Lithium Articles 1

© 2011

Linoleic acid in the treatment of lithium toxicity and familial tremor

            (Anton 1980) Download

Lithium in Drinking Water and Thyroid Function

            (Broberg, Concha et al. 2011) Download

Background: High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function. Objectives: To assess associations between exposure to lithium from drinking water and other environmental sources and thyroid function . Methods: Women (N=202) were recruited in 4 Andean villages in Northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T4) and pituarity gland thyroid-stimulating hormone (TSH), analyzed by routine immunometric methods. Results: The median urine lithium concentration was 3,910 mug/L (5th/95th percentiles 270/10,400 microg/L). Median plasma concentrations (5th/95th percentiles) of T4 and TSH were 17 pmol/L (13/21 pmol/L) and 1.9 mlU/L, (0.68/4.9 mlU/L), respectively. Urine lithium was inversely associated with T4 (beta for a 1000-mug/L increase -0.19, 95% CI -0.31 to -0.068; p=0.002) and positively associated with TSH (beta=0.096, 95% CI 0.033 to 0.16; p=0.003). Both associations persisted after adjustment (T4: beta=-0.17, 95% CI -0.32 to -0.015; p=0.032; TSH: beta=0.089, 95% CI 0.024 to 0.15; p=0.007). Urine selenium was positively associated with T4 (adjusted T4 for a 1-mug/L increase: beta=0.041, 95% CI 0.012 to 0.071; p=0.006). Conclusions: Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources.

Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium

            (Camins, Verdaguer et al. 2009) Download

Lithium is a monovalent cation that was introduced in 1949 by John Cade for the treatment of bipolar disorder. Clinical reports and subsequent studies confirmed this application and the beneficial effects of this compound. However, over the last 15 years, various authors have also demonstrated the neuroprotective effects of lithium against several neurotoxic paradigms. Thus, experimental studies in neuronal cell cultures and animal models of Alzheimer disease and others pathologies have provided strong evidence for the potential benefits of lithium. The main mechanism underlying its neuroprotective effects is thought to be inhibition of glycogen synthase kinase-3 (GSK-3), although other biochemical pathways in the brain could also be affected. In this review, the main mechanisms of lithium action are summarized, including the modulation of glutamate receptors, effects on arachidonic acid metabolism, its role with respect to AKT, and other potential mechanisms. In addition, its effects on neuroprotective proteins such as Bcl-2 and p53 are also discussed. Although the cellular and molecular biological effects of lithium may constitute an effective therapeutic strategy for Alzheimer disease, further clinical and experimental studies with this drug and specific GSK-3 inhibitors are necessary to confirm the use of lithium in therapeutic approaches to neurodegenerative diseases.

Lithium action on adrenomedullary and adrenocortical functions and serum ionic balance in different age-groups of albino rats

            (Chaudhuri-Sengupta, Sarkar et al. 2003) Download

The aim of the current study was to investigate lithium action on adrenomedullary and adrenocortical functions and on serum ionic balance in rats. Three age-groups of male rats (juvenile: 30 days, adult: 100 days and aged: 3 years) were used. Each age-group of animal was exposed to short- (10 days) and long-term (25 days) treatments with lithium. Each age-group of rat received lithium at a dose 2mEq/kg body weight daily for 10 and 25 days. Each daily dose (2mEq) was divided equally into half (1 mEq) and each half was injected intraperitoneally twice (at 9 am and 9 pm) for both the durations of experiments. Control animals received physiological saline for similar duration of experiments. Thirty animals were used for each age-group and they were divided equally into 6 groups with 5 each. After termination of all the experiments rats were sacrificed and, adrenal glands were quickly dissected out and processed for epinephrine, norepinephrine and corticosterone estimations and, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSDH) activity of the adrenal gland. Blood was drawn from the heart of each rat and, serum was collected and stored at -20 degrees C until assayed for lithium, calcium, sodium, potassium and corticosterone concentrations. The findings revealed that lithium in both short- and long-term treatments was maintained well within the therapeutic range (0.3-0.8 mEq/l) in all the age-groups of rats. This alkali metal caused depletions of both epinephrine and norepinephrine concentrations from adrenal glands, and elevations of corticosterone in both adrenal and blood serum of each age-group of rat (juvenile, adult and aged). Additionally adrenal 3beta-HSDH activity was also increased in all the age-groups of rats irrespective of duration of the treatments. Short-term treatment of lithium elevated only serum K+ level in juvenile and adult rats and, Ca+ level only in adult animals. Significant elevations of serum K+ and Ca+ levels were observed following long-term treatments of lithium in all the age group of rats. No significant change in serum Na+ level was recorded after lithium treatment, irrespective of duration of treatments, in any age-group of rats. The findings suggest that lithium action, in respect of adrenomedullary and adrenocortical functions and, serum ionic balance, may not be largely related to the age-group of rats and that, lithium acts on adrenomedullary activity probably by stimulating the release mechanism of epinephrine and norepinephrine from the adrenal gland of rats, but stimulates adrenocortical activity by stimulating both synthesis (including 3 beta-HSDH activity) and release of corticorterone. Simultaneously, lithium disturbs normal ionic balance by elevating K+ and Ca+ levels in all the age-group of rats. Thus, the antimanic drug certainly disturbs both adrenomedullary and adrenocortical functions and, serum ionic balance in all the age-group of rats.

Implication of serum concentration monitoring in patients with lithium intoxication

            (Chen, Shen et al. 2004) Download

The aim of the present study was to determine the relationships between serum lithium level, duration of lithium intoxication, severity of symptoms, and the outcome of the disease. Subjects with a serum lithium level of >/=1.2 mEq/L were included in the study. Seventy-eight patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. The demographic characteristics, clinical manifestations, and concomitant medications were recorded. Most patients with acute lithium intoxication had mild symptoms, independent of the serum lithium levels. In patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in those with acute intoxication. None of the 78 intoxicated patients in the present survey died or suffered from persistent neurological sequelae. Patients with concomitant medications, older age, and existing neurological illness may have an increased susceptibility to lithium toxicity. Regular monitoring of serum lithium level is essential for lithium-treated patients. Clinicians should pay attention to patients with pre-existing neurological illness, older age, or receiving medications that may interact with lithium.

Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

            (Chiu and Chuang 2010) Download

Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.

Preventing lithium intoxication. Guide for physicians

            (Delva and Hawken 2001) Download

OBJECTIVE: To raise awareness of risk factors for, and symptoms of, lithium intoxication. QUALITY OF EVIDENCE: The literature was searched via MEDLINE from January 1970 to December 1999 using the MeSH headings Lithium, Lithium Carbonate, Drug Toxicity, and Aging. Articles were selected based on clinical relevance and design. Most were case reports, case series, or reviews. MAIN MESSAGE: A case study illustrates both risk factors predisposing patients to lithium intoxication and the symptoms of lithium intoxication. Lithium intoxication can be avoided by conservative dosing, care in combining drug therapies, regular clinical observation, monitoring drug plasma concentrations, and educating patients and caregivers to recognize early signs of intoxication. CONCLUSION: Knowing about lithium intoxication and how to avoid it is most important for family physicians who regularly treat patients receiving lithium.

Cellular consequences of inositol depletion

            (Deranieh and Greenberg 2009) Download

The inositol-depletion hypothesis was suggested to explain the therapeutic mechanism of mood-stabilizing drugs. Focus was previously on the phosphatidylinositol signalling pathway and on the regulatory roles of Ins(3,4,5)P(3) and DAG (diacylglycerol). Recent findings indicate that inositol and inositol-containing molecules, including phosphoinositides and inositol phosphates, have signalling and regulatory roles in many cellular processes. This suggests that depleting inositol may lead to perturbation of a wide range of cellular functions, at least some of which may be associated with bipolar disorder.

Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation

            (Dickstein, Towbin et al. 2009) Download

OBJECTIVE: The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD) by Leibenluft, has been the focus of increasing concern. We conducted the first randomized double-blind, placebo-controlled trial in SMD youth, choosing lithium on the basis of its potential in treating irritability and aggression and neuro-metabolic effects. METHODS: SMD youths 7-17 years were tapered off their medications. Those who continued to meet SMD criteria after a 2-week, single-blind, placebo run-in were randomized to a 6-week double-blind trial of either lithium (n = 14) or placebo (n = 11). Clinical outcome measures were: (1) Clinical Global Impressions-Improvement (CGI-I) score less than 4 at trial's end and (2) the Positive and Negative Syndrome Scale (PANSS) factor 4 score. Magnetic resonance spectroscopy (MRS) outcome measures were myoinositol (mI), N-acetyl-aspartate (NAA), and combined glutamate/glutamine (GLX), all referenced to creatine (Cr). RESULTS: In all, 45% (n = 20/45) of SMD youths were not randomized due to significant clinical improvement during the placebo run-in. Among randomized patients, there were no significant between-group differences in either clinical or MRS outcome measures. CONCLUSION: Our study suggests that although lithium may not result in significant clinical or neurometabolic alterations in SMD youths, further SMD treatment trials are warranted given its prevalence.

Lithiated lemon-lime sodas

            (El-Mallakh and Roberts 2007) Download

Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium

            (Fornai, Longone et al. 2008) Download

In a pilot clinical study that we recently published we found that lithium administration slows the progression of Amyotrophic Lateral Sclerosis (ALS) in human patients. This clinical study was published in addition with basic (in vitro) and pre-clinical (in vivo) data demonstrating a defect of autophagy as a final common pathway in the genesis of ALS. In fact, lithium was used as an autophagy inducer. In detailing the protective effects of lithium we found for the first time that this drug stimulates the biogenesis of mitochondria in the central nervous system and, uniquely in the spinal cord, it induces neuronogenesis and neuronal differentiation. In particular, the effects induced by lithium can be summarized as follows: (i) the removal of altered mitochondria and protein aggregates; (ii) the biogenesis of well-structured mitochondria; (iii) the suppression of glial proliferation; (iv) the differentiation of newly formed neurons in the spinal cord towards a specific phenotype. In this addendum we focus on defective autophagy as a "leit motif" in ALS and the old and novel features of lithium which bridge autophagy activation to concomitant effects that may be useful for the treatment of a variety of neurodegenerative disorders. In particular, the biogenesis of mitochondria and the increase of calbindin D 28K-positive neurons, which are likely to support powerful neuroprotection towards autophagy failure, mitochondriopathy and neuronal loss in the spinal cord.

Lithium delays progression of amyotrophic lateral sclerosis

            (Fornai, Longone et al. 2008) Download

ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.

Lithium inhibits carcinoid cell growth in vitro

            (Greenblatt, Ndiaye et al. 2010) Download

Carcinoids are slow growing neuroendocrine tumors that often cause debilitating symptoms due to excessive secretion of hormones such as serotonin. Surgery is the only potentially curative treatment, but many patients have unresectable metastatic disease. Lithium is a non- competitive inhibitor of GSK-3 with an established safety profile. The objective of this study was to investigate the effects of lithium on carcinoid cell growth in vitro. Lithium treatment caused a dose-dependent reduction in carcinoid cancer cell (BON and H727) growth. Western blot analysis revealed increased expression of cleaved poly (ADP-ribose) polymerase (PARP), indicating the induction of apoptosis. Lithium treatment also suppressed cellular levels of serotonin and chromogranin A. In summary, lithium inactivates GSK-3, induces apoptosis, and suppresses carcinoid cancer cell growth in vitro. The drug has been used clinically since the 19(th) century to treat a variety of diseases including bipolar disorder, and its safety profile is well documented. Therefore, based on these findings, we have undertaken a clinical trial of lithium chloride in the treatment of patients with unresectable carcinoid cancer.

The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain

            (Hallcher and Sherman 1980) Download

myo-Inositol-1-phosphatase has been partially purified from bovine brain. The enzyme has a molecular weight of about 58,000. Both L-myo-inositol 1-phosphate and D-myo-inositol 1-phosphate are hydrolyzed by the enzyme as well as (-)-chiro-inositol 3-phosphate and 2'-AMP. Triphosphoinositide is not a substrate. The phosphatase is completely dependent on Mg2+, which has a Km of 1 mM. Calcium and manganese ions are competitive inhibitors of Mg2+ binding with Ki values of 18 microM and 2 microM, respectively. Lithium chloride inhibits the hydrolysis of both L- and D-myo-inositol 1-phosphate to the extent of 50% at a concentration of 0.8 mM. The phosphatase from testis is similarly inhibited by lithium. Lithium ion is a noncompetitive inhibitor of Mg2+ binding and an uncompetitive inhibitor of myo-inositol 1-phosphate binding. Because lithium chloride administration elicits both an increase in the levels of myo-inositol 1-phosphate and a decrease in the levels of myo-inositol in rat brain (Allison, 1978), and because these actions are blocked by anticholinergic agents, we examined the effects of cholinergic agonists and antagonists on the enzyme and found none. The possibility that the inhibition of this enzyme by lithium ion is related to the pharmacological actions of lithium is discussed.

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

            (Han, Serrano et al. 2009) Download

Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt-beta-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt-beta-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

            (Harwood 2005) Download

Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li(+)) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

Lithium increases synapse formation between hippocampal neurons by depleting phosphoinositides

            (Kim and Thayer 2009) Download

The mood-stabilizing effects of lithium are well documented, although its mechanism of action remains unknown. Increases in gray matter volume detected in patients with bipolar disorder who were treated with lithium suggest that changes in the number of synapses might underlie its therapeutic effects. We investigated the effects of lithium on the number of synaptic connections between hippocampal neurons in culture. Confocal imaging of neurons expressing postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP) enabled visualization of synaptic sites. PSD95-GFP fluorescent puncta represented functional synapses, and lithium (4 h, 5 mM) increased their number by 150 +/- 12%. The increase was time- and concentration-dependent (EC(50) = 1.0 +/- 0.6 mM). Lithium induced a parallel increase in the presynaptic marker synaptophysin-GFP. Valproic acid, another mood stabilizer, also increased the number of fluorescent puncta at a clinically relevant concentration. Inhibition of postsynaptic glutamate receptors or presynaptic inhibition of neurotransmitter release significantly reduced lithium-induced synapse formation, indicating that glutamatergic synaptic transmission was required. Pretreatment with exogenous myo-inositol inhibited synapse formation, demonstrating that depletion of inositol was necessary to increase synaptic connections. In contrast, inhibition of glycogen synthase kinase 3beta did not mimic lithium-induced synapse formation. Pharmacological and lipid reconstitution experiments showed that new synapses formed as a result of depletion of phosphatidylinositol-4-phosphate rather than a build-up of polyphosphoinositides or changes in the activity of phospholipase C, protein kinase C, or phosphatidylinositol-3-kinase. Increased synaptic connections may underlie the mood-stabilizing effects of lithium in patients with bipolar disorder and could contribute to the convulsions produced by excessive doses of this drug.

Lithium and thyroid

            (Lazarus 2009) Download

One in 200 people receive lithium for treatment of bipolar disorder. The common clinical side effects of the drug are goitre in up to 40% and hypothyroidism in about 20%. Lithium increases thyroid autoimmunity if present before therapy. Treatment with levothyroxine is effective and lithium therapy should not be stopped. Lithium may cause hyperthyroidism due to thyroiditis or rarely Graves' disease. As lithium inhibits thyroid hormone release from the thyroid gland it can be used as an adjunct therapy in the management of severe hyperthyroidism. It also increases thyroidal radioiodine retention and may be effective in reducing administered activity in hyperthyroidism. There is no clinical benefit of lithium therapy in thyroid cancer. More research is required on the cellular proliferative effects of lithium as well as its impact on the immune system.

Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness

            (Lenox and Watson 1994) Download

Lithium, an effective treatment for mania and the prevention of recurrent episodes of both mania and depression in patients with manic depressive illness, exerts multiple biochemical effects. However, any clinically relevant site of action of lithium must occur at therapeutic concentrations attained in the brain of patients and must account for the lag period accompanying onset of action as well as effects persisting beyond discontinuation of treatment. This monovalent cation acts as a potent uncompetitive inhibitor in the receptor-coupled breakdown of inositol phospholipids, resulting in a relative depletion of inositol and an alteration in the generation of diacylglycerol, an endogenous activator of protein kinase C. In our laboratory, we are examining the action of chronically administered lithium on posttranslational modification of specific phosphoproteins involved in regulating signal transduction in the brain. We have found that chronic, but not acute, administration of lithium in rats markedly reduces a major phosphoprotein substrate of protein kinase C in the hippocampus, an effect that persists beyond the cessation of lithium treatment. This protein, myristoylated alanine-rich C kinase substrate ("MARCKS"), is implicated in synaptic neurotransmission, calcium regulation, and cytoskeletal restructuring. These findings have relevance for the long-term action of lithium in stabilizing an underlying dysregulation in the brain and may move us closer to formulating a molecular basis of manic depressive illness.

Linoleic acid in the treatment of lithium toxicity and familial tremor

            (Lieb 1980) Download

Lithium inhibits the synthesis of prostaglandin (PG) EI by blocking the mobilisation of dihomogammalinolenic acid (DGLA). Toxicity due to lithium might re related to reduced PGEI formation. In five patients who developed toxic effects on low doses of lithium, linoleic acid in the forms of the safflower oil was given in an attempt to raise levels of the linoleic acid metabolite, DGLA. In al five patients the safflower oil was effective in remitting the symptoms of neurotoxicity. Safflower oil was also effective in a patient with familial tremor.

Treatment of lithium-induced tremor and familial essential tremor with essential fatty acids

            (Lieb and Horrobin 1981) Download

Lithium-mediated protection against ethanol neurotoxicity

            (Luo 2010) Download

Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar) disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD) are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke-Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3) which has recently been identified as a mediator of ethanol neurotoxicity. Lithium's neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms.

The clinical manifestations of lithium intoxication

            (Meltzer and Steinlauf 2002) Download

BACKGROUND: Lithium has been a part of the psychiatric pharmacopoeia for more than half a century. Its efficacy is marred by a narrow therapeutic index and significant toxicity. OBJECTIVES: To increase physicians' awareness of the various manifestations of lithium intoxication. METHODS: We reviewed the clinical data of cases of lithium poisoning occurring in a municipal hospital during a 10 year period. RESULTS: Eight patient records were located. The mortality rate was 12.5%. All patients were women and the mean age was 66.4 years. The most common symptoms were neurologic. One illustrative case is described in detail with lithium serum levels showing the usual two-phase decline. CONCLUSIONS: Lithium poisoning can present in many forms. Increased physician awareness and the early use of effective treatment, mainly hemodialysis, will prevent mortality and protracted morbidity associated with this condition.

Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder

            (Nemets, Stahl et al. 2002) Download

OBJECTIVE: Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. METHOD: Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week, parallel-group, double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. RESULTS: Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. CONCLUSIONS: It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own.

Use of lithium in the treatment of thyrotoxicosis

            (Ng, Tiu et al. 2006) Download

OBJECTIVES: To evaluate the efficacy and safety of lithium in the treatment of thyrotoxicosis, and to study the dose and serum levels at which therapeutic response occurs. DESIGN: Retrospective study. SETTING: Thyroid clinic of a regional hospital in Hong Kong. PATIENTS: Thirteen patients with thyrotoxicosis pending therapy with radioiodine or surgery, in whom thionamides were contra-indicated due to adverse reactions or failure of treatment. MAIN OUTCOME MEASURES: Free thyroxine levels, time to euthyroidism, and side-effects of lithium. RESULTS: A satisfactory response, defined as a fall by 40% or more in free thyroxine levels and clinical improvement, was achieved in eight patients within 1 to 2 weeks of lithium therapy. In four others, response occurred in 3 to 5 weeks. Response was slow and inadequate in one patient due to 'escape'. The median dosage of lithium was 750 mg daily, with a range of 500 to 1500 mg daily. The median serum lithium level was 0.63 mmol/L. Lithium toxicity was observed in one patient. CONCLUSIONS: A relatively low dose of lithium offers a safe and effective alternative means of controlling thyrotoxicosis in patients who cannot tolerate or do not respond to thionamides.

Lithium levels in drinking water and risk of suicide

            (Ohgami, Terao et al. 2009) Download

Although lithium is known to prevent suicide in people with mood disorders, it is uncertain whether lithium in drinking water could also help lower the risk in the general population. To investigate this, we examined lithium levels in tap water in the 18 municipalities of Oita prefecture in Japan in relation to the suicide standardised mortality ratio (SMR) in each municipality. We found that lithium levels were significantly and negatively associated with SMR averages for 2002-2006. These findings suggest that even very low levels of lithium in drinking water may play a role in reducing suicide risk within the general population.

Lithium nephrotoxicity.

            (Oliveira, Silva Junior et al. 2010) Download

Lithium is widely used in the therapy of bipolar disorder. Its toxicity includes urinary concentration deficit and natriuresis, renal tubular acidosis, tubulointerstitial nephritis which complicates with chronic kidney disease and hypercalcemia. The most common adverse effect is diabetes insipidus, which occurs in 20-40% of patients some weeks after initiation of treatment. Such chronic nephropathy correlates with duration of lithium use. Early detection of renal dysfunction should be achieved by rigorous monitoring of patients and collaboration between the psychiatrist and nephrologist. Recent experimental and clinical studies are now clarifying the mechanisms by which lithium induces renal abnormalities. The aim of this work is to review the pathogenesis, clinical presentation, histopathologic aspects and treatment of lithium nephrotoxicity.

Lithium in migraine and cluster headache: a review

            (Peatfield 1981) Download

Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized

Pomerantz 2010 Download

Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment

            (Schifitto, Zhong et al. 2009) Download

The objective of this study was to assess lithium safety and tolerability and to explore its impact on cognition, function, and neuroimaging biomarkers in human immunodeficiency virus (HIV)-infected subjects with cognitive impairment. Fifteen cognitively impaired HIV-infected subjects were enrolled in this 10-week open-label study of lithium 300 mg twice daily. Neuroimaging was performed at baseline and following 10 weeks of treatment and included magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI). Thirteen of the 14 subjects (93%) that complied with the study visits were able to complete the study on lithium and 11 out of 13 (79%) completed the study at the originally assigned dose of 300 mg twice daily. There were no significant changes in CD4(+) lymphocyte cell count and plasma HIV RNA. Cognitive performance and depressive mood did not improve significantly after the 10-week lithium treatment; however, neuroimaging revealed a decrease in the glutamate+glutamine (Glx) peak in the frontal gray matter, increased fractional anisotropy, and decreased mean diffusivity in several brain areas, and changes in brain activation patterns, suggestive of improvement. These results suggest that lithium can be used safely in HIV-infected individuals with cognitive impairment. Furthermore, the neuroimaging results suggest that lithium may improve HIV-associated central nervous system (CNS) injury; thus, further investigations of lithium as an adjunctive treatment for HIV-associated cognitive impairment are warranted.

Linoleic acid in the treatment of lithium-induced tremor: a pilot trial with negative outcome

            (Schou 1980) Download

Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder

            (Stolk, Souverein et al. 2010) Download

OBJECTIVES: Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms. METHODS: Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone. RESULTS: Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for > or =180 or > or =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0. CONCLUSIONS: Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.

Combined estradiol and lithium increase ER-alpha mRNA in embryonic C57BL/6J primary hippocampal cultures

            (Valdes and Weeks 2010) Download

Estrogen replacement therapy (ERT) is commonly prescribed during menopause. Post-menopausal women also tend to suffer from bipolar disorders and as a result are prescribed mood stabilizers - in addition to ERT. There is a paucity of data on how combined hormones and mood stabilizers interact in regulating gene expression that led us to hypothesize that in primary cultures of mixed brain cells predominated by glia, combined 17beta-estradiol (E2) and lithium chloride (LiCl) (E2/LiCl) will alter estrogen receptor-alpha (ER-alpha) mRNA expression. We quantified mRNA expression of ER-alpha using the cDNA of treated primary cultures of mixed brain cells from a previous study. Our results indicate that hippocampal cultures predominated by glia increase in ER-alpha mRNA expression when treated for 48 h with combined E2/LiCl. Our findings may encourage further investigation on the molecular mechanisms involved in combined estrogen and lithium treatment.

Estradiol and lithium chloride specifically alter NMDA receptor subunit NR1 mRNA and excitotoxicity in primary cultures

            (Valdes and Weeks 2009) Download

Glutamate facilitates calcium influx via NMDAR, and excess calcium influx increases excitotoxicity--a pathological characteristic of neurological diseases. Both 17beta-estradiol (E2) and lithium influence NMDAR expression/signaling and excitotoxicity. This led us to hypothesize that combined E2 and lithium will alter NMDAR expression and excitotoxicity. We tested this hypothesis using primary cell cultures from the cortex and hippocampus of C57BL/6J fetal mice pretreated with E2, lithium chloride (LiCl) and combined E2/LiCl for 12, 24 or 48 h. We examined cultures for brain cell type and changes in cell type caused by experimental procedures using glia and neuron gene specific primers. These cultures expressed increased glial fibrillary acidic protein (GFAP) mRNA with low neurofilament-heavy chain (NF-H) mRNA expression. Subsequent analysis of cortical cell cultures indicated that combined E2/LiCl decreased NR1 mRNA expression after a 12 and 48 h treatment period. Combined E2/LiCl also reduced NR1 mRNA expression in hippocampal cultures but only after a 48 h treatment period. LiCl-treated hippocampal cultures also reduced NR1 mRNA expression after a 24 and 48 h treatment. We next examined the response of 48 h pretreated cultures to a toxic level of glutamate. Excitotoxicity was measured using fluorescein diacetate/propidium iodide (FDA/PI) cell viability assay. Results from FDA/PI assay revealed that LiCl pretreatment increased viability for cortical cultures while E2 and combined E2/LiCl reduced viability. All pretreatments for hippocampal cultures failed to increase viability. Our results showed combined E2/LiCl reduced NR1 mRNA and prevented protection against glutamate excitotoxicity in glial primary cultures.

Trace elements in glucometabolic disorders: an update

            (Wiernsperger and Rapin 2010) Download

ABSTRACT: Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed.


Anton, R. F. (1980). "Linoleic acid in the treatment of lithium toxicity and familial tremor." Prostaglandins Med 5(4): 321-2.

Broberg, K., G. Concha, et al. (2011). "Lithium in Drinking Water and Thyroid Function." Environ Health Perspect.

Camins, A., E. Verdaguer, et al. (2009). "Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium." CNS Neurosci Ther 15(4): 333-44.

Chaudhuri-Sengupta, S., R. Sarkar, et al. (2003). "Lithium action on adrenomedullary and adrenocortical functions and serum ionic balance in different age-groups of albino rats." Arch Physiol Biochem 111(3): 246-53.

Chen, K. P., W. W. Shen, et al. (2004). "Implication of serum concentration monitoring in patients with lithium intoxication." Psychiatry Clin Neurosci 58(1): 25-9.

Chiu, C. T. and D. M. Chuang (2010). "Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders." Pharmacol Ther 128(2): 281-304.

Delva, N. J. and E. R. Hawken (2001). "Preventing lithium intoxication. Guide for physicians." Can Fam Physician 47: 1595-600.

Deranieh, R. M. and M. L. Greenberg (2009). "Cellular consequences of inositol depletion." Biochem Soc Trans 37(Pt 5): 1099-103.

Dickstein, D. P., K. E. Towbin, et al. (2009). "Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation." J Child Adolesc Psychopharmacol 19(1): 61-73.

El-Mallakh, R. S. and R. J. Roberts (2007). "Lithiated lemon-lime sodas." Am J Psychiatry 164(11): 1662.

Fornai, F., P. Longone, et al. (2008). "Lithium delays progression of amyotrophic lateral sclerosis." Proc Natl Acad Sci U S A 105(6): 2052-7.

Fornai, F., P. Longone, et al. (2008). "Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium." Autophagy 4(4): 527-30.

Greenblatt, D. Y., M. Ndiaye, et al. (2010). "Lithium inhibits carcinoid cell growth in vitro." Am J Transl Res 2(3): 248-53.

Hallcher, L. M. and W. R. Sherman (1980). "The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain." J Biol Chem 255(22): 10896-901.

Han, M., M. C. Serrano, et al. (2009). "Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies." Dis Model Mech 2(9-10): 467-78.

Harwood, A. J. (2005). "Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited." Mol Psychiatry 10(1): 117-26.

Kim, H. J. and S. A. Thayer (2009). "Lithium increases synapse formation between hippocampal neurons by depleting phosphoinositides." Mol Pharmacol 75(5): 1021-30.

Lazarus, J. H. (2009). "Lithium and thyroid." Best Pract Res Clin Endocrinol Metab 23(6): 723-33.

Lenox, R. H. and D. G. Watson (1994). "Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness." Clin Chem 40(2): 309-14.

Lieb, J. (1980). "Linoleic acid in the treatment of lithium toxicity and familial tremor." Prostaglandins Med 4(4): 275-9.

Lieb, J. and D. F. Horrobin (1981). "Treatment of lithium-induced tremor and familial essential tremor with essential fatty acids." Prog Lipid Res 20: 535-7.

Luo, J. (2010). "Lithium-mediated protection against ethanol neurotoxicity." Front Neurosci 4: 41.

Meltzer, E. and S. Steinlauf (2002). "The clinical manifestations of lithium intoxication." Isr Med Assoc J 4(4): 265-7.

Nemets, B., Z. Stahl, et al. (2002). "Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder." Am J Psychiatry 159(3): 477-9.

Ng, Y. W., S. C. Tiu, et al. (2006). "Use of lithium in the treatment of thyrotoxicosis." Hong Kong Med J 12(4): 254-9.

Ohgami, H., T. Terao, et al. (2009). "Lithium levels in drinking water and risk of suicide." Br J Psychiatry 194(5): 464-5; discussion 446.

Oliveira, J. L., G. B. Silva Junior, et al. (2010). "[Lithium nephrotoxicity.]." Rev Assoc Med Bras 56(5): 600-606.

Peatfield, R. C. (1981). "Lithium in migraine and cluster headache: a review." J R Soc Med 74(6): 432-6.

Schifitto, G., J. Zhong, et al. (2009). "Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment." J Neurovirol 15(2): 176-86.

Schou, M. (1980). "Linoleic acid in the treatment of lithium-induced tremor: a pilot trial with negative outcome." Prostaglandins Med 5(5): 343-4.

Stolk, P., P. C. Souverein, et al. (2010). "Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder." Prostaglandins Leukot Essent Fatty Acids 82(1): 9-14.

Valdes, J. J. and O. I. Weeks (2009). "Estradiol and lithium chloride specifically alter NMDA receptor subunit NR1 mRNA and excitotoxicity in primary cultures." Brain Res 1268: 1-12.

Valdes, J. J. and O. I. Weeks (2010). "Combined estradiol and lithium increase ER-alpha mRNA in embryonic C57BL/6J primary hippocampal cultures." Acta Neurobiol Exp (Wars) 70(3): 297-302.

Wiernsperger, N. and J. Rapin (2010). "Trace elements in glucometabolic disorders: an update." Diabetol Metab Syndr 2: 70.