Lithium Articles 12


Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension.
            (Aprahamian et al., 2014)  Download
BACKGROUND:  Recent studies evaluated the disease-modifying properties of lithium in mild cognitive impairment and dementia. Although potentially effective for these purposes, chronic lithium use in regard to safety in the elderly needs to be better explored. OBJECTIVE:  To evaluate the effect of long-term lithium treatment at subtherapeutic doses on renal function in older adults. Secondary aims were to evaluate the clinical safety and tolerability of this treatment and its effects on thyroid, immune, and glycemic functions. METHOD:  Between February 2007 and October 2011, a 2-year randomized, double-blind, placebo-controlled trial followed by a single-blinded phase for an additional 2 years. Sixty-one patients with mild cognitive impairment (Mayo Clinic criteria) were randomized to receive lithium or placebo. Renal function was estimated by the abbreviated Modification of Diet in Renal Disease (aMDRD) and the Chronic Kidney Disease-Epidemiology study (CKD-EPI) equations. Leukocytes, serum thyroid-stimulating hormone (TSH) and free thyroxine (T₄), and serum glucose and insulin were determined. Tolerability was evaluated at 3-month intervals through systematic clinical examinations and by the UKU Side Effect Rating Scale. RESULTS:  Analysis of longitudinal regression indicated that no significant changes in renal function were detected by the aMDRD (P = .453) and CKD-EPI (P = .213) equations after 4 years of lithium treatment. Significant increases in the number of neutrophils (P = .038), serum TSH (P = .034), and body weight (P = .015) were observed in the lithium group. The lithium group presented more overall adverse events (P = .045), particularly interfering in daily activities (P < .001). In addition, those patients had a higher incidence of diabetes mellitus (P = .037) and arrhythmia (P = .028). CONCLUSIONS:  Chronic use of lithium at low doses did not affect renal function and was clinically safe. However, some other potentially relevant adverse events were observed and others could not be ruled out due to limitations of the study design. TRIAL REGISTRATION: identifier: NCT01055392.

The Newcastle chronic depression study: results of a treatment regime.
            (Barker et al., 1987)  Download
A trial is described of new therapeutic approaches in treatment-resistant chronic depression. Phenelzine, L-tryptophan and lithium ("5HT-cocktail") was used as the major pharmacological strategy, and a regime aimed at reducing vanadium concentrations was added in the second part of the trial. Patients were randomly assigned to cognitive behaviour therapy in addition. All but 1 of the patients who ultimately entered the trial were unipolar depressives; 2 bipolar patients were withdrawn in the initial drug-free period because of the development of mixed affective states. Eleven of 20 patients showed an improvement to less than 50% of their initial scores on the Hamilton Rating Scale for Depression, and all those who improved did so in the first 6 weeks. Cognitive behaviour therapy did not seem to influence the response, but it is recognized that the short duration of therapy may be inadequate in these circumstances. It is suggested that intensive drug treatment is a necessary preliminary in management and may allow the effective use of rehabilitation aimed at the secondary handicaps of chronic depression.

Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.
            (Castillo-Quan et al., 2016)  Download
The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life.

The feasibility of low-dose oral lithium therapy and its effect on thyroidal radioiodine uptake, retention, and hormonal parameters in various subcategories of hyperthyroid patients: a pilot study.
            (Chouhan et al., 2016)  Download
BACKGROUND:  Radioactive iodine (I) (RAI) is used widely for the treatment of hyperthyroidism either as a first-line treatment or following relapse after antithyroid drug treatment. Intrathyroidal retention of RAI is considered an important determinant of its effectiveness, which is believed to be prolonged by lithium. AIMS AND OBJECTIVES:  To study the impact of low-dose oral lithium therapy on RAI uptake and retention parameters in different subgroups of hyperthyroidism patients, and thus explore its potential role in enhancing the therapeutic efficacy of RAI in these groups of patients. MATERIALS AND METHODS:  A total of 28 patients (age range=18-70 years) who were being considered for RAI therapy were included in this prospective pilot study. The patients were divided into two groups: (i) those who had not received any RAI therapy before were included in 'group I' (n=22), whereas (ii) 'group II' (n=6) included patients who were found to be persistently hyperthyroid on biochemical and clinical follow-up despite previous RAI therapy for hyperthyroidism. Patients in group I were further divided into four subgroups on the basis of the underlying etiopathology: (a) subgroup Ia - diffuse toxic goiter (n=15), (b) subgroup Ib - autonomous functioning module (n=2), (c) subgroup Ic - toxic multinodular goiter (n=4), and (d) subgroup Id - nontoxic multinodular goiter (n=1) on the basis of scintigraphic and clinical findings. All patients first underwent 25 μCi I uptake estimation at 2, 24, and 48 h and values thus obtained were considered the baseline for further evaluation. After biochemical assessment of normal renal and liver functions, patients received 900 mg lithium per day in three divided doses orally, and on the fourth day after starting tab lithium, the serum lithium level was estimated with continued lithium administration. On the fifth, sixth, and seventh day, patients underwent lithium-primed 25 μCi I uptake estimation at 2, 24, and 48 h. Retention index (RI) was calculated using the formula [RI=(48 h uptake-24 h uptake)/24 h uptake×100]. A day after completion of uptake study, that is, on the third day from diagnostic (25 μCi I) RAI administration, patients received a fixed 5 mCi therapeutic RAI dose after their suitability for the same was ascertained using clinical, biochemical, and scintigraphic findings as the criteria. Lithium administration was stopped 5 days after therapy. RESULTS:  Lithium priming resulted in a significantly reduced serum FT4 level in subgroup Ia (diffuse goiter) of group I. Similarly, lithium priming resulted in a statistically significant increase in the radioiodine RI in subgroup Ia. Lithium priming resulted in increased retention of radioiodine and reduced serum FT4 level in the rest of the study population also, but the difference was not statistically significant (likely because of fewer patients in these subgroups). The low-dose lithium priming regimen used in the present study was found to be feasible and safe. The mean serum lithium concentration was 0.6 mEq/l with the dose protocol administered and hence was considered safe. Only one patient had achieved a level of 1.5 mEq/l, without any obvious side effects, and it was clinically uneventful. One patient experienced headache necessitating dose reduction. CONCLUSION:  The results of this study, carried out in different groups of patients with hyperthyroidism, suggested that a short course of lithium is safe and could be beneficial for hyperthyroid patients considered for RAI therapy as it increased the RAI retention in thyroid, and thus had the potential to increase the effect of RAI therapy. Alternatively, it is proposed that lithium priming could help reduce the dose of RAI administered without compromising on therapeutic efficacy, with possible potential implications for cost reduction, radiation safety precautions, and lowered radiation dose to nontarget organs.

Efficacy of Vitamin B6 in Lithium-Associated Tremor: A Case Series.
            (Dias Alves et al., 2017)  Download
In conclusion, our case series rein- forces the potential utility of vitamin B6 treatment in reducing tremors associated with lithium. Dosages between 750 mg and 1 g/d seem to be well tolerated and effective after several weeks of treatment. The optimal treatment duration after efficacy achievement remains to be explored, and we as well as others have observed a relapse of tremor on cessation of vitamin B6.8 As a consequence, this therapeutic alternative deserves further exploration, both in terms of effectiveness in randomized controlled trials and in terms of tolerance and clinical management.


Inositol augmentation of lithium or valproate for bipolar depression.
            (Eden Evins et al., 2006)  Download
OBJECTIVE:  Despite promising new therapies, bipolar depression remains difficult to treat. Up to half of patients do not respond adequately to currently approved treatments. This study evaluated the efficacy of adjunctive inositol for bipolar depression. METHODS:  Seventeen participants with DSM-IV criteria for bipolar depression and a 17-item Hamilton Rating Scale for Depression (HRSD) > or =15 on proven therapeutic levels of lithium or valproate for >2 weeks were randomized to receive double-blind inositol or placebo for 6 weeks. At the end of double-blind treatment, subjects were eligible for an 8-week open-label trial of inositol. RESULTS:  Response was defined a priori as >50% reduction in the HRSD and a Clinical Global Impression of 1-2. Four of nine subjects (44%) on inositol and zero of eight subjects on placebo met response criteria (p = 0.053). There was no difference between groups in the average change score for the HRSD or Young Mania Rating Scale (YMRS). Response to inositol was highly variable. Of nine subjects randomized to inositol, two had >50% worsening in HRSD scores at the end of treatment, three had no change and four had >50% improvement. Those who had worsening in depressive symptoms on inositol had significantly higher scores at baseline on the YMRS total score and irritability, disruptive/aggressive behavior and unkempt appearance items. CONCLUSIONS:  There was a trend for more subjects on inositol to show improvement in bipolar depression symptoms, but, on average, inositol was not more effective than placebo as an adjunct for bipolar depression. Baseline levels of anger or hostility may be predictive of clinical response to inositol.

Trace lithium in Texas tap water is negatively associated with all-cause mortality and premature death.
            (Fajardo et al., 2018)  Download
Lithium in tap water was previously found to have life-extending effects across 18 Japanese municipalities. Using a larger dataset with several Texas counties, our study shows that lithium concentrations in tap water are negatively associated with all-cause mortality (r = -0.18, p = 0.006, 232 counties) and years of potential life lost (r = -0.22, p = 0.001, 214 counties). Thus, our present findings extend and reinforce lithium's purported life-prolonging effect in humans.

Inhibition of GSK3 by lithium, from single molecules to signaling networks.
            (Freland and Beaulieu, 2012)  Download
For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects.

Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets.
            (Guelen et al., 1992)  Download
The bioavailability of lithium citrate syrup was compared with that of regular lithium carbonate tablets in 18 healthy male human volunteers. Blood samples were collected up to 48 h after dosing. Lithium serum concentrations were determined by means of AAS. The absorption rate following oral administration of the syrup was greater (tmax 0.8 h) than following administration of regular tablets (tmax 1.4 h). Maximum lithium serum concentrations, however, were only about 10 per cent higher after syrup dosing and serum concentrations resulting from syrup and tablets were almost superimposable from 2 h after dosing. The terminal half-life of lithium was found to be 22 h after syrup as well as after tablet dosing. No side-effects were observed during the study. The bioavailability of lithium from syrup relative to tablets was found to be bioequivalent with respect to the maximum lithium serum concentration and the extent of drug absorption (AUC).

Low risk of male suicide and lithium in drinking water.
            (Ishii et al., 2015)  Download
OBJECTIVE:  Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. METHOD:  From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). RESULTS:  Lithium levels in drinking water were significantly (β = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. CONCLUSIONS:  The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences.

Association of Lithium in Drinking Water With the Incidence of Dementia.
            (Kessing et al., 2017)  Download
Importance:  Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition. Objective:  To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water. Design, Setting, and Participants:  This Danish nationwide, population-based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013. Main Outcomes and Measures:  A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls. Results:  A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 µg/L; interquartile range, 6.5-14.9 µg/L) and controls (median, 12.2 µg/L; interquartile range, 7.3-16.0 µg/L; P < .001). A nonlinear association was observed. Compared with individuals exposed to 2.0 to 5.0 µg/L, the incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 µg/L (IRR, 0.83; 95% CI, 0.81-0.85; P < .001) and 10.1 to 15.0 µg/L (IRR, 0.98; 95% CI, 0.96-1.01; P = .17) and increased with 5.1 to 10.0 µg/L (IRR, 1.22; 95% CI, 1.19-1.25; P < .001). Similar patterns were found with Alzheimer disease and vascular dementia as outcomes. Conclusions and Relevance:  Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded.


A feasibility and tolerability study of lithium in Alzheimer's disease.
            (Macdonald et al., 2008)  Download
OBJECTIVE:  To assess the safety and feasibility of prescribing long term lithium to elderly people with mild to moderate Alzheimer's disease (AD). METHODS:  An open label treatment group with low dose lithium for up to 1 year with the Lithium Side Effects Rating Scale as the primary outcome measure. A comparison group matched for cognition and age not receiving lithium therapy. RESULTS:  Twenty-two people with AD initiated lithium. Fourteen participants discontinued therapy after a mean of 16 weeks of treatment compared to the 39 weeks for those continuing to take treatment at the end of the study. Three patients discontinued treatment due to possible side effects that abated on ceasing therapy. The reports of side effects on the primary outcome scale did not differ between those discontinuing therapy and those remaining in the study. Two patients died whilst receiving lithium--in neither case was the treatment felt to be related to cause of death. There was no difference in deaths, drop outs or change in MMSE between those receiving lithium and the comparison group. CONCLUSIONS:  Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.

Lithium-induced tremor treated with vitamin B6: a preliminary case series
            (Miodownik et al., 2002)  Download
OBJECTIVE: The occurrence of tremor in patients receiving lithium is well known, but the management of this side effect is a significant problem both for patients and physicians. Although some reports have suggested that beta-blockers may be useful in treating lithium-induced tremor (LT), these agents have different side effects which limit the possibility of their use. Vitamin B6 has been reported to be effective in treatment of patients suffering from different kinds of neuroleptic-induced movement disorders including parkinsonism and tardive dyskinesia. METHODS: This report presents the results of a preliminary four-week open-label clinical trial of five patients who suffered from LT and who were treated with vitamin B6 (900-1200 mg/d). The severity of tremor was assessed using the tremor subscale from the Simpson-Angus Scale (SAS) and Subjective Clinical Improvement Impression scale (SCII). RESULTS: After the addition of vitamin B6 to their treatment, according to the SAS scores four patients showed an impressive improvement until total disappearance of tremor. The subjective scale, on which the patients' scored their impression of clinical improvement, showed similar results. None of the patients suffered from any side effects attributable to vitamin B6. CONCLUSIONS: The results suggest that vitamin B6 may alleviate LT, double-blind controlled trials are needed to establish this effect.


Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions.
            (Saraswati et al., 2018)  Download
Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase which is ubiquitously expressed and is regarded as a regulator for various cellular events and signalling pathways. It exists in two isoforms, GSK-3α and GSK-3β and can phosphorylate a wide range of substrates. Aberrancy in the GSK-3 activity can lead to various diseases like Alzheimer's, diabetes, cancer, neurodegeneration etc., rendering it an attractive target to develop potent and specific inhibitors. The present review focuses on the recent developments in the area of GSK-3 inhibitors and also enlightens its therapeutic applicability in various disease conditions.

Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients.
            (Squassina et al., 2016)  Download
Bipolar disorder (BD) has been suggested to be associated with accelerated aging and premature cell senescence. While findings on shorter telomeres in BD are controversial, a recent study showed that long-term lithium treatment correlates with longer telomeres in BD. In our study, we sought to investigate the correlation between leukocyte telomere length (LTL) and long-term lithium treatment in a sample of 200 BD patients characterized for lithium response. We also compared data from two different methods commonly used to measure telomere length, quantitative PCR (qPCR) and quantitative fluorescence in situ hybridization (Q-FISH). We also measured, for the first time, the effect of lithium in vitro on the expression of the telomerase gene in human-derived neural progenitor cells (NPCs). Our findings showed that LTL correlated negatively with age (p=0.0002) and was independent of sex, diagnosis, age at onset, suicidal behavior, number of mood episodes, response to lithium and use of other psychotropic medications. After correcting for age, LTL was positively correlated with lithium treatment duration in patients treated for more than two years (n=150, R=0.17, p=0.037). There was a significant correlation between data measured with qPCR and Q-FISH (p=0.012, R=0.826). Lithium treatment increased telomerase expression in NPCs, though this effect was not statistically significant. Our data support previous findings showing that long-term lithium treatment associates with longer telomeres in BD, though this effect appeared to be independent from clinical response to the treatment. Moreover, we suggested for the first time that lithium increases the expression of telomerase gene in human neural progenitor cells.



Aprahamian, I, et al. (2014), ‘Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension.’, J Clin Psychiatry, 75 (7), e672-8. PubMed: 25093483
Barker, WA, J Scott, and D Eccleston (1987), ‘The Newcastle chronic depression study: results of a treatment regime.’, Int Clin Psychopharmacol, 2 (3), 261-72. PubMed: 3121718
Castillo-Quan, JI, et al. (2016), ‘Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.’, Cell Rep, 15 (3), 638-50. PubMed: 27068460
Chouhan, A, A Abhyankar, and S Basu (2016), ‘The feasibility of low-dose oral lithium therapy and its effect on thyroidal radioiodine uptake, retention, and hormonal parameters in various subcategories of hyperthyroid patients: a pilot study.’, Nucl Med Commun, 37 (1), 74-78. PubMed: 26465804
Dias Alves, M, et al. (2017), ‘Efficacy of Vitamin B6 in Lithium-Associated Tremor: A Case Series.’, J Clin Psychopharmacol, 37 (2), 267-69. PubMed: 28099184
Eden Evins, A, et al. (2006), ‘Inositol augmentation of lithium or valproate for bipolar depression.’, Bipolar Disord, 8 (2), 168-74. PubMed: 16542187
Fajardo, VA, PJ LeBlanc, and VA Fajardo (2018), ‘Trace lithium in Texas tap water is negatively associated with all-cause mortality and premature death.’, Appl Physiol Nutr Metab, 43 (4), 412-14. PubMed: 29206474
Freland, L and JM Beaulieu (2012), ‘Inhibition of GSK3 by lithium, from single molecules to signaling networks.’, Front Mol Neurosci, 5 14. PubMed: 22363263
Guelen, PJ, et al. (1992), ‘Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets.’, Biopharm Drug Dispos, 13 (7), 503-11. PubMed: 1489941
Ishii, N, et al. (2015), ‘Low risk of male suicide and lithium in drinking water.’, J Clin Psychiatry, 76 (3), 319-26. PubMed: 25700119
Kessing, LV, et al. (2017), ‘Association of Lithium in Drinking Water With the Incidence of Dementia.’, JAMA Psychiatry, 74 (10), 1005-10. PubMed: 28832877
Macdonald, A, et al. (2008), ‘A feasibility and tolerability study of lithium in Alzheimer’s disease.’, Int J Geriatr Psychiatry, 23 (7), 704-11. PubMed: 18181229
Miodownik, C., E. Witztum, and V. Lerner (2002), ‘Lithium-induced tremor treated with vitamin B6: a preliminary case series’, Int J Psychiatry Med, 32 (1), 103-8. PubMed: 12075913
Saraswati, AP, et al. (2018), ‘Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions.’, Eur J Med Chem, 144 843-58. PubMed: 29306837
Squassina, A, et al. (2016), ‘Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients.’, Eur Neuropsychopharmacol, 26 (7), 1241-47. PubMed: 27084304