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Janusz Rybakowski’s reply to Hector Warnes’ comment
Janusz K. Rybakowski: The Faces of Manc Depressive Illness
Reviewed by Barry Blackwell


I would like to thank Hector Warnes for his friendly and favorable comments on my book. As he rightly pointed out, my aim was to discuss bipolar disorder from different angles. In response to him, I should like to mention some new developments, in some way related to the book, which have taken place since its publication in 2009.

There are a great number of painted masterpieces showing the depressive pole of bipolar illness, bearing the title “melancholia.” On the other hand, a painting depicting a pure manic pole, as an element of bipolar mood disorder, is very difficult to find. However, it seems that such criteria could be met in the painting presented on page 37 of the book entitled "Mania" by Florencio Yllana, a contemporary Filipino artist (born 1977) who studied in the USA and is presently living in Brazil. The painting was done in 2001 following an acute manic episode in the course of the artist’s bipolar mood disorder. I visited the him in Arraial d’Ajuda, Porto Seguro, Brazil, and described both him and his painting in an article published in Journal of Affective Disorder in 2011 (Rybakowski 2011). I also acquired the painting which now embellishes my home in Poznan.

Recently, I tried to summarize some new developments in the understanding and management of bipolar disorder in adults which was published in F1000 Research (Rybakowski 2017). Among the topics I discussed was the genetic overlap of bipolar disorder, gene-environmental interaction in bipolar disorder, the concept of mood stabilizers and the update on lithium. The latter two issues will be further elaborated here.

Ten years ago, I proposed a classification of mood stabilizers (MSs) based on the chronology of their introduction into psychiatric armamentarium. A definition of MS should reflect its role in the acute and long-term treatment of bipolar disorder, such as  reducing or ameliorating manic and/or depressive symptoms during an acute episode and a prevention of manic and/or depressive recurrences during long-term administration, when a drug is given as monotherapy, and a trial is performed for at least one year. Furthermore, the drug should not induce or worsen either manic or depressive episodes or mixed states. The first two publications describing a long-term mood-stabilizing properties of lithium carbonate by a British psychiatrist Geoffrey Hartigan (1963) and a Danish psychiatrist Paul Christian Baastrup (1964) appeared in the early 1960s. The reports of French authors Pierre Lambert (1971) and his co-workers describing a possible mood-stabilizing effect of valproate salts took place at the turn of 1960/1970 and this property was named by the authors as “thymoregulatrice." In the early 1970s, Japanese researchers led by Teruo Okuma (1973) showed that carbamazepine can also demonstrate MS effects. Because lithium and the anticonvulsant drugs mentioned above preceded the introduction of newer MS agents by more than two decades, a proposal was suggested to group lithium, valproate and carbamazepine as first generation MSs. In 1995, Carlos Zarate Jr and his colleagues observed that a typical antipsychotic drug, clozapine, may fulfil the criteria for MS and their observation can be regarded as the beginning of the second generation MS. Subsequently, other atypical antipsychotics (olanzapine, quetiapine, aripiprazole) have been found to have MS properties according to the definition above. A suggestion that the anticonvulsant, lamotrigine, may have MS characteristics was made in 2002 by Terrence Ketter and Joseph Calabrese. Therefore, a proposal was made that these agents can be collectively named as second generation MSs (Rybakowski 2007, 2009). In 2010, Jorge Quiroz and colleagues demonstrated a prophylactic efficacy of monotherapy with long-acting risperidone in bipolar I disorder during a two-year trial and, according to the definition, risperidone could join the family of the second generation MSs (Quiroz, Yatham and Palumbo 2010). Recently, this classification was elaborated in my commentary published in Bipolar Disorders journal (Rybakowski 2018).

The last section of this writing will be devoted to lithium which, as you may imagine, is my favorite topic and was also a subject of my contribution to the discussion of Barry Blackwell’s essay: “The lithium controversy. A historical autopsy.” We, in Poznan, have a longitudinal experience with lithium which was substantiated by our recent report on excellent lithium responders receiving lithium for 40 years or more (Permoda-Osip et al. 2016). Among the plethora of subjects connected with lithium in recent years, I selected just two, i.e., a contribution of lithium research to a purinergic hypothesis of mood disorders and a possible neuropsychiatric role of trace concentration of this ion.

“The uric acid connection” was underlying the introduction of lithium treatment both in the 19th and 20th centuries. Carl Georg Lange (1834-1900) administered lithium to depressive patients based on his hypothesis that depression is caused by an excess of uric acid in the nervous system (gout of the brain) and that lithium makes the best soluble urate compound (Lange 1896). In this respect, he followed the recommendation of Alfred Baring Garrod (1819-1907) who introduced lithium for the treatment of gout and other rheumatic diseases with a supposed excess of urate deposits. In the 20th century, the introduction of lithium into modern psychiatry by John Cade (1912-1980) followed his experiments on uric acid with guinea pigs.  On the 100th anniversary of Lange’s publication, German psychiatrist Werner Felber named a connection between uric acid and lithium therapy “a genial error” (Felber 1987). However, in the 21st century this connection was revived as a purinergic hypothesis of mood disorders. As uric acid is the end product of purine metabolism, a lot of evidence accumulated on the role of the purinergic system in the pathogenesis and treatment of mood (including bipolar) disorders (Ortiz et al. 2015).

          That the trace amounts of lithium may play some neuropsychiatric role was evidenced in recent correlations between suicide, dementia and lithium in drinking water. The evident negative correlations between incidence of suicide and concentration of lithium in drinking water were obtained in Japan and Austria several years ago (Ohgami et al. 2009; Kapusta et al. 2011). However, quite recently, Kessing et al. (2017), in a Danish nationwide study, examined individual data on the municipality of residence and data from drinking water measurements in patients aged 50 to 90 years with a diagnosis of dementia from 1970-2013 (n=73, 731) compared with 733, 653 controls. Lithium exposure was significantly different between patients with a diagnosis of dementia and controls and the incidence rate ratio of dementia was decreased in those exposed to more lithium than 10.1 µg/L. Also, Fajardo et al. (Fajardo, Fajardo and LeBlanc 2018) examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties. The authors found that changes in AD mortality were negatively correlated with trace lithium levels and statistical significance was maintained after controlling for most risk factors.

Last but not least, during an upcoming conference of the International Society of Bipolar Disorder in Mexico City, March 7-10, 2018, I am to receive the Mogens Schou Award for research. This fact is particularly moving for me because Mogens was my initial mentor on lithium in 1972 and had remained a personal friend until his passing away in 2005, shortly after he participated in the International Group for Study of Lithium-treated patients (IGSLI) conference in Poznan. Mogens Schou, together with Paul Grof (Czechoslovakian-Canadian) and Bruno Mueller-Oerlinhausen (German), were the founding fathers of IGSLI in 1989. During the recent IGSLI meeting in Dresden, we had a pleasure to host his daughter, Jette Kraft, who became an honorary member of the IGSLI.



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Permoda-Osip A, Abramowicz M, Kraszewska A, Suwalska A, Chlopocka-Wozniak M, Rybakowski JK. Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients. Ther Adv Psychopharmacol. 2016; 6: 277-282.

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March 22, 2018