Sunday, 19.09.2021

Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry 

 

Robert H.  Belmaker’s comments

 

       This slim paperback is a fun read. It goes from a history of psychiatry to a history of lithium treatment and brief but comprehensive reviews of lithium in various psychiatric indications. The historical photos are  subtly illuminating and the personalities bring the text to life. The author mixes photos of ancient classics such as Aretaeus of Cappadocia with photos just a few pages away of modern lithium researchers, all friends of the author. This personal approach succeeds in a surprising way and the reader feels part of a secret society of ancient origin that continues until today, centered on the worship of lithium. The various physical side effects of lithium are very well reviewed but on the other hand are made to seem somehow pleasantly acceptable. The biological uniqueness of lithium as the only drug in psychiatry that is a single inorganic ion is built into a mystery story that leads the reader into a state of suspended disbelief somewhat akin to that of a good novel. 

       The potential readership of this 2020 thriller certainly includes the small but dogged international community of lithium researchers and clinical advocates. Disclosure: I myself am a member of this group as I have had a career of more than 45 years of using lithium clinically and studying it in the laboratory. For me the book is as close to an autobiography as a book written by someone else can be. I saw in the book at every turn  people I know, ideas that I have admired and clinical cases that I have seen. However, it is not clear to me if the potential audience for this book includes  psychiatrists and pharmacologists outside of the lithium club. 

       The book does not clearly present the difficult clinical decisions that must be weighed in deciding whether to use lithium or another mood stabilizer including atypical antipsychotics in the treatment of the bipolar patient. The text, while   mentioning  that lithium can be used adjunctively in many cases of schizoaffective disorder, some cases of unipolar depression and some cases of borderline personality or antisocial or explosive personality disorder, does not really provide a reasoned cost-benefit analysis of lithium vs. other treatment approaches.

       I think the most serious deficit in this book, and one that gives me concern, is the over-optimistic  approach to lithium’s potential use in conditions other than major affective disorder. The chapter on lithium in neurodegenerative diseases is an example. Lithium inhibits the enzyme glycogen synthase kinase (Shaldubina, Agam and Belmaker 2001), which is related to accumulation of tau in brain deposits in Alzheimer’s disease and in some animal models of Alzheimer’s. There have been some published reports that micro concentrations of lithium in drinking water correlate inversely in epidemiological studies with the incidence of dementia (Kessing, Gerds, Knudsen et al. 2017). These facts brought together do not mean that lithium could be a major therapeutic advance in preventing/treating Alzheimer or other neurodegenerative diseases. The inhibition by lithium of GSK-3beta takes place at cellular concentrations of lithium that at best are at the high end of levels that could be achieved in a patient.

       Any effects of lithium at the minute concentrations possible in drinking water could logically  not have anything to do with GSK-3beta  and tau accumulation. Putting the two together is kind of like a science fiction story. It makes for easy, fun and optimistic reading. But I think the current events equivalent of this would be like saying that hydroxychloroquine, a proven anti-malarial drug, inhibits attachment of corona virus to its receptor in the test tube and that people should therefore try hydroxychloroquine to protect themselves  from the corona virus. Rybakowski does review the  recent equivocal and negative clinical studies of lithium in Alzheimer’s and Huntington’s, but only the specialist reader would understand that these negatives weigh far greater than the theoretical potential.  The potential misunderstanding by the public and by clinicians who are not researchers is of considerable worry to me. In fact, this attitude is presaged by the title of this book, Lithium: The Amazing Drug in Psychiatry.

       Actually, all our drugs are amazing! Who would have believed 100 years ago that we would have effective antidepressants, effective antipsychotic agents and effective antianxiety agents?  None of these medicine classes help every patient and they all have side effects. But the same is true of lithium. There are many classical bipolar patients who are lithium non-responders  and patients with many atypical psychiatric disorders who seem to be helped by lithium. We are not very good at predicting that yet. Moreover, lithium’s uniqueness as an ion may just be because we have not looked hard enough. It was discovered 120 years ago that the bromide anion seems to have sedative potential but some side effects seem to have precluded its further development (Parent and Aminoff 2008). Perhaps the side effects can be managed and some day it might be a treatment? Moreover, and more recently rubidium (Belmaker, Hamburger-Bar, Newman and Bannet 1984), an ion in the same column of the periodic table as lithium, clearly had effects in animal models and in early clinical trials of depression before its use was stopped by the FDA because of the potential inability to manage an overdose.

       The chapter on lithium as an antiviral and immunoregulatory drug is speculative. There are many articles on similar antiviral and immune effects of SSRI antidepressants and phenothiazine antipsychotics but I am not sure they really belong in a book meant for psychiatrists. They need to be evaluated by scientists who are experts in that field and not as a way to boost our ego by making us think, “Here is a psychiatric drug that belongs to us that is great for all of those other real diseases like viruses and auto immune diseases!” I am concerned that Chapter 17 would lead a patient or non-specialist to think it proven  by evidence to allow us to tell a patient that lithium is good for his immune system or will cause him/her to have fewer herpes infections.  

       I love the up-to-date quality of this book – the first book fully devoted to lithium that has come out since 2016. Clearly the popularity of lithium and lithium research is waning. This book is like a pleasant drink of brandy for an old man late in the day, full of good memories and a sense of accomplishment. I am not sure it will help his younger clinicians find their way among the myriad contradictions, claims and counterclaims in this hard-nosed world of competing challenges in clinical medicine and research. 

       The chapter on the well-known artists and writers with bipolar disorder was fun and illustrated with great photos. The mentions were brief and the validity of the diagnosis not mentioned. A serious student of this area should consult Kay Jamison’s Touched with Fire (Jamison 1996). Similarly, it was great to see the photos of the various textbooks about lithium since the author of this volume, just like myself, collects books devoted to lithium research.

       The study of lithium and its use does often induce a passion and devotion of an almost religious quality. Some of this could be because one sees wonderful clinical results occasionally that seem to be almost miraculous. However, books like Peter D. Kramer’s Listening to Prozac (Kramer 1997) seemed to present a similar devotional loyalty to the newly discovered SSRIs. That rosy colored view of SSRIs seen today is much more tempered by high placebo effects and a reasonable list of side effects and social dangers. In a more extreme way marijuana and LSD and MDMA (ecstasy) also seem to make their devotees into missionaries. I am deeply worried by that trend without for a minute doubting that tetrahydrocannabinol as well as ecstasy and LSD will find clinical usefulness in specific circumstances and with correct regulation and administration.

       I would not want my love of lithium and my career in its research and clinical use to ever be framed in a vocabulary of religious devotion that would encourage or be a precedent for devotees of other specific psychotropic compounds. We need to see all of these drugs for what they are – interventions to be used when necessary,  that have value when used correctly and almost always have side effects and a price to be paid.  

 

References: 

Belmaker RH, Hamburger-Bar R, Newman M, Bannet J. The effect of rubidium and lithium on adenylate cyclase and neurotransmitter receptors. In: Corsini G, editor. Current Trends in Lithium and Rubidium Therapy. MPT Press, London. 1984, pp. 59-75. 

Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Kjær EA. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry. 2017; 74(10):1005-10.

Kramer PD. Listening to Prozac. Penguin Books. 1997. 

Parent JM, Aminoff MJ. Seizures and General Medical Disorders. In: Aminoff MJ, editor. Neurology and General Medicine. Churchill Livingstone. 2008, pp. 1077-93. 

Jamison KR. Touched with Fire: Manic-Depressive Illness and the Artistic Temperament. Free Press. 1996. 

Shaldubina A, Agam G, Belmaker RH. The mechanism of lithium action: state of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry. 200; 25(4):855-66.

 

December 31, 2020