Samuel Gershon: Lithium history
Hector Warnes’ comment


           I am most impressed by Samuel Gershon's minute details on the use of lithium since the Lange brothers' introduction of this compound into medical therapeutics and the countless trial, errors and impasses undertaken by Cade himself on the use of lithium in psychiatric disorders.

            Apparently, most of these vicissitudes were described in Johan Schioldann's History of the introduction of Lithium into Medicine and Psychiatry reviewed by Barry Blackwell on in Books, September 14, 2017. Lithium, just like Clozapine, is a drug which fits best in the ancient Greek definition of pharmakon which means both a remedy and a poison.

            There are many other drugs used in medicine which would enter into this category should they be wrongly used in terms of: a) for the wrong illness; b) for the wrong age group; c) in combination with other drugs; d) in excessive dosages; and/or e) without clinical acumen f) in the wrong setting.

            We are sadly aware that there is no panacea (pan, all; akos or akeia, remedy) in medicine and that any drug could have adverse side effects, particularly when least expected.  After decades of clinical experience, I tend to be cautious with the use of certain drugs, particularly when I read carefully reports of controlled studies and best research carried out before they are released to the market (which show no more than a 50-60 % success rate in well-selected patients).
             I am inclined to support are centstudy  on "Mapping susceptibility genes for bipolar disorder" (Turecki, Grof, Grof et al. 2001) regarding the selection of suitable patients likely to respond to Lithium therapy.

            Obviously, there are subgroups of bipolar disorders who are likely to respond to lithium and another group who are not. Those who are likely to respond have a genetic profile different from those who are not likely to respond. Furthermore, the Cytochrome P450 enzymes show variations in pharmacodynamics or pharmacokinetics of the drug pathways in addition to other neuro-metabolic disturbances (Turecki, Grof, Grof et al 2001.). 

            The narrow therapeutic "window" (0.7 and 1.2 mmol/l or 0.4 to 1.0 mmol/l) brings to mind the therapeutic "window" of anti-epileptic compounds and the theory of "kindling" of Bipolar Disorders which was borrowed from the neurosciences.  The erratic history of lithium research has hardly considered the fact  that frequently the  psychiatric pathology  for which it has been used are treated in combination with other anti-psychotics and co-morbidity is the rule rather than the exception. Unfortunately, we are not aware of the exact number of casualties caused by drug toxicology. Epidemiological studies can only identify reported cases or cases of those hospitalized but not those who are not reported or wrongly diagnosed.

            A variant of migraine headache called chronic cluster headache, found to have a good response to lithium, displayed a higher frequency of the antigens HLA-B18 and HLA-A9 than did non-responders. The non-responders had a higher frequency of HLA-A1. Karl Axel Ekbom (the neurologist who first described the Restless leg syndrome) noticed in 1974 (Teive, Munhoz and Barbosa 2009), and confirmed later in several studies, that cluster headache responded to lithium therapy (Abdel-Maksoud, Nasr and Abdul-Aziz 2009). It has also been shown that infants born to women who take lithium during the first trimester of pregnancy are at increased risk of developing Ebstein's cardiac anomaly (Patorno,  Huybrechts,  Batemann et al.  2017).



Abdel-Maksoud NA, Abdul-Aziz A. Lithium treatment in cluster headache, review of literature. Eur. J. Psychiat 2009; 23, 53-60.

Teive HA, Munhoz RP, Barbosa ER. Professor Karl-Axel Ekbom and restless legs syndrome. Parkinsonism Relat Disord 2015; 9:254-7.

Turecki G1, Grof P, Grof E, D'Souza V, Lebuis L, Marineau C, Cavazzoni P, Duffy A, Bétard C, Zvolský P, Robertson C, Brewer C, Hudson TJ, Rouleau GA, Alda M. Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry 2001; 6: 570-8.

Patorno, E. Huybrechts, KF, Bateman, B.T. et al. Lithium use in Pregnancy and the risk of cardiac malformations. N Engl J Med 2017; 376: 2245-54.


January 10, 2019