Lithium therapy – a personal tale of the recent decade
Amazon; 2021, p.451
Reviewed by Januz Rybakowski
Lithium was one of the three constituents (next to hydrogen and helium) that formed after the Big Bang explosion and was identified as a chemical element in 1817. The first medical use dates to the year 1859 when an English physician, Alfred Baring Garrod (1819-1907), introduced lithium salts for the treatment of gout. In the second half of the 19th century, an American neurologist, William Alexander Hammond (1828-1900), used lithium bromide for the treatment of mania, and a Danish physician and scientist, Carl Lange (1834-1900), based on the “uric acid diathesis” theory of depression, reported on his experiences with lithium carbonate in the treatment and prophylaxis of periodic depression.
Whereas modern psychiatric history of lithium began in 1949 by the publication of an Australian psychiatrist, John Cade (1912-1980) who demonstrated a therapeutic effect of lithium in manic patients. In the early 1960s, the first papers appeared on a prophylactic effect of lithium for the prevention of manic and depressive recurrences in mood disorders. They have received robust subsequent confirmation in a great number of clinical studies. Therefore currently, lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of bipolar disorder. In the early 1980s, the augmentation of antidepressants by lithium was shown, and nowadays, such augmentation in treatment-resistant depression makes probably the second most important use of lithium in psychiatry. In recent decades, it has been also demonstrated that, in addition to its mood-stabilizing properties, lithium exerts anti-suicidal, antiviral, immunomodulatory, and neuroprotective action. Lithium's long-term administration may protect against dementia and some promising effects of the drug in neurodegenerative disorders have been observed.
The research on clinical use and mechanism of therapeutic action of lithium have been my leitmotiv since I began my work in 1970 at the Department of Psychiatry, Medical Academy in Poznań, Poland. This venture in lithium research has resulted in multiple publications, 163 of which are featured in the PubMed database. I am also the author of the book: Lithium – the amazing drug in psychiatry, published in 2020, the e-book of which is available on www.termedia.pl/eBook/-231.
For this book, I would like to report on my research journey with lithium in the recent decade. Throughout this time, I have been the sole author or co-author of 86 publications on lithium. Thirty-nine articles were selected here, in all of them I am the first or the last author.
In 2010, I wrote the editorial to the special issue of the Neuropsychobiology, of which I was the editor, on the occasion of the 60th anniversary of lithium introduction into modern psychiatry. In this issue, prominent lithium specialists offered current views on neurobiological and clinical studies of the drug [p.12]. In the next year, I presented the 2010 update on lithium in neuropsychiatry. The main topics were the efficacy of lithium in mood disorders, with a special focus on cognitive functions, and the neuroprotective effects of the drug. Neuroprotective properties of lithium evidenced in both experimental research and clinical studies with brain imaging, suggested a possible use of lithium for dementia and in neurodegenerative disorders, such as Huntington’s disease and amyotrophic lateral sclerosis [p.26].
In 1999, at the 50th anniversary of lithium introduction, Paul Grof, the Canadian psychiatrist of Czech origin, proposed a term “excellent lithium responders” for patients whom on monotherapy with lithium experienced a dramatic change in their life as their mood episodes were completely prevented. Shortly after this, we demonstrated that such patients constitute about one-third of lithium-treated bipolar patients (Rybakowski, Chłopocka-Woźniak and Suwalska 2001).
In 2010, we found that the excellent lithium responders present normal cognitive functions and plasma levels of the brain-derived neurotrophic factor (BDNF) On neuropsychological tests from the CANTAB battery, measuring spatial working memory and sustained attention, they performed better on all, and had higher plasma BDNF levels than the remaining lithium patients but not different from those of healthy controls. It was suggested that they may constitute a specific subgroup of bipolar patients in which long-term lithium administration can produce complete normality. Of note is also the normal plasma BDNF despite long-term lithium treatment of these subjects, as the low BDNF was proposed as a marker of the late stage of bipolar illness [p.17].
Several years later, I published a review paper on the effect of lithium on neurocognitive functioning. In most experimental studies, lithium in therapeutic doses, exerts a favourable influence on various cognitive functions. On the other hand, among clinicians, a negative impact on cognitive functioning is sometimes considered one of the side effects of the drug. However, it should be kept in mind that bipolar patients themselves present cognitive problems of mild intensity across mood states, worsening during manic or depressive episodes and sometimes, also persisting during euthymia. In our studies, the effect of lithium on cognitive function was shown to be associated with prophylactic efficacy. I also suggested that the possible mechanisms alleviating a possible negative impact of lithium on cognition besides prevention of affective recurrences can be connected with the improvement of neural plasticity, antiviral action against herpes infection and using the drug in appropriate doses [p.183].
In Poznań center, we attempted to study a relationship between lithium prophylactic efficacy and affective temperaments using Hagop Akiskal’s Temperament Scale of Memphis, Pisa, Paris, and San Diego - Autoquestionnaire (TEMPS-A). This scale measures five temperaments: depressive, cyclothymic, hyperthymic, irritable and anxious. We found that the response to lithium correlated significantly positively with hyperthymic temperament score, and negatively with anxiety, cyclothymic and depressive temperaments scores [p.104]. In further analysis, we observed that long-term treatment with lithium can reduce the scores of cyclothymic and irritable temperaments on the TEMPS-A [p.175]. We also studied the affective temperaments among the offspring of the excellent lithium responders and found that healthy offspring had lower scores on depressive and anxious temperaments and higher on hyperthymic temperament compared to subjects with mood disorders [p.164]. Therefore, a favorable role of hyperthymic temperament for several aspects of bipolar illness was validated.
A degree of lithium’s prophylactic response makes it a convenient subject for molecular-genetic research. Such research in psychiatry up to the second decade of the 21st century has been dominated by the strategy of the “candidate gene.” In this approach, a specific gene based on its function is tested for possible involvement in the pathogenesis of disease or mechanism of pharmacological treatment. Genetic markers of known function or located in potentially important regulatory gene regions are analyzed in case-control studies to determine if the variant is involved in disease or pharmacological treatment of it. In Poznań center, much research of prophylactic lithium efficacy in bipolar disorder has been performed in the last decade using the candidate gene method, e.g. [p.42] and [p.111].
In 2012, our group presented the results on a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder. The association was found for the polymorphisms of 5HTT, DRD1, COMT, BDNF and FYN genes, but not for 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9 genes [p.50]. Whereas in 2013, I reviewed the current status of knowledge on the association of lithium efficacy with the polymorphism of candidate genes [p.87]. In the article, the formation of the Consortium on Lithium Genetics (ConLiGen) aimed to perform the genome-wide association study (GWAS) of lithium response in bipolar disorder was highlighted. The author of this book was one of the “founding fathers” of the ConLiGen. The first results of lithium's GWAS study were published in 2016 by Hou, Heilbronner, Degenhardt et al.
Many studies established that excellent lithium responders are clinically characterized by an episodic course of illness with periods of complete remission, a bipolar family history, low psychiatric co-morbidity, mania-depression episode sequences, a moderate number of episodes and a few hospitalizations in the pre-lithium period. Several other clinical, biochemical and genetic factors can be associated with lithium’s efficacy. The review of such factors was presented in two articles published in 2014 [p.124, 133].
An adverse effect of lithium such as a decrease of urinary concentration ability, which clinically manifests by polyuria and polydipsia may appear after several weeks of lithium therapy. In lithium-treated patients, urinary concentrating capacity is diminished by about 10–30%, which results in the increase of urine volume by about 10–60%. In our molecular-genetic study, we found that lithium-induced impairment of renal concentrating ability in long-term lithium-treated bipolar patients may be connected with the polymorphism of the glycogen synthase kinase-3beta (GSK-3β) gene [p.77]. Incidentally, it should be noted that recently, this enzyme has been regarded as one of the main biological targets of lithium's therapeutic effect in mood disorders and also in neurodegenerative disorders. However, a big clinical concern pertains to patients receiving lithium for 10–20 years, because in some of them, chronic interstitial nephropathy may develop, resulting in increased serum creatinine and a reduction of glomerular filtration rate (GFR). In our study of 80 patients with bipolar mood disorder (26 male, 54 female), aged 60±11 years and receiving lithium for 5–38 (mean16) years, decreased GFR values <60 ml/min/1.732 were found in 23% of patients, significantly more frequently in men than in women (38% vs 16%), and specific gravity of the urine, equal to or below 1.005, was recorded in 21% of men and 14% of women . We also compared 120 patients with bipolar disorder of which 90 (30 males and 60 females) had been receiving lithium for 5–38 (mean 16) years, and 30 (10 males and 20 females) had never been exposed to lithium. Lithium-induced impairment of kidney function was reflected by abnormal levels of such markers of kidney injury as neutrophil gelatinase-associated lipocalin (NGAL) and beta-2 microglobulin (β2-MG). Of these, urinary β2-MG, as a marker of tubular function seems to be a better predictor than serum NGAL because it showed multiple clinical and biochemical correlations, especially in men. [p.69]. The ultrasonographic study showed that in the lithium-treated group, patients with macrocysts (22%) had poorer renal function compared with the patients without macrocysts. Changes characteristic for lithium nephropathy (punctate hyperechoic foci, microcysts <2 mm, and increased echogenicity) were seen in three patients treated with lithium for more than 20 years. Sixteen percent of patients in the control group had macrocysts; however, no correlation between their presence and impaired renal function was found [p.199]. Our clinical experience suggests that long-term lithium-treated patients should be closely monitored for creatinine level and the GFR, and if needed, the lithium dose should be reduced. Hasty discontinuation of lithium, due to its impairing effect on the kidney, and replacing it with another mood-stabilizing drug is not recommended. Such a decision should be taken with caution because other mood-stabilizing drugs, especially in excellent lithium responders may not be effective, and the further course of the illness can deteriorate and be drug-resistant.
Lithium is concentrated by the thyroid at levels three to four times that of plasma, and the major lithium‐induced thyroid side effects are goiter and hypothyroidism. In our study, we compared the structure and function of the thyroid in 98 patients (68 female and 30 male), aged 62 ±13 years, receiving lithium for 3–47 years (mean 19±10 years), and 39 patients (27 female and 12 male), aged 57±10 years, receiving other mood-stabilizing drugs but never treated with lithium. Compared with patients not receiving lithium, lithium‐treated patients had significantly higher concentrations of the thyroid-stimulating hormone (TSH) and free thyroxine (fT4) and the lower concentration of free triiodothyronine (fT3). However, the percentage of hypothyroidism was not different in both groups which may suggest that a predisposition to hypothyroidism is not directly connected with lithium treatment but may be associated with other factors such as gender, (in both groups 3-4 times higher in females), family history of thyroid disorder or even with the bipolar illness itself. In the lithium group, most hypothyroidism cases appeared during the first years of lithium administration. All hypothyroid subjects were successfully treated with thyroxine [p.319]. Lithium‐treated patients had significantly higher thyroid volume, a higher number of focal changes >1 cm, and a more frequent goiter. This abnormality was similar in male and female patients. However, the structural changes were not related to the hormone’s concentrations [p.319]. Also, no significant connections between long-term lithium treatment and antithyroid antibodies were found (Kraszewska, Ziemnicka, Sowiński et al. 2019). The cross-sectional study was also performed to measure levels of thyroid hormones and antibodies in patients with bipolar disorder receiving lithium for 10–20 years and those taking the drug for more than 20 years. The greater susceptibility of female subjects for disturbances of thyroid hormones during lithium therapy was confirmed, with one-fifth of them showing some features of hypothyroidism. However, in contrast to the effect of lithium on kidney function, our results do not show an association between the duration of lithium therapy and thyroid dysfunction [p.154].
In 2016, the effects of lithium on hematopoietic, mesenchymal and neural stem cells were reviewed [p.219]. Following this, in a series of articles, the effects of long-term lithium treatment on very-small embryonic-like stem cells (VSELs) and the mRNA expression of neural and glial markers, in peripheral blood, in patients with bipolar disorder (BD) with the long-term duration of the illness were investigated. Fifteen BD patients (aged 53±7 years) not treated with lithium, with the duration of illness >10 years, 15 BD patients (aged 55±6 years) treated with lithium for 8–40 years (mean 16 years) and 15 control subjects (aged 50±5 years) were included. In BD patients not taking lithium, the number of VSELs was significantly higher than in control subjects and correlated with the duration of illness. The mRNA expression of most markers was significantly higher than in the controls and correlated with the number of VSELs. In lithium-treated BD patients, the number of VSELs was similar to controls and correlated negatively with the duration of lithium treatment and serum lithium concentration. In these patients, the mRNA levels of most neural and glial markers were not different from controls. Based on the results, it was concluded that the long-term treatment with lithium may suppress the activation of regenerative processes by reducing the number of VSELs circulating in PB. These cells, in BD patients not treated with lithium, may provide a new potential biological marker of the illness and its clinical progress. The higher expression of peripheral mRNA markers in BD patients may involve ongoing inflammatory processes, compensatory mechanisms and regenerative responses. Long-term lithium treatment may attenuate these mechanisms [p.238-273, 295].
We also evaluated serum levels of the antineuronal antibodies anti-N-methyl-D aspartate receptor (NMDAR) and anti-glutamic acid decarboxylase (GAD), and insulin-like growth factor 1 (IGF-1), in patients with BD, during manic and depressive episodes and in remission compared to euthymic patients receiving long-term lithium therapy. Higher levels of NMDAR and anti-GAD antibodies during episodes and increased levels of IGF-1 during an acute manic episode and in remission after mania were found. During long-term lithium treatment, a lowering of anti-NMDAR, anti-GAD antibodies and IGF-1 were observed that may reflect normalization of glutamatergic system in BD, contributing to mood stabilization [p.333].
In 2018, I was the first author of a review paper on clinical perspectives of lithium's neuroprotective effect. In this article, neurochemical mechanisms of neuroprotective action of lithium were characterized, and possible associations between this effect and the results of neuroimaging and neurocognitive studies were considered. Data from experimental, epidemiological and clinical studies point to an anti-dementia effect of lithium, and some therapeutic effect in the treatment of mild cognitive impairment and Alzheimer's disease. The results of employing lithium in other neurodegenerative disorders are still controversial (Rybakowski, Suwalska and Hajek 2018).
Thirty years ago, we presented the results of the retrospective collaborative study performed at the Department of Adult Psychiatry, Poznan University of Medical Sciences, and the Department of Psychiatry of the University of Pennsylvania showing that long-term treatment with lithium can greatly prevent the recurrences of labial herpes due to herpes simplex virus type 1 (HSV1) infections. The Polish population consisted of 69 patients (24 male, 45 female) receiving lithium for 8 years, with 28 persons who had recurrent labial herpes. In 13 patients the recurrences disappeared and the overall drop in their frequency amounted to 64%. The American population consisted of two groups of 52 people, matched by gender (21 males and 31 females in each group), age (on average 45 years) and duration of treatment (mean 5 years). In the first sample including bipolar patients receiving lithium, the recurrences compared with the 5-years before lithium were reduced by 73%. In the second sample containing patients with recurrent depression treated with antidepressant drugs, no difference was noted (Rybakowski and Amsterdam 1991). In 2018, in her review paper, Dr. Ruth Itzhaki provided evidence that infection with HSV1 makes a significant risk factor for Alzheimer’s Disease (AD). She speculated that the use of antiviral drugs may decrease such a risk (Itzhaki 2018). In a commentary on this, I proposed a hypothesis that the anti-herpes activity of lithium can link a possible prophylactic and therapeutic action of this ion in the AD [p.312]
In 2016, we described five patients (two men aged 64 years and 79 years) and three women (aged 64 years, 65 years and 75 years) who have received lithium treatment for 40–45 years. Lithium was usually initiated in the early phase of the illness (in three patients within the first two years). In four patients, lithium concentration was between 0.60 and 0.65 mmol/l, and in one patient, between 0.7 and 0.8 mmol/l. Four were very good lithium responders. One man had stage 3 chronic kidney disease and the other stage 2/3 chronic kidney disease. All three women had asymptomatic stage 2 chronic kidney disease. One woman had severe thyroid dysfunction (Hashimoto’s disease) with extremely high levels of antithyroid peroxidase antibodies and antithyroglobulin antibodies and was receiving thyroxine. In these patients, most cognitive functions were comparable to healthy persons of similar gender, age and years of education. All the patients were professionally active until 55–65 years and their family and social functioning were satisfactory [p.210]. And in last year, a case of successful continuous lithium treatment for 50 years in a 79-year-old female patient was reported. The patient worked successfully as an ophthalmologist until 2007. In her, apart from maintaining a euthymic state, long-term lithium treatment also exerted a favorable effect on general health, especially the elimination of viral and other respiratory infections This patient could be considered the epitome of an excellent lithium responder. Among the factors that predisposed her to a good response, hyperthymic personality and early lithium treatment (5 years after onset) can be indicated [p.415].
Recently, I praised the benefits of long-term lithium treatment in the commentary for the appeal of Gin Malhi, the Editor-in-Chief of the journal Bipolar Disorder: “Make lithium great again!” [p.430]. Given the clinical and biological properties of lithium, it looks like this drug is presently greatly underutilized in mood disorders. Therefore, efforts should be undertaken for challenging skepticism about the use of lithium and optimizing its long-term administration. In such a way, more patients with mood disorders can become the beneficiaries of lithium’s therapeutic action. Such a message was expressed in a paper published in 2018. In this article, the negative perception of lithium by some clinicians was challenged. The data were presented showing lithium superiority over other mood stabilizers, the lithium-induced side effects were delineated, and their proper management described. Finally, an issue of benefits of long-term administration of lithium was discussed, including the phenomenon of the “excellent lithium responders” as well as a subject of starting lithium prophylaxis early in the course of the illness [p.274].
Lithium use in my home country, Poland, in the years 2004–2017 was also estimated. It was found that in the seven-year period 2004–2010, a minimal increase in lithium use (4%) occurred, while in 2011–2017, this increase amounted to 16%. However, in the second half of 2017, the use of other mood-stabilizers such as valproates was nearly three times higher than lithium while that of quetiapine, olanzapine, and lamotrigine about twice as high. Therefore, compared with other mood-stabilizing drugs, lithium has been clearly underutilized and more extensive use of this drug would be recommended [p.348]
In 2020, I performed three general reviews of lithium therapy. The title of the first was: “Lithium treatment in the era of personalized medicine.” In the article, it was indicated that the knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences of mood disorders makes an important component of personalized medicine. The antisuicidal effect of lithium during its long-term administration should be also undoubtedly taken into account in the context of personalized medicine. Furthermore, in the article, the studies on personalized medicine of lithium treatment of acute mood episodes and augmentation to antidepressants were discussed [p.358]. The second review was named: “Lithium – past, present future.” A narrative exploration on this topic was performed with the most important references, including the author’s works. The issue of the underutilization of lithium was also touched upon, with future recommendations [p.371]. The third review entitled “Lithium treatment – the state of the art for 2020” discussed among others the effect of lithium on preventing suicidal behaviors, antiviral (mainly against herpes viruses), and immunomodulatory as well as neuroprotective and ‛antidementia’ properties of this drug. It was also mentioned that the biochemical mechanism of lithium is associated mainly with the inhibition of glycogen synthase kinase-3 and an effect on intracellular signaling. The recommendations for managing lithium-induced adverse effects both in the early and late period of treatment as well as for lithium use in pregnancy and perinatal period were given. The necessity of overcoming negative perceptions of lithium was also pointed out [p.394].
The greatest lithium researcher of the second part of the 20th century was a Danish doctor, Mogens Schou (1918-2005). My relationship with this great scientist dates back to 1971, when we began our correspondence on lithium, and then maintained our close contacts for over 30 years until his death, initially as his student and later as a partner in lithium research. Since 2001, the International Society of Bipolar Disorders (ISBD) award is granted in his name for outstanding scientific, educational, and organizational achievements in the scope of bipolar affective disorder. I became an awardee of Mogens Schou research award presented at the 2018 ISBD conference in Mexico City. On the occasion of the 100th anniversary of Mogens Schou’s birthday, a scientific conference was held in Copenhagen on November 23, 2018, a day before his birthday. At this conference, I had the honor of delivering the main lecture on the influence of Mogens Schou on the history of lithium in psychiatry. The conference was followed by an editorial published in Bipolar Disorders entitled “Mogens Schou (1918-2005): A scientist, a doctor and a lithium champion” [p.290].
In a short article of 2019, I also paid a tribute to another lithium supporter and advocate, an American psychiatrist, James Walter (Jeff) Jefferson (1937–2019). In 1975, Jeff Jefferson, together with his colleagues from the Madison University in Madison, WI, established the Lithium Information Center, aiming to organize and disseminate all emerging publications connected with lithium in medicine. He was also the principal author of the first American lithium handbook titled Lithium Encyclopedia in Clinical Practice published in 1984 and was greatly engaged in the important topics of lithium administration. I remember him from numerous lithium conferences, as an extremely friendly person and sincerely committed to the promulgation of lithium therapy [p.316].
The review of the research on lithium is concluded with the article covering descriptions of lithium therapy in literature and art. The paper presents the connections of lithium therapy with such characters as John Cade, Salvador Luria, Patty Duke, Kay Jamison, Jerzy Broszkiewicz, Ota Pavel, Robert Lowell, Jaime Lowe, Nicole Lyons, Kurt Cobain, Sting and the band Evanescence. This article shows how important lithium has proved to be in psychiatry and how its extraordinary properties are praised by celebrities who were enabled by it to lead good, creative and fulfilled lives. The last three examples show that lithium has also entered the world of pop culture and has become an inspiration for musical creation [p.433].
Grof P. Excellent lithium responders: people whose lives have been changed by lithium prophylaxis. In: Birch NJ, Gallicchio VS, Becker RW, editors. Lithium: 50 Years of Psychopharmacology, New Perspectives in Biomedical and Clinical Research. Weidner Publishing Group, Cheshire, Connecticut; 1999, pp. 36-51.
Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet 2016;387:1085-93.
Itzhaki RF. Corroboration of a major role for herpes simplex virus type 1 in Alzheimer’s disease. Front Aging Neurosci 2018;10:324.
Kraszewska A, Ziemnicka K, Sowiński J, Ferensztajn-Rochowiak E, Rybakowski JK. No connection between long term lithium treatment and antithyroid antibodies. Pharmacopsychiatry 2019;52:232-6.
Rybakowski JK, Amsterdam JD. Lithium prophylaxis and recurrent labial herpes infections. Lithium 1991;2:43-7.
Rybakowski JK, Chłopocka-Woźniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord 2001;3:63-7.
Rybakowski JK, Suwalska A, Hajek T. Clinical perspectives of lithium's neuroprotective effect. Pharmacopsychiatry 2018;51:194-9.
Febuary 10, 2022