Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry 

Janusz Rybakowski’s reply to Robert Haim Belmaker’s comment

       I appreciate very much Haim Belmaker’s favorable comments on my book (Rybakowski 2020). There are manifold reasons for being personally moved by them. One of the most important is the acknowledgment of his Polish roots. In Poland, his name would be written with the initial “ch” (Chaim).

       Since 1970s, both Haim and I have been driving in the same truck as far as lithium research and therapy are concerned. My book describes lithium as the main motive of my half-century psychiatric career. Similarly, lithium research and treatment have also been very important in Haim’s biography. When he visited me at my house in Poznan in 2007, I showed him my collection of lithium books and he was very proud of being also in the possession of most of them.

       Since that time, my collection has expanded. The books making the “must” for this assemblage include Johan Schioldann’s History of the introduction of lithium into medicine and psychiatry, published in  2009, and a concise textbook The essential guide to lithium treatment written by the Michaels, Bauer and Gitlin in 2016. Also in recent years, two biographies of John Cade’s were published. The first, in 2016, was written by Australian authors Greg de Moore and Ann Westmore titled Finding sanity: John Cade, lithium and the taming of bipolar disorder, and the second by an American psychiatrist, Walter Brown, from the Brown University, as Lithium: a doctor, a drug, and a breakthrough, in 2019. In 2017,  the book of Kay Jamison appeared, Robert Lowell. Setting the river on fire. A study of genius, mania, and character, describing the illness and lithium treatment of one of the greatest American poets of the 20^th century. I am sure that Haim made himself the owner of all of them.                     

       In my book, I awarded a deserved credit to Haim for his excellent research on the role of the inositol system in the pathogenesis of bipolar disorder and the mechanism of lithium action. This has been in some way a verification of the inositol depletion hypothesis of bipolar disorder and a therapeutic mechanism of lithium, formulated by a British physiologist and biochemist, Michael Berridge, more than 30 years ago (Berridge, Downes and Hanley 1989). This first biochemical concept of lithium mechanism seems still pretty impregnable. Haim and his colleagues, mostly Galila Agam, performed a series of elegant knock-out experiments on mice, depriving them of one of the two genes associated with the phosphatidylinoinositol system: IMPA1 (inositol monophosphatase-1) and SMIT1 (sodium myo-inositol transporter-1). It turned out that both genetic knock-out procedures caused behavior resembling the situation after lithium administration.

       Both Haim and I concur in deploring an underutilization of lithium in psychiatry. Two years ago, I wrote a paper titled “Challenging the negative perception of lithium and optimizing its long-term administration,” in which I indicated the advantage of lithium over other mood-stabilizing drugs and the possibilities of effective management of lithium side-effects (Rybakowski 2018). In the same year, Robert Post found it unacceptable that lithium is greatly underutilized in the USA, even more than in Europe. He pointed to the multiple assets of lithium and argued that the fear of lithium adverse effects can be exaggerated (Post 2018).

       Recently, Gin Malhi, the current Chief Editor of the journal Bipolar Disorder, also called upon a better utilization of lithium’s therapeutic potential and more frequent use of the drug in the editorial titled “Make lithium great again” (Malhi, Bell, Boyce et al. 2020). I was to chair a session titled “The advancing quality of psychiatric care with broader lithium use” during the APA 2020 in Philadelphia which is a stomping ground for me, where I did lithium work in collaboration with Jay Amsterdam, Alan Frazer, and William “Dutch” Dyson. The other speakers of the session were to include Michael Bauer from Dresden, Germany, the current president of the IGSLI (International Group for the Study of Lithium-treated Patients), Bob Post, and Michael Gitlin from LA. Unfortunately, due to the pandemic, this did not materialize. However, I submitted the same session, changing the title into “Finding mood equity through broader lithium use,” for the APA 2021 in LA, hoping that it will be accepted.

       In connection with Haim’s commentary, there are several issues that can be touched upon. An important Haim objection to the book was my allegedly over-optimistic approach to lithium's potential use in conditions other than major affective disorders such as neurodegenerative disorders and viral illnesses. As to the first subject, I have pointed out on the epidemiological, experimental and clinical data connected with a possibility of lithium being the “antidementia” agent. However, I was far from recommending using lithium in these conditions.

       As to the second issue, there have been convincing data showing that lithium can exert antiherpetic action in both systematic and topical administration. Efficacy for the first has been amply demonstrated in a retrospective epidemiological study on a sample of affective patients I performed with Jay Amsterdam (Rybakowski and Amsterdam 1991), and in numerous case reports for more than 40 years (Lieb 1979; Gillis 1983; Bschor 1999). Topical lithium ointment was found effective for herpes changes by Gordon Skinner, the discoverer of the antiherpes lithium activity (Skinner 1983), and also by our group (Rybakowski, Gwieździński and Urbanowski 1991). As to the antiviral effect of lithium against RNA viruses, including coronaviruses, the data are tentative (Amsterdam, García-España and Rybakowski 1998; Nowak and Walkowiak, 2020; Murru, Manchia, Hajek  et al. 2020).

       The other issue is the epidemiological and clinical significance of the trace or very low doses of lithium. In the recent decade, an inverse association between lithium concentration in drinking water was found in countries such as Japan (Ohgami, Terao, Shiotsuki et al. 2009), Austria (Kapusta, Mossaheb, Etzersdorfer et al. 2011), the USA (Blüml, Regier, Hlavin et al. 2013) and Greece (Giotakos, Nisianakis, Tsouvelas et al. 2013), although there were also negative studies in England (Kabacs, Memon, Obinwa et al. 2011),  Denmark (Knudsen, Schullehner, Hansen et al. 2017) and Portugal (Oliveira, Zagalo, Madeira and Neves 2019).  These findings resulted in a suggestion of drinking water supplementation with lithium in the areas of its low level. A fresh addition to this topic is a paper of the largest nationwide epidemiological study from Japan showing an inverse association of lithium level with suicides in male subjects  (Kugimiya, Ishii, Kohno et al. 2020). Also, a recent meta-analysis of ecological studies may support the hypothesis for a protective (or inverse) association between lithium intakes from public drinking water and suicide mortality at the population level (Memon, Rogers, Fitzsimmons et al. 2020)

       A negative association between tap water lithium and dementia was observed in Denmark (Kessing, Gerds, Knudsen et al. 2017) and in the USA (Fajardo, Fajardo, LeBlanc and MacPherson 2018). There were also findings of the therapeutic efficacy of the trace doses of lithium. Nunes, Viel and Buck (2015) showed a beneficial effect of lithium, 300 µg/day, on a decline of performance in patients with Alzheimer’s disease. Therefore, taking also into account suicide data, it seems that the concept of lithium as a trace element for mental health formulated by Japanese researcher Takeshi Terao in 2015 may have some merit (Terao 2015). This could be in some way the aftermath of John Cade’s speculations in this respect that he did in his seminal paper on lithium (Cade 1949).

       But what about the very low dose of lithium, say, 150 mg of lithium carbonate/day? According to Barreilher and Ghaemi (2020), this can be legitimate for the prevention of suicide and dementia. In good lithium responders with lithium-induced kidney injury, discontinuing lithium results in a high risk of relapse and further treatment resistance. In such patients, even a very low dose can be helpful.  Recently, Gadh (2020) assessed the effectiveness of 150 mg of lithium carbonate in a residential addiction treatment center. He found many beneficial results such as reduction in buprenorphine-naloxone use by 50%, benzodiazepines by 99%, atypical antipsychotics by 70% and smoking cessation increased by 300%. The completion rate of those who took low-dose lithium improved by almost 100%.

       At the end of the day, a question may be asked: Am I worshiping lithium? The answer concurs with Haim's statement that all contemporary psychotropic drugs are amazing and reads that I am worshiping the psychopharmacology as such. As a clinical psychiatrist working for half a century, I can testify that practicing prudent and perfectionistic psychopharmacology has enabled me to bring effective help to thousands of patients with psychiatric disorders and lithium had a significant place there. This was the source of my great personal gratification.

       An asset of psychopharmacology is that the results of studies in any place in the world, published in scientific journals or presented during scientific conferences, can be rapidly implemented into clinical practice. Certainly, psychopharmacological treatment should be conducted in the context of a given patient and their family and with adequate psychotherapeutic support. However, in most patients, supportive psychotherapy, oriented on their specific personality features and life situation can be usually sufficient.

References:

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Barroilhet SA, Ghaemi SN. When and how to use lithium. Acta Psychiatr Scand, 2020;142(3):161-72.

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Blüml V, Regier MD, Hlavin G, Rockett IR, König F, Vyssoki B, Bschor T, Kapusta ND. Lithium in the public water supply and suicide mortality in Texas. J Psychiatr Res, 2013;47:407-11.

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Gadh S. Low-dose lithium impact in an addiction treatment setting. Personalized Med Psychiatry, 2020;21-2:100059.

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Kugimiya T, Ishii N, Kohno K, Kanehisa M, Hatano K, Hirakawa H, Terao T. Lithium in drinking water and suicide prevention: The largest nationwide epidemiological study from Japan. Bipolar Disord, 2020. Online ahead of print.

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Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res, 2013;10:104-7.

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Rybakowski JK. Lithium – the Amazing Drug in Psychiatry. Termedia Wydawnictwa Medyczne, Poznań, 2020. E-book: www.termedia.pl/eBook/-231

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Terao T. Is lithium potentially a trace element? World J Psychiatry, 2015;5:1-3.

February 25, 2021