Clinical Use of Lithium Salts: Guide for Users and Prescribers
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Tondo et al. Int J Bipolar Disord (2019) 7:16 https://doi.org/10.1186/s40345-019-0151-2 REVIEW Open Access Clinical use of lithium salts: guide for users and prescribers Leonardo Tondo1,2,3* , Martin Alda4, Michael Bauer5, Veerle Bergink6,7, Paul Grof8, Tomas Hajek4, Ute Lewitka5, Rasmus W. Licht9,10, Mirko Manchia11,12, Bruno Müller‑Oerlinghausen13, René E. Nielsen9,10, Marylou Selo14, Christian Simhandl15, Ross J. Baldessarini1,2 and for the International Group for Studies of Lithium (IGSLi) Abstract Background: Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers. Main text: We summarized recommendations concerning safe clinical use of lithium salts to treat major mood dis‑ orders, including indications, dosing, clinical monitoring, adverse efects and use in specifc circumstances including during pregnancy and for the elderly. Conclusions: Lithium continues as the standard and most extensively evaluated treatment for bipolar disorder, espe‑ cially for long‑term prophylaxis. Keywords: Bipolar disorder, Blood testing, Dosing, Lithium, Side‑efects Historical introduction and efective treatment was not immediately adopted In 1949, John Cade (1929–1996), an Australian psychia- by psychiatry. As Cade himself observed, “a discovery trist, serendipitously initiated a new era in psychiatric by an unknown psychiatrist without research training, treatment by using lithium carbonate to treat mania. working in a small hospital for the chronically mentally His use of lithium arose from the hypothesis that major ill, with primitive techniques and negligible equipment, mental illnesses might be associated with defciencies could not attract much attention” (Cade 1999). In addi- or excesses of unidentifed chemical substances, includ- tion, several cases of severe, acute intoxication associ- ing accumulations of nitrogenous metabolites. Tis idea ated with use of lithium salts as a substitute for table salt led him to give lithium carbonate to laboratory animals (sodium chloride) were reported in 1949, and some expe- to limit toxicity of test substances including uric acid and rience was required to learn how to use lithium safely. noting calming and other behavioral changes. Subse- Tis could be achieved by measuring its concentration in quently, he reported on benefcial efects of treating ten blood (Amdisen 1967; Baldessarini 2013; Bauer and Git- patients with lithium carbonate (a medically accepted, lin 2016). though unproved, treatment for gout) for mania and In 1954, Professor Erik Strömgren (1909–1993), a on risks of discontinuing such treatment (Cade 1949). prominent academic psychiatrist at the University of Tese encouraging initial results are now widely consid- Aarhus Medical Center in Denmark, read of Cade’s ered a revolutionary discovery, although this innovative experience with lithium for mania and asked his then- junior colleague Mogens Schou (1918–2005) to repli- *Correspondence: [email protected] cate the Australian findings. Schou not only did so but 3 Lucio Bini Mood Disorders Centers, Lucio Bini Center, Via Cavalcanti 28, pursued the study of lithium to contribute in a major 09128 Cagliari and Rome, Italy way to establishing its safe and effective clinical use for Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Tondo et al. Int J Bipolar Disord (2019) 7:16 Page 2 of 10 the treatment of manic-depressive illness. His research Lithium today in collaboration with another Danish psychiatrist, Poul Lithium treatment remains the “gold standard” of treat- Baastrup (1918–2001), established the most important ment for preventing recurrences in bipolar disorder, effect of lithium—its ability to prevent recurrences of both types I (with mania and major depression) and manic-depressive illness (Baastrup 1964; Baastrup and II (with depression and hypomania). It also has evi- Schou 1968). In Zurich, Jules Angst (born 1926) and dence of efectiveness for preventing suicidal behavior his collaborators confirmed the prophylactic benefits in patients with bipolar or major depressive disorder. of lithium treatment (Angst et al. 1970). In addition, However, it has gradually become less widely utilized, Angst with Paul Grof (born 1935) and other colleagues particularly for mania, mainly due to more vigorously proposed methods of clinical trial-design suitable for promoted and more rapidly efective alternatives which testing for long-term, prophylactic effects of a treat- do not require blood tests. Tese alternatives include ment such as lithium (Grof et al. 1970). drugs developed for other purposes, including cer- Gradually lithium became accepted in clinical prac- tain anti-epilepsy agents (carbamazepine, lamotrig- tice around the world, though not without some resist- ine, sodium valproate) and most antipsychotics. Teir ance. There was, in fact, a strong skepticism about its adverse efects include metabolic syndrome (weight- long-term efficacy, based on reasonable considerations gain with diabetes, high blood pressure, and increased (Blackwell and Shepherd 1968). These included the lipids in the blood), insulin resistance, abnormal move- requirement for evidence from blinded, randomized, ments, and cognitive dulling with antipsychotics, as controlled trials. The first of these helped to con- well as markedly increased risks of birth defects includ- vince the scientific and clinical community (Baastrup ing spina bifda and severe cardiac anomalies during et al. 1970). Lithium treatment finally received regula- pregnancy in association with valproate and carbamaz- tory approval by the US Food and Drug Administra- epine (Patel et al. 2018). Concerns about the safety of tion (FDA) in 1970 for treatment of acute mania, and lithium have not entirely disappeared, despite long- in 1974 as the first—and for many years, the only— established standards for its safe use with monitoring of approved treatment for prevention of recurrences in its serum concentrations. bipolar disorder. In addition to its potentially toxic Fears about lithium treatment currently are most often effects, lithium being an unpatentable natural prod- directed to putative renal toxicity with its long-term use. uct with limited commercial interest had difficulties In fact, such efects are uncommon and usually can be in attracting extensive support for research or clinical anticipated by rising serum concentrations of creatinine promotion by pharmaceutical corporations. or declining creatinine clearance (McKnight et al. 2012; Clinical applications of lithium were made feasible Baldessarini 2013; Bauer and Gitlin 2016; Haussmann by introducing sensitive, reliable, quantitative meth- et al. 2017; Perugi et al. 2019). Tis adverse efect of lith- ods of monitoring lithium concentrations in serum, ium is modest, and greatly overlaps with age-associated initially with flame spectrophotometry and later with declining renal function (Nielsen et al. 2018). An indi- atomic absorption, electrochemical, and other detec- cation of declining renal function (at least one elevated tion methods. These established circulating concentra- serum concentration of creatinine) was documented in tions of lithium required for safe and effective clinical about 30% of subjects treated with lithium for 15 years or dosing (Amdisen 1967; Bauer and Gitlin 2016). Such more and aged 55 years or older (Tondo et al. 2017). monitoring was required because of the narrow mar- Some patients and families may feel that lithium treat- gin between the safe and potentially toxic dose of lith- ment has a “stigmatizing” efect, as lithium is perceived ium, or its “therapeutic index” (ratio of median toxic as a medication for severely ill patients, in contrast to to therapeutically effective doses, of approximately 3) seemingly less stigmatizing anticonvulsant, antidepres- (Baldessarini 2013; Bauer and Gitlin 2016; Perugi et al. sant, antipsychotic and other psychotropic medicines 2019). Indeed, lithium remains unique in not being (Baldessarini 2013; Bauer and Gitlin 2016). In some dosed adequately by the mg dose of drug given per countries, particularly in the US, vigorous promotion of day, but instead by achieving serum concentrations alternative and patented treatments, sometimes more 10–14 h after the last taken dose (most stable range of rapidly acting against mania, have led to substantial dis- the day) on the range of 0.5–1.0 mEq/L, while being placement of lithium for acute mania. Nevertheless, aware that earlier, daily peak concentrations can be lithium continues to hold a major position among treat- 2–3-times higher (Amdisen 1967; Baldessarini 2013; ments for bipolar disorder internationally, especially for Bauer and Gitlin 2016;