Treatment of lithium intoxication: facing the need for evidence

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Abstract

Lithium has been used as the gold standard in the treatment of major depressive and bipolar disorders for decades. Due to its narrow therapeutic index, lithium toxicity is a common clinical problem. Although risk factors for lithium intoxication seem to be well-described, lacking patient education and inexperience of treatment are assumed to contribute to the probability of lithium intoxication. A review of literature shows that the treatment of lithium intoxication has not been adequately studied or standardized. The aim of this literature review is to compile and present current evidence on the treatment of lithium intoxication and contribute to a standardization regarding general treatment recommendations as well as evidence on indication for extracorporeal methods. Against the background of this common and potentially life-threatening condition, the standardization of the treatment of lithium intoxication is definitely a task for the future.

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Review of lithium effects on brain and blood.

Wise Young (2008)

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

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Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis

Emanuel Severus, Matthew J. Taylor, Cathrin Sauer … (2014)

Background In a previous meta-analysis of randomized controlled trials comparing lithium with placebo as a long-term treatment in bipolar disorders, we observed a clear preventative effect for manic episodes; however, the effect was equivocal for depressive episodes. Since then, the evidence base has grown further. In this update, we furthermore present the data on efficacy of lithium in comparison to alternative drug treatments. In addition, we analyze the data comparing lithium with placebo and other treatments regarding drop-outs due to reasons other than a mood episode and completion of study (no mood episode and no drop-out to reasons other than a mood episode). Methods Randomized controlled trials (RCTs) were sought comparing lithium with placebo and lithium with an alternative treatment in bipolar disorders where the stated intent of treatment was prevention of mood episodes. To this purpose, the Cochrane Central Register of Controlled Trials (CENTRAL) was searched. Reference lists of relevant papers and major textbooks of mood disorders were examined. Authors, other experts in the field, and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Results For the comparison of lithium with placebo, seven trials (1,580 participants) were included. Lithium was more effective than placebo in preventing overall mood episodes (random effects RR 0.66, 95% CI 0.53 to 0.82), manic episodes (random effects RR 0.52, 95% CI 0.38 to 0.71), and, dependent on the type of analyses applied, depressive episodes (random effects RR 0.78, 95% CI 0.59 to 1.03; fixed effect RR 0.73, 95% CI 0.60 to 0.88). Lithium was inferior to placebo in leading to drop-outs for reasons other than a mood episode (random effects RR 1.33, 95% CI 1.07 to 1.65) but superior to placebo on study completion (random effects RR 1.69, 95% CI 1.12 to 2.55). For the comparison of lithium with anticonvulsants, seven trials were included (n = 1,305). In prevention of manic episodes, lithium showed superiority compared to anticonvulsants (random effects RR 0.66, 95% CI 0.44 to 1.00). However, there was no significant difference regarding prevention of overall mood episodes, depressive episodes, dropping-out to reasons other than a mood episode, or study completion. Conclusions The evidence base for lithium in the long-term treatment of bipolar disorders has strengthened. With no other drug available having such ample and consistent evidence for its efficacy lithium remains the most valuable treatment option in this indication.

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Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy.

Robert Boton, Moises Gaviria, Daniel C. Batlle (1987)

From the analysis of several studies published from 1979 to 1986 comprising 1,172 patients, we estimated that glomerular filtration rate (GFR) was normal in 85% of unselected patients on chronic lithium therapy. The remaining 15% of patients displayed only mild reduction in GFR, clustering at approximately 60 mL/min. Thus, the data available to date do not support earlier concerns that long-term lithium therapy could eventuate into renal insufficiency. The most prevalent renal effect of lithium is impairment of concentrating ability, which we estimated to be present in at least 54% of 1,105 unselected patients on chronic lithium therapy. This defect translated into overt polyuria in only 19% of unselected cases. A renal lesion confined to the collecting tubule has been described in humans who have taken lithium for short periods of time. This lesion may represent the collecting tubule's response to the intracellular accumulation of lithium, which interferes with cAMP formation and results in an early and probably reversible inhibition of antidiuretic hormone (ADH)-mediated water transport. However, long-term lithium therapy may induce a progressive and partly irreversible defect in concentrating ability. The potential risk for dehydration associated with lithium-induced polyuria, as well as the discomfort inherent to this side effect, deserves evaluation and consideration for therapeutic intervention. Amiloride has additional advantages over conventional treatment of nephrogenic diabetes insipidus using thiazide diuretics. The action of amiloride on ADH-mediated water transport seems specific in as much as it is capable of preventing the uptake of lithium in high resistance epithelia and thereby prevents the inhibitory effect of intracellular lithium on water transport. Unlike thiazides, amiloride has a weak natriuretic effect and is less likely to increase plasma lithium levels by causing volume contraction. In addition, amiloride, by conserving potassium, obviates the need for potassium supplementation that is usually required to prevent hypokalemia when thiazides are used to treat lithium-induced polyuria. Since amiloride may prevent chronic intracellular lithium accumulation in the collecting tubule, future studies should elucidate whether amiloride also has a role in preventing lithium-induced chronic tubulo-interstitial damage.

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Author and article information

Contributors

R. Haussmann: robert.haussmann@uniklinikum-dresden.de

M. Bauer: michael.bauer@uniklinikum-dresden.de

S. von Bonin: Simone.vonBonin@uniklinikum-dresden.de

P. Grof: paulgrof75@gmail.com

U. Lewitzka: +49 (0351) 458 3671 , ute.lewitzka@uniklinikum-dresden.de

Journal

Journal ID (nlm-ta): Int J Bipolar Disord

Journal ID (iso-abbrev): Int J Bipolar Disord

Title: International Journal of Bipolar Disorders

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Electronic): 2194-7511

Publication date (Electronic): 22 October 2015

Publication date PMC-release: 22 October 2015

Publication date Collection: 2015

Volume: 3

Electronic Location Identifier: 23

Affiliations

[ ]Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany

[ ]Department of Internal Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

[ ]Mood Disorders Center of Ottawa, Ottawa, Canada

Article

Publisher ID: 40

DOI: 10.1186/s40345-015-0040-2

PMC ID: 4615994

PubMed ID: 26493348

SO-VID: bab439f1-7079-4438-a434-de00717bef26

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/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.

History

Date received : 17 July 2015

Date accepted : 24 September 2015

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Keywords: lithium,intoxication,affective disorders,bipolar disorder,treatment,extracorporeal methods,hemodialysis

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Keywords: lithium, intoxication, affective disorders, bipolar disorder, treatment, extracorporeal methods, hemodialysis

Treatment of lithium intoxication: facing the need for evidence

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Most cited references 23

Review of lithium effects on brain and blood.

Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis

Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy.

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