Saturday, 18.09.2021

Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry 

 

Barry Blackwell’s comments

      

        Lithium is not only an “amazing” drug but also one to which controversy has clung like a limpet since its rediscovery by the Australian psychiatrist John Cade in 1949, at the threshold of the modern psychopharmacology era.

        In 2014 INHN.org launched a “historical autopsy” into these controversies (Blackwell 2014). Over the next two years 10 living principals contributed 40 postings to a collated document. They included Jules Angst, Tom Ban, Barry Blackwell, Sam Gershon, Paul Grof, Gordon Johnson, Martin Katz, Malcom Lader, Januz Rybakowski and Hector Warnes (Blackwell 2017).

        In the four following years another four new books about lithium were published.

        The first, by an Australian psychiatrist and a historian (de Moore and Westmore 2016), was a colorful biography of John Cade.

        The second was an encyclopedic account of the historical role of lithium in medicine through the ages, followed by a positive account of Cade’s role in the evolution of psychopharmacology (Schioldann 2017).

        The third, primarily for lay readers, was a populist account of lithium in medicine including Cade’s role (Brown 2019).   

        Now comes the fourth book (Rybakowski 2020).

        The resurgence of interest in lithium by psychiatrists with links to Australia, America, Denmark and Poland is worthy of comment. Psychopharmacology is in the doldrums characterized by a dearth of innovative new compounds and an absence of credible etiologic assumptions for the causes of mental disorders or the efficacy of their treatments. All this is contributed to by corruption in the pharmaceutical industry and complicit clinicians (Blackwell 2016).

        Against a bleak background this slender volume by Rybakowski is positive and uplifting, giving short shrift to the controversies in 195 pages and 25 chapters. It is comprehensive and scholarly, an autobiographical account of a lifetimes’ research that included 150 scientific articles published by Janusz and the Poznan Research Centre in Poland. Janusz’s body of work has a Hirsch Index of 53 that reflects both productivity and scholarly impact (40 is good and 60 exceptional). The book itself has a bibliography of 470 citations but sadly lacks an index.  Chapters 1-4 set the stage, beginning with Kraepelin’s classification of mental disorders although later chapters relate  lithium’s use mostly to the ICD 9 and DSM systems. Next  comes a historical overview of lithium’s place in history that leans heavily on Schioldann’s account, leading into Cade’s rediscovery of its specific anti-manic effect, soon overtaken by the discovery and widespread use of the phenothiazines.    

        But the spark that really lit Janusz’s enthusiasm and lifelong interest in lithium was Mogens Schou, “undisputed leader” of the field.  So, it was Janusz who in 2018, at the 100th anniversary of Schou’s birthday, gave a lecture on his influence on the history of lithium.

        Chapter 5 discusses the diagnoses of recurrent unipolar depression and bipolar disorder. Interestingly, the former includes the term “melancholia,” a neglected and now overlooked condition in DSM nosology. The chapter also includes a 2002 Polish epidemiology study involving 96 psychiatrists in all the cantons that included 860 patients, aged 16-68.  The results showed that bipolar patients did less well on antidepressants alone, indicating the use of mood stabilizers “of which lithium is the most effective drug.” Janusz relates this to Schou’s late life interest in “hidden bipolars,” a category that might have included his own brother as well as outpatients considered by Carl Lange to be recurrent depression where brief hypomanic episodes might be welcome and unremarked.

        Chapter 6 looks in depth at the use of antidepressants, anti-manic and mood stabilizing drugs. Janusz suggests classifying mood stabilizers according to their chronology beginning with lithium and the anti-convulsants, followed by neuroleptics as second generation drugs. He also suggests distinguishing between anti-depressant and anti-manic propensity. Interestingly, this sophisticated analysis does not mention cost as a criterion, one which lithium wins hands down, or side effects, more troublesome with neuroleptics. Worth mentioning is that regulatory agencies like the FDA fail to require that new drugs in this category do not require they be tested directly against lithium as the gold standard before approving a mood stabilizing indication.

        Chapter 7 is a sophisticated discussion of lithium metabolism, its kinetics and biological processes (primarily enzyme systems) and the purinergic concepts (uric acid hypothesis).

        Chapter 8 is a brief two pages identifying the indications and contraindications for lithium.The latter includes acute renal failure or myocardial infarction, impaired kidney function or decreased glomerular filtration.

        Chapters 9 through 21 provide a detailed scientific account of lithium and the wide range if its clinical uses. Included are potentiation of antidepressants (Chapter 9); mood stabilization and prevention of relapse (Chapter 10), characteristics of excellent responders, around a third identified by Paul Grof, who benefit for up to 20 years (Chapter 11); adverse effects (Chapter 12); interaction with other drugs (chapter 13); comparison to other mood stabilizers (Chapter 14); use in pregnancy (Chapter 15); suicide prevention (Chapter 16); anti-viral and immune regulatory function (Chapter 17); effects on cognitive function (Chapter 18); neuroleptic properties (Chapter 19); potential in neurodegenerative disease (Chapter 20); and other uses in and outside psychiatry (Chapter 21).

A Cautionary Tale

        Janusz Rybakowski’s  Lithium  is an incomparable synopsis of the science surrounding this simple metallic ion and its unique capacity as the most effective, least costly, mood stabilizer for the management of recurrent affective disorders, among the most common and damaging mental illnesses. This cautionary tale links art to science.

        The most frequent and frustrating aspect of therapeutics is failure of the patient to meet the prescriber’s intentions. It’s presence was noted by Hippocrates: “Keep watch also on the faults of the patients which often makes them lie about the taking of things prescribed” (Wright 1993).

        Largely denied or neglected by both patients and prescribers, this characteristic was dismissively coded in Index Medcus as “patient drop out” until 1975 when McMaster University in Toronto sponsored the First International Conference on Patient Compliance, followed by a second in 1979 (Haynes and  Sackett 1979).

        Given a name, research into noncompliance flourished with psychiatry and pediatrics as the top concerns. A multi-authored book, Patient Compliance & the Therapeutic Alliance, provides many details of the emerging field (Blackwell 1997).

        Among psychiatric medications lithium serves as a prototype of the problems for two reasons, the nature of the disorder and the toxicity of the treatment.

        Untreated, the depressive nature of the disorder spawns pessimism, inertia and forgetfulness, the mania produces skepticism, irrationality, lack of caution, risk taking, pleasure seeking and rejection of authority. Fragmentation of the therapeutic alliance may also be contributed to by differences in culture, belief systems and language.

        The lethal toxicity of lithium and the treatment regimen necessary to mitigate the risks have been clear from the early days of its modern use adding to the burden of treatment. Regular clinic visits with needles and venipuncture are frequently unpopular or inconvenient necessities.

        Recent evidence of problems in compliance was provided by an article in JAMA on the incidence of adverse effects from psychiatric medication on emergency room visits (Hampton, Daubresse, Chang et al. 2014). Of 10,000 visits, 16.4% were due to lithium toxicity, just over half of which (53.6%) led to hospitalization. Like many large multi-center statistical studies details were lacking. There was no information about who prescribed the lithium (subspecialists, primary care doctors or psychiatrists). There was nothing about the treatment regimens or the nature of the side effects and no follow up with the prescriber.

        A review of the study and its findings was published in JAMA  (Olsen 2015). It concluded, “The high frequency and clinical severity of adverse events associated with lithium should be considered among calls to expand lithium treatment in bipolar disorder.”

        No citation accompanied the assumption of increased lithium use but it might be credible as a rebuttal to the vigorous advertising of second generation neuroleptics as mood stabilizers that are less effective, more expensive and have more side effects. Lithium, meanwhile, a naturally occurring metallic ion, has no patent or seductive advertising to promote its use.

        Concerned about the implication of this flawed study that lithium was overused I wrote a letter to the Editor of JAMA with the requisite number of supporting references (Blackwell 2015). It stated, “It is a disservice to science, medicine and psychiatry to suggest that alleged sloppy diagnosis or overprescribing become an excuse for limiting the use of  a highly specific  and effective remedy for a disabling disorder.”

        My letter was rejected by a sub-committee of junior editors because it did not have a sufficient “impact score” and I was advised I might wish to contact the author but they could not guarantee a response. I gave up!

 

References:

Blackwell B, editor. Treatment Compliance and the Therapeutic Alliance. Netherlands. Harwood Academic Press. 1997

Blackwell B. The Lithium Controversy: a Historical Autopsy. inhn.org.controversies. June 19, 2014.

Blackwell B. Unpublished letter to the Editor of JAMA. inhn.org.perspectives. June 25, 2014.

Blackwell B. Corporate Corruption in the Psychopharmacology Industry (revised). inhn.org.controversies. March 16, 2017.

Blackwell B. The lithium controversy. A historical autopsy. Collated by Olaf Fjetland (Contributions by Jules Angst, Thomas A. Ban, Barry Blackwell, Samuel Gershon, Paul Grof, Gordon Johnson, Martin Katz, Malcolm Lader, Janusz Rybakowski, Hector Warnes). inhn.org.controversies. April 6, 2017.

Brown W. Lithium, a Doctor, A Drug and a Breakthrough. New York/London, Liveright. 2019.

de Moore G, Westmore A. Finding Sanity, John Cade, Lithium and the Taming of Bipolar Disorder. Sydney/Melbourne/Aukland/London. Allen & Unwin. 2016.

Hampton LM, Daubresse M, Chang H-Y, Alexander GC, Budnitz DS .Emergency Department Visits by Adults for Psychiatric Medication Adverse Events. JAMA Psychiatry. 2014; 71(9): 1006-14.

Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, editors. Compliance in Health Care Baltimore Johns Hopkins University Press. 1979, pp.1-7.

Olsen M. Surveillance of Psychiatric Medication Adverse Events. JAMA. 2015; 313(12):1273.

Wright EC. Non Compliance – How many Aunts has Matilda? Lancet. 1993; 34:904-13.

 

December 24, 2020