie experience as a bipolar patient, she finally discovered that she was an excellent lithium responder. Schou in 1979 published a paper in the British J. of Psychiatry on “Artistic productivity and lithium prophylaxis in manic-depressive illness” which put an end to the fear that lithium might affect cognitive functions or creativity in the artistic temperament.

        The chapter on lithium treatment in the era of personalized medicine is an outstanding overview of the latest research including the interaction of genetic polymorphism and endophenotypes. The role of stress factors was underlined by the author: "We found an association between prophylactic lithium efficacy and the genes connected with stress axis such as glucocorticoid receptor (NR3CI) gene and FKBP5 gene" (page 364). Further, "It was found that in bipolar patients on prophylactic lithium with long-term remission, the concentration of inflammatory cytokines were similar to those of healthy subjects."

        On page 297 the author states that "Neuroinflammation, with microglial activation as an important element, plays a role in the pathogenesis of bipolar disorder." Further research reported on the chapter on Glutamate-Related Antibodies and Peripheral Insulin-Like Growth Factor in Bipolar Disorder and Lithium prophylaxis suggest that glutamate-related antibodies can contribute to the pathogenesis of mood disorders in some population of patients. There can be a need to characterize the phenotypes of such patients. We also confirmed the results of previous studies showing a pathogenic involvement of Insulin Growth Factor-1 in bipolar disorders.

        In the chapter “Lithium-the state of the art for 2020” the author reported on his research on the 48A/G polymorphism of the DRD1 (dopamine receptor D1) gene and the polymorphism of so-called "clock" genes related to biological rhythms, such as ARNTL (aryl hydrocarbon receptor nuclear translocator-like) gene and TIM (timeless) gene and the PER3 gene (Period homolog), gene that controls the circadian rhythm (recent Nobel Prize winners discovered this gene). Lithium has been also successfully used in the treatment of herpes simplex and in some neurodegenerative disorders based on experimental findings on animal models. Lithium inhibits the serine/threonine kinase enzyme (GSK-3P) activity that regulates gene transcription, synaptic plasticity, apoptosis, cellular structure, resilience and the circadian cycle, all of which are implicated in the pathophysiology of mood disorders (page 382).

        Some patients receiving lithium prophylaxis for 10 to 20 years may develop an interstitial nephropathy and thyroid dysfunction. In several chapters the author has researched this issue and particularly on the chapter on kidney, thyroid and other organ functions after 40 years or more of lithium therapy (page 210) reaching a sparingly conclusion.

        This is only a bird’s eye view of the extreme complexity of lithium research which Professor Rybakowski has devoted most of his career not only because of its efficacy in the treatment of bipolar disorders but because of its unique mechanism of action in the Central Nervous System.



Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: Update and new findings. The Journal of Clinical Psychiatry 2003;64(Suppl.5):44–52. 

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

Goodwin FK, Jamison KR. Manic-depressive Illness. New York: Oxford University Press; 1990. 

Jamison KR. An Unquiet Mind: A Memoir of Moods and Madness. New York: Vintage Books Random House; 1995. 

Jamison KR. Touched with Fire: Manic-Depressive Illness and the Artistic Temperament. New York: The Free Press;1993. 

Jamison KR. The Night Falls Fast. Understanding Suicide. New York: Vintage Books Random House; 1999. 

Rybakowski JK, Dembinska D, Kliwicki S, Akiskal KK, Akiskal HH. TEMPS-A and long-term lithium response: positive correlation with hyperthymic temperament. J Affect Disord 2013;145(2):187-9. 

Rybakowski JK, Suwalska A. Excellent Lithium responders have normal cognitive functions and plasma BDNF levels. Int. J. of Neuropharmacology 2010;13(5):617-22. 

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


April 28, 2022