Lithium Articles 11


Lithium in the Kidney: Friend and Foe
            (Alsady et al., 2016) Download
Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for >60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

Insulin-like growth factor binding protein-2 expression is decreased by lithium.
            (Bezchlibnyk et al., 2006) Download
Lithium has been shown to possess cytoprotective properties in both cellular and animal models. Moreover, previous studies indicate that lithium treatment alters the expression of insulin-like growth factor binding protein-1 (IGFBP-1), a critical modulator of insulin-like growth factor bioactivity. Given the critical roles played by insulin-like growth factors in cellular mitogenesis, differentiation, and cell death, and that IGFBP-2 is the major brain resident IGFBP, we assessed IGFBP-2 expression in primary cortical neuroncultures subsequent to lithium treatment. We report that 7 days of lithium treatment at therapeutically relevant doses attenuates the expression of IGFBP-2 mRNA and protein in a dose and time-dependent manner. Therefore, these results suggest a possible role for the insulin-like growth factor system in lithium's mechanism of action.


Lithium reduces blood glucose levels, but aggravates albuminuria in BTBR-ob/ob mice.
            (de Groot et al., 2017) Download
Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known. We tested the effect of lithium, the only clinical GSK3 inhibitor, on the development of diabetes mellitus and kidney injury in a mouse model of diabetic nephropathy. Twelve-week old female BTBR-ob/ob mice were treated for 12 weeks with 0, 10 and 40 mmol LiCl/kg after which the development of diabetes and diabetic nephropathy were analysed. In comparison to BTBR-WT mice, ob/ob mice demonstrated elevated bodyweight, increased blood glucose/insulin levels, urinary albumin and immunoglobulin G levels, glomerulosclerosis, reduced nephrin abundance and a damaged proximal tubule brush border. The lithium-10 and -40 diets did not affect body weight and resulted in blood lithium levels of respectively <0.25 mM and 0.48 mM. The Li-40 diet fully rescued the elevated non-fasting blood glucose levels. Importantly, glomerular filtration rate was not affected by lithium, while urine albumin and immunoglobulin G content were further elevated. While lithium did not worsen the glomerulosclerosis, proximal tubule function seemed affected by lithium, as urinary NGAL levels were significantly increased. These results demonstrate that lithium attenuates non-fasting blood glucose levels in diabetic mice, but aggravates urinary albumin and immunoglobulin G content, possibly resulting from proximal tubule dysfunction.

Effect of Lithium on the Mechanism of Glucose Transport in Skeletal Muscles.
            (Jung et al., 2017) Download
While lithium is known to stimulate glucose transport into skeletal muscle, the mechanisms of the increased glucose transport by lithium in skeletal muscle are not well defined yet. We excised epitrochlearis muscles from male Wistar rats and measured the transport rates of a glucose analog into lithium-, insulin-, and muscular contraction-stimulated skeletal muscle tissue and we also analyzed the levels of cell surface glucose transport 4 using a photolabeling and multicolor immunofluorescence method. In addition, we generated a cell line that stably expresses myc-tagged GLUT4 to measure the rates of GLUT4 internalization and externalization. Lithium significantly increased 2-DG glucose transport rate in skeletal muscles; however, it was significantly lower than the stimulation induced by the maximum concentration of insulin or tetanic contraction. But co-treatment of lithium with insulin or tetanic contraction increased glucose transport rate by ∼200% more than lithium alone. When skeletal muscle tissues were treated with lithium, insulin, and muscular contraction, the levels of cell surface GLUT4 protein contents were increased similarly by ∼6-fold compared with the basal levels. When insulin or lithium stimuli were maintained, the rate of GLUT4myc internalization was significantly lower, and lithium was found to suppress the internalization of GLUT4myc more strongly. The lithium-induced increase in glucose uptake of skeletal muscles appears to increase in cell surface GLUT4 levels caused by decreased internalization of GLUT4. It is concluded that co-treatment of lithium with insulin and muscular contraction had a synergistic effect on glucose transport rate in skeletal muscle.

Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study.
            (Machado-Vieira et al., 2017) Download
OBJECTIVE:  Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using proton magnetic resonance spectroscopy (H-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. METHODS:  Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 ± 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. RESULTS:  Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. CONCLUSIONS:  This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.

Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease.
            (Nunes et al., 2013) Download
A lower incidence of dementia in bipolar patients treated with lithium has been described. This metal inhibits the phosphorylation of glycogen-synthase-kinase 3-α and β, which are related to amyloid precursor protein processing and tau hyperphosphorylation in pathological conditions, respectively. Following the same rationale, a group just found that lithium has disease-modifying properties in amnestic mild cognitive impairment with potential clinical implications for the prevention of Alzheimer's Disease (AD) when a dose ranging from 150 to 600 mg is used. As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months. In the evaluation phase, the treated group showed no decreased performance in the mini-mental state examination test, in opposition to the lower scores observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment, and increasing progressively. This data suggests the efficacy of a microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease.
            (Nunes et al., 2015) Download
The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.


Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study.
            (Saroukhani et al., 2013) Download
OBJECTIVES:  The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD). METHODS:  In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist. RESULTS:  Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time × treatment interaction were observed for total score [Greenhouse-Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse-Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [χ(2) (1) = 10.800, p = 0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups. CONCLUSION:  Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD.



Alsady, M, et al. (2016), ‘Lithium in the Kidney: Friend and Foe’, J Am Soc Nephrol, 27 (6), 1587-95. PubMed: 26577775
Bezchlibnyk, YB, et al. (2006), ‘Insulin-like growth factor binding protein-2 expression is decreased by lithium.’, Neuroreport, 17 (9), 897-901. PubMed: 16738484
de Groot, T, et al. (2017), ‘Lithium reduces blood glucose levels, but aggravates albuminuria in BTBR-ob/ob mice.’, PLoS One, 12 e0189485. PubMed: 29244860
Jung, S, et al. (2017), ‘Effect of Lithium on the Mechanism of Glucose Transport in Skeletal Muscles.’, J Nutr Sci Vitaminol (Tokyo), 63 (6), 365-71. PubMed: 29332897
Machado-Vieira, R, et al. (2017), ‘Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study.’, J Clin Psychopharmacol, 37 (1), 40-45. PubMed: 27902528
Nunes, MA, TA Viel, and HS Buck (2013), ‘Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease.’, Curr Alzheimer Res, 10 (1), 104-7. PubMed: 22746245
Nunes, MA, et al. (2015), ‘Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer’s Disease.’, PLoS One, 10 (11), e0142267. PubMed: 26605788
Saroukhani, S, et al. (2013), ‘Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study.’, Bipolar Disord, 15 (6), 650-56. PubMed: 23924261