Dose Of Lithium Research Articles

Effect of age on the severity of chronic lithium poisoning

Objectives: Severe lithium toxicity is commonly observed in older people. We aimed to determine the extent to which age is associated with increased severity of chronic lithium poisoning and of which a range of possible factors might explain the associations.Method: We did a retrospective review of patients aged ≥15 years old with serum lithium concentrations ≥1.3 mmol/L from three hospitals. Clinical details, treatment and outcomes were recorded. eGFR, creatinine and lithium clearance were calculated. The severity of lithium toxicity was graded into five categories (Amdisen score). ANOVA was used to quantify the association between age and severity. Spearman correlation coefficient was used to explore relationships between age and different factors expected to alter severity. Ordinal regression analysis was used to determine the interdependence of age and these factors and age on severity of lithium toxicity.Results: From 2008–2018, there were 242 patients with a median age of 56.5 years (IQR: 41–69). There were 156 females (64%). There was a statistically significant association between Amdisen severity scores and age (p = .0004). The median calculated eGFR was 65 mL/min/1.73 m2 (IQR: 41–91) with a corresponding estimated lithium clearance of 18 mL/min (IQR: 13.8–22.8). There was no correlation of age with initial serum lithium concentration (p = .76). There was a strong correlation between age and estimated lithium clearance (r = –0.72, 95% CI: –0.78 to –0.66, p < .001), lithium daily dose (r = –0.65, 95% CI: –0.72 to –0.57, p < .0001) and lithium concentration/dose (r = 0.62, 95% CI: 0.53–0.69, p < .0001). There was a weak correlation between age and infection (r = 0.18, 95% CI: 0.04–0.31, p = .009) and drug interactions (r = 0.25, 95% CI: 0.11–0.37, p = .0003). Ordinal regression indicated the independent predictors for severity of lithium toxicity were lithium concentration (p < .0001) and lithium clearance (p = .03) adjusted for age and dose.Conclusions: Despite lower lithium doses, older patients had more severe toxicity. Increased severity of lithium toxicity in the elderly is largely explainable by decreased lithium clearance from multiple factors such as age-related decline in renal function, drug interactions and infection.

Sex difference in the progression of manic symptoms during acute hospitalization: A prospective pilot study.

ObjectivesAcute mania is a serious medical condition that impacts men and women equally. Longtime presentation of manic symptoms is sex‐dependent; however, little is known about acute symptoms of mania. The objective of this study is to track and compare acute manic symptoms for sex differences during inpatient hospitalization.MethodsAll patients with bipolar mania admitted to a large university hospital between January and October 2017 were invited to participate in this longitudinal naturalistic follow‐up study. Manic (YMRS), depressive (MADRS), and psychotic (PAS) symptoms were tracked daily from admission to discharge.ResultsThe total YMRS scores decreased significantly overtime (p < .0001) in both male (n = 34) and female (n = 23) patients (p = .7). However, male patients scored significantly higher in sexual interest (p = .01), disruptive and aggressive behavior (p = .01), and appearance (p < .001) while females had better insight into their illness (p = .01). Males and females received similar doses of lithium (p = .1), but males received significantly higher doses of valproic acid (VPA) in comparison with females (p = .003). However, plasma lithium and VPA concentrations at discharge were not significantly different between sexes.ConclusionOur results show sex differences in the progression of certain domains of manic symptoms in a cohort of 23 female and 34 male patients admitted to a large academic center in Turkey. Males, in this sample, exhibited more sexual interest, disruptive and aggressive behaviors, better grooming, and less insight compared to females. While these results are concordant with our preclinical findings and with anecdotal clinical observations, replication in larger samples is needed.

The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine.

Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.

Implication of glycogen synthase kinase 3 in diabetes-associated islet inflammation.

Islet inflammation is associated with defective β cell function and mass in type 2 diabetes (T2D). Glycogen synthase kinase 3 (GSK3) has been identified as an important regulator of inflammation in different diseased conditions. However, the role of GSK3 in islet inflammation in the context of diabetes remains unexplored. In this study, we investigated the direct implication of GSK3 in islet inflammation in vitro and tested the impact of GSK3 inhibition in vivo, on the reduction of islet inflammation, and the improvement of glucose metabolism in the Goto-Kakizaki (GK) rat, a spontaneous model of T2D. GK rats were chronically treated with infra-therapeutic doses of lithium, a widely used inhibitor of GSK3. We analyzed parameters of glucose homeostasis as well as islet inflammation and fibrosis in the endocrine pancreas. Ex vivo, we tested the impact of GSK3 inhibition on the autonomous inflammatory response of non-diabetic rat and human islets, exposed to a mix of pro-inflammatory cytokines to mimic an inflammatory environment. Treatment of young GK rats with lithium prevented the development of overt diabetes. Lithium treatment resulted in reduced expression of pro-inflammatory cytokines in the islets. It decreased islet fibrosis and partially restored the glucose-induced insulin secretion in GK rats. Studies in non-diabetic human and rat islets exposed to inflammatory environment revealed the direct implication of GSK3 in the islet autonomous inflammatory response. We show for the first time, the implication of GSK3 in islet inflammation and suggest this enzyme as a viable target to treat diabetes-associated inflammation.

Serum Lithium in Patients in Remission of Bipolar Disorder

Introduction: Bipolar affective disorder a chronic, and highly disabling psychiatric disorder is one of the leading causes of disability and is estimated to affect more than 1% of the global population irrespective of origin, ethnicity, nationality or socioeconomic status. The effectiveness of lithium in mania and psychotic excitement was proven first proven in 1960 and since then lithium is considered to be a gold standard treatment for bipolar disorder. &#x0D; Material and Method: A total of one hundred thirty five patients with bipolar disorder were enrolled in a prospective study to analyze the serum lithium levels on maintenance dose of lithium. After ethical clearance data was collected from patients attending BG Hospital and Research Centre from July 2013 to July 2019. The patients who were on maintenance treatment with different doses of lithium only were included. These patients were tested for serum lithium concentration as per lithium monitoring guidelines. Serum Lithium, serum electrolytes, height and weight of the patients were recorded. The psychiatric diagnosis was made according to the ICD-10 criteria. Data were computed and analyzed by using SPSS version 21. Parametric and non-parametric statistical technique was applied wherever appropriate. &#x0D; Results: The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was found at 0.16 mmol/l and maximum serum levels was 1.51 mmol/l. The mean serum lithium level was 0.596 mmol/l with standard deviation of 0.237 mmol/l. &#x0D; Conclusion: There is substantial variation in between the serum lithium levels of patients in remission on long term treatment. The uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder leads to the suggestion of the treatment of individual patients to be based on clinical response rather than on serum lithium levels.

The quality of gosling meat depending on the level of lithium in mixed fodders

Micronutrients are an important component of a complete poultry feeding. Current detailed feeding standards provide guaranteed feed additives for farm poultry of the microelement complex. Among the normalized microelements there is no lithium, which according to the classification based on biological role for living organisms belongs to the group of conditionally essential elements. The purpose of the study was to investigate the effect of various doses of lithium in compound feed on the chemical composition and toxicological and biological parameters of caterpillar meat. The effect of additives of different doses of lithium (0.05 mg/kg, 0.10 and 0.15 mg/kg) in compound forages on the quality and safety of the products of slaughter of 70-day gosling was studied. The studies were conducted on gosling of the Legart breed. Feeding of gosling from day to 70 days of age was carried out by full-feed compound feeds. The birds of the experimental groups were additionally injected with lithium in the feed, mg/kg: the second group was 0.05; third – 0.10 and fourth – 0.15. The gosling of the control group did not receive lithium. Analysis of the results of the studies revealed differences between the control and experimental groups in the chemical composition of the muscular tissue of the gosling in favor of the latter. It was found that the introduction of lithium compound feed had a positive effect on the deposition of dry matter, protein and fat in the gosling of the experimental groups, which contributed to its increased energy and biological value. The best indicators of meat quality were in young animals, which during the growing period were fed compound feeds enriched with lithium at the rate of 0.1 and 0.15 mg/kg.

A case of skew deviation and downbeat Nystagmus induced by Lithium

BackgroundLithium salts have been commonly used for prophylaxis and treatment of bipolar disorder and have numerous side effects. However, there has been no report of skew deviation and downbeat nystagmus associated with lithium. Herein, we report the first case of lithium-induced skew deviation and downbeat nystagmus.Case presentationA 39 years-old woman presented with intermittent vertical diplopia and dizziness within 1–2 months. Ophthalmologic examination revealed downbeat nystagmus and 6 prism diopters of right hypertropia. Funduscopic examination showed mild incyclotorsion on right eye. However, ductions and versions were within normal range. Other neurological examinations were also normal. She had a history of bipolar disorder treated with daily 600-900 mg of lithium for past 6 years, and 2 months before the first visit, daily dose of lithium was increased to 1200 mg. We referred the patients to psychiatrist. Although the serum level of lithium was within the normal therapeutic range, her daily dose of lithium was reduced to 600 mg and then stopped. 6 days after cessation of lithium, down beat nystagmus and right hypertropia were completely resolved and symptoms did not recur over a year.ConclusionEven within a normal therapeutic range, downbeat nystagmus and skew deviation can occur as side effect of lithium. Dehydration may contribute to the neurotoxicity of lithium.

Synergistic but not additive effect between ACPA and lithium in the dorsal hippocampal region on spatial learning and memory in rats: Isobolographic analyses

Lithium and cannabinoids can disrupt learning and memory performance. The goal of the present study is to investigate the additive or synergistic effect of lithium and cannabinoid combination doses on spatial learning and memory in rats by isobolographic analyses. Although several studies have suggested synergistic effects of cannabinoids or lithium in response to other compounds, in most of them isobolographic analyses were not used; Thus, there is a need for more detailed studies using isobolographic analyses. In this study, spatial memory was evaluated in the Morris Water Maze (MWM) apparatus by eight trials in the training day and one trial in the test day. Lithium was injected intraperitoneal and ACPA (cannabinoid type 1 receptor agonist) was injected into the dorsal hippocampal region (intra-CA1). For the isobolographic analyses, the ED50 of lithium (2.5 mg/kg) and ACPA (0.5 μg/rat) was measured by linear regression analysis, considering the doses were tested in our previous research. The results showed that, combinations of low, medium and high doses of lithium (0.312 mg/kg, 0.625 mg/kg and 1.25 mg/kg, respectively) and ACPA (0.0625 μg/rat, 0.125 μg/rat and 0.25 μg/rat, respectively) had synergistic but not additive effect on spatial learning and spatial memory. In conclusion, we suggest that combination doses of lithium and ACPA have synergistic but not additive effect on spatial learning and memory in the rat's dorsal hippocampal region.

A Low-Therapeutic Dose of Lithium Inhibits GSK3 and Enhances Myoblast Fusion in C2C12 Cells.

Glycogen synthase kinase 3 (GSK3) slows myogenic differentiation and myoblast fusion partly by inhibiting the Wnt/β-catenin signaling pathway. Lithium, a common medication for bipolar disorder, inhibits GSK3 via Mg+ competition and increased Ser21 (GSK3α) or Ser9 (GSK3β) phosphorylation, leading to enhanced myoblast fusion and myogenic differentiation. However, previous studies demonstrating the effect of lithium on GSK3 have used concentrations up to 10 mM, which greatly exceeds concentrations measured in the serum of patients being treated for bipolar disorder (0.5–1.2 mM). Here, we determined whether a low-therapeutic (0.5 mM) dose of lithium could promote myoblast fusion and myogenic differentiation in C2C12 cells. C2C12 myotubes differentiated for three days in media containing 0.5 mM lithium chloride (LiCl) had significantly higher GSK3β (ser9) and GSK3α (ser21) phosphorylation compared with control myotubes differentiated in the same media without LiCl (+2–2.5 fold, p < 0.05), a result associated with an increase in total β-catenin. To further demonstrate that 0.5 mM LiCl inhibited GSK3 activity, we also developed a novel GSK3-specific activity assay. Using this enzyme-linked spectrophotometric assay, we showed that 0.5 mM LiCl-treated myotubes had significantly reduced GSK3 activity (−86%, p < 0.001). Correspondingly, 0.5 mM LiCl treated myotubes had a higher myoblast fusion index compared with control (p < 0.001) and significantly higher levels of markers of myogenesis (myogenin, +3-fold, p < 0.001) and myogenic differentiation (myosin heavy chain, +10-fold, p < 0.001). These results indicate that a low-therapeutic dose of LiCl is sufficient to promote myoblast fusion and myogenic differentiation in muscle cells, which has implications for the treatment of several myopathic conditions.

Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate.

Background and ObjectiveOlanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and, either as monotherapy or as an adjunct to lithium or valproate, for bipolar I disorder. Multiple daily doses of olanzapine do not affect the pharmacokinetics of lithium or valproate; therefore, concomitant olanzapine administration does not require dosage adjustment of lithium or valproate. ALKS 3831, a combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM), is currently under development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Olanzapine is recognized as one of the most efficacious antipsychotics; however, the benefits of olanzapine are offset by its propensity to cause significant weight gain, which may lead to long-term metabolic sequelae. This study evaluated the effects of multiple daily doses of OLZ/SAM on the pharmacokinetics of lithium or valproate in healthy subjects.MethodsThis was an open-label, single-sequence, two-cohort study (ALKS3831-B101) conducted at a single center in the USA. Thirty-four healthy adult subjects were assigned (1:1) to receive lithium carbonate 300-mg tablets (cohort 1) or divalproex sodium 500-mg tablets (cohort 2), once every 12 h on days 1–7. Once-daily oral doses of OLZ/SAM (olanzapine 10 mg/samidorphan 10 mg) bilayer tablets were administered on days 8–18. Subjects resumed every 12-h doses of lithium or valproate concomitantly with the once-daily oral doses of OLZ/SAM on days 12–18. Plasma concentrations of lithium and valproic acid (valproate) were quantified in blood samples collected prior to and up to 12 h after lithium or valproate dose administration on days 7 and 18. Pharmacokinetic parameters of lithium and valproate, including maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval, were calculated. The ratio of geometric means of maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval in the presence and absence of OLZ/SAM, and its two-sided 90% confidence intervals, were derived from a mixed-effects model. Adverse events were monitored throughout the study.ResultsThe 90% confidence intervals for the ratios of geometric means, in the presence vs. absence of OLZ/SAM, were within the equivalence interval of 80–125% for both maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval of lithium and of valproate. The safety profiles of lithium or valproate co-administered with OLZ/SAM were consistent with what has been previously reported for lithium or valproate. The safety profile of OLZ/SAM was consistent with that observed in previous clinical studies with OLZ/SAM.ConclusionsConsistent with previously reported findings on olanzapine, administration of multiple doses of OLZ/SAM did not have a clinically significant effect on the pharmacokinetics of lithium or valproate. Co-administration of OLZ/SAM and lithium or valproate was generally well tolerated; the safety profile of OLZ/SAM was consistent with that observed in previous clinical studies.

Combination of lithium and electroconvulsive therapy (ECT) is associated with higher odds of delirium and cognitive problems in a large national sample across the United States

BackgroundLithium is a helpful adjunct to patients undergoing ECT. However, only case reports and limited data suggest increase risk of delirium. Thus, this continues to be a controversial issue. ObjectiveIn this study, we examine 1) The association and odds of delirium and cognitive problems with ECT and lithium (ECT + Li) combination compared to ECT alone, 2) If positively associated, would this association vary by both type of mood episode and type of disorder? MethodsA national sample of 64,728 adult psychiatric inpatients across the US (identified from a total data of about 70 million total discharges annually) was analyzed using linear-by-linear association and logistic regression to assess the odds ratio (OR) for delirium and cognitive impairment for those treated with lithium (N = 158), ECT (N = 64148), or ECT + Li (N = 422) after adjusting for demographics and psychiatric diagnoses. ResultsThe prevalence of delirium was higher in the ECT + Lithium group (5.7%) vs. ECT only (0.6%) or lithium only groups (0%). Patients managed with ECT + Lithium have 11.7-fold higher odds (95% CI 7.55–17.99, P < 0.001) of delirium compared to ECT alone. In the ECT + Li group, delirium prevalence was 7.8% in unipolar depression, 3.4% in bipolar depressed, 0% in bipolar mania. ConclusionThese results are surprising given the fading concern about delirium association with ECT + lithium combination. The high odds in the combination group warrant clinical caution, use of lower lithium doses (if combinations cannot be avoided), and vigilance regarding early signs of delirium. These results warrant replication in future studies.

Pharmacological evidence for lithium-induced neuroprotection against methamphetamine-induced neurodegeneration via Akt-1/GSK3 and CREB-BDNF signaling pathways.

Objective(s):Neurodegeneration is an outcome of Methamphetamine (METH) abuse. Studies have emphasized on the neuroprotective properties of lithium. The current study is designed towards evaluating the role of Akt-1/GSK3 and CREB-BDNF signaling pathways in mediating lithium neuroprotection against METH-induced neurodegeneration in rats. Materials and Methods:Sixty adult male rats were randomly divided into five groups: control group (received 0.7 ml normal saline per rat for 28 days), METH group (given 10 mg/kg of METH intraperitoneally for 28 days), groups 3, 4, and 5 (given METH (10 mg/kg) and lithium (75, 150, and 300 mg/kg intraperitoneally, individually for 28 days). Morris water maze (MWM) was used to assess mental functions. In addition to hippocampal neurodegeneration, Brain-derived neurotrophic factor (BDNF), cAMP response element binding (CREB), Glycogen synthase kinase 3 (GSK3), and Protein kinase B (Akt-1) were assessed in isolated hippocampus. Results:METH abuse caused marked disorders in learning and memory that were dramatically improved with various doses of lithium. Furthermore, METH increased lipid peroxidation and the levels of oxidized form of interleukin 1 beta (IL-1β), glutathione (GSSG), Bax, tumor necrosis factor alpha (TNF-α), and GSK3, while attenuating the extent of glutathione (reduced form (GSH)), P-CREB, Bcl-2, BDNF, and Akt-1 in the hippocampus. Moreover, METH declined superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) activity in the hippocampus. Conversely, lithium attenuated METH-stimulated apoptosis, oxidative stress, and inflammation; while improving the extent of BDNF and P-CREB.Conclusion:Probably lithium possesses neuroprotection against METH-stimulated neurodegeneration in the hippocampus via Akt-1/GSK3β and CREB/BDNF signaling pathways.

Recruitment, Retainment, and Biomarkers of Response; A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment.

Lithium has been used for decades to treat Bipolar Disorder. Some of its therapeutic benefits may be through inhibition of Glycogen Synthase Kinase (GSK)-3. Enhanced GSK3 activity associates with development of Alzheimer’s disease (AD), therefore lithium is a currently used therapeutic with potential to be repurposed for prevention of Dementia. An important step toward a clinical trial for AD prevention using lithium is to establish the dose of lithium that blocks GSK3 in Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. We investigated volunteer recruitment, retention, and tolerance in this population, and assessed biomarkers of GSK3 in MCI compared to control and after lithium treatment. Recruitment was close to target, with higher than anticipated interest. Drop out was not related to lithium blood concentration. Indeed, 33% of the withdrawals were in the first week of very low dose lithium. Most made it through to the highest dose of lithium with no adverse events. We analyzed 18 potential biomarkers of GSK3 biology in rat PBMCs, but only four of these gave a robust reproducible baseline signal. The only biomarker that was modified by acute lithium injection in the rat was the inhibitory phosphorylation of Ser9 of GSK3beta (enhanced in PBMCs) and this associated with reduced activity of GSK3beta. In contrast to the rat PBMC preparations the protein quality of the human PBMC preparations was extremely variable. There was no difference between GSK3 biomarkers in MCI and control PBMC preparations and no significant effect of chronic lithium on the robust GSK3 biomarkers, indicating that the dose reached may not be sufficient to modify these markers. In summary, the high interest from the MCI population, and the lack of any adverse events, suggest that it would be relatively straightforward and safe to recruit to a larger clinical trial within this dosing regimen. However, it is clear that we will need an improved PBMC isolation process along with more robust, sensitive, and validated biomarkers of GSK3 function, in order to use GSK3 pathway regulation in human PBMC preparations as a biomarker of GSK3 inhibitor efficacy, within a clinical trial setting.

Lithium bioaccumulation in Lentinus crinitus mycelial biomass as a potential functional food

Lentinus crinitus is an important basidiomycete consumed by ethnic groups from the Amazon, commonly found in decomposing trees with high lignolytic and antioxidant activities. Lithium is a mood stabilizer, antiepileptic, antipsychotic, and antidepressant used in clinical practice. This study aimed to evaluate L. crinitus mycelial biomass bioaccumulated with lithium in liquid cultivation medium. The malt extract medium was added from zero to 100 mg L−1 lithium from two lithium sources (Li2CO3 and LiCl). The maximum mycelial biomass production was 7218.89 mg L−1 in the culture medium added with 5 mg L−1 lithium from LiCl. The highest lithium concentration in the mycelial biomass was of 574.72 μg g−1 produced in the culture medium with 25 mg L−1 lithium from Li2CO3. Pearson's correlation showed that Li2CO3 reduces the mycelial biomass and increases lithium bioaccumulation. The maximum translocated lithium from cultivation medium to mycelial biomass was up to 19 or 28% with LiCl or Li2CO3, respectively. Therefore, although Li2CO3 presents greater inhibition on the mycelial biomass production, it promoted greater lithium bioaccumulation in L. crinitus mycelial biomass and resulted in greater yield of lithium translocation. The equivalent daily dose of lithium for psychiatric treatment, without bioavailability studies, could be reached with 97.4 g lithium-enriched mycelial biomass and, based in the literature, for reduction of violence and criminality rates the amount could be reached with 0.24–0.58 mg. Thus, the development of lithium-enriched mycelial biomass could be an alternative functional food.

Lithium Neurotoxicity Due to Second-Generation Antipsychotics Combined With Lithium: A Systematic Review.

To study cases of lithium neurotoxicity (LN), both reversible (RLN) and irreversible (ILN), due to second-generation antipsychotics (SGAs) combined with lithium. A comprehensive search was conducted in MEDLINE, PsycINFO, EMBASE, and the Cochrane Library from their inception to July 31, 2017. Free terms and MeSH headings were combined as follows: [(lithium) AND (adverse events OR safety OR side effects OR neurotoxicity OR neurologic manifestations OR central nervous system) AND (risperidone OR paliperidone OR olanzapine OR aripiprazole OR clozapine OR quetiapine OR ziprasidone OR amisulpride OR asenapine OR lurasidone OR iloperidone)]. Only English-language articles reporting about LN due to SGAs combined with lithium were selected. The age, sex, diagnostic categories, clinical features, lithium doses, serum lithium levels, antipsychotic dosages, causative factors, and preventive measures of 11 cases of LN (8 RLN and 3 ILN) due to the lithium and SGA combination were extracted. Forty-five percent of patients were aged > 60 years. The diagnostic categories were schizoaffective disorders, bipolar disorders, and schizophrenia. Cases of RLN presented as an acute brain syndrome, which recovered completely. Cases of ILN presented as a chronic brain syndrome and only partially recovered. The lithium doses in 9 cases were < 1,200 mg/d. The serum lithium levels in 2 cases in each of the groups were > 1.7 mEq/L. The SGAs implicated were clozapine, risperidone, aripiprazole, and quetiapine. One patient with RLN received 2 different first-generation antipsychotics and 1 patient with ILN received 2 different SGAs with lithium. Both groups had patients with medical comorbidities who were taking prescription medication. LN, both reversible and irreversible, due to SGAs combined with lithium presents with certain causative factors and a clinical profile. Early detection and prompt management will help prevent LN.

Managing polyuria during lithium treatment: a preliminary prospective observational study.

Lithium-treated patients with polyuria are at increased risk of lithium toxicity. We aimed to describe the clinical benefits and risks of different management strategies for polyuria in community lithium-treated patients. This is a naturalistic, observational, prospective 12-month cohort study of lithium-treated patients with polyuria attending a community mental health service in Dublin, Ireland. When polyuria was detected, management changed in one of four ways: (a) no pharmacological change; (b) lithium dose decrease; (c) lithium substitution; or (d) addition of amiloride. Thirty-four participants were diagnosed with polyuria and completed prospective data over 12 months. Mean 24-hour urine volume decreased from 4852 to 4344 ml (p = 0.038). Mean early morning urine osmolality decreased from 343 to 338 mOsm/kg (p = 0.823). Mean 24-hour urine volume decreased with each type of intervention but did not attain statistical significance for any individual intervention group. Mean early morning urine osmolality decreased in participants with no pharmacological change and increased in participants who received a change in medication but these changes did not attain statistical significance. Only participants who discontinued lithium demonstrated potentially clinically significant changes in urine volume (mean decrease 747 ml in 24 hours) and early morning urine osmolality (mean increase 31 mOsm/kg) although this was not definitively proven, possibly owing to power issues. Managing polyuria by decreasing lithium dose does not appear to substantially improve objective measures of renal tubular dysfunction, whereas substituting lithium may do so. Studies with larger numbers and longer follow-up would clarify these relationships.

Lithium Preparations in Psychiatry, Addiction Medicine and Neurology (To the 70th Anniversary of John Cade’s Discovery). Part I. History

The use of lithium salts in psychiatry has a long, more than two-thousand-year history. It goes back to the ideas of Hippocrates II, Galen and Soran of Ephesus regarding the feasibility of using mineral waters from certain sources, which, as we know today, were rich in lithium, magnesium and bromine salts, for the treatment of both manic and depressive states. Later, this effect of lithium salts was rediscovered – independently of each other – in the mid-19th century by the American psychiatrist William Alexander Hammond and the Danish psychiatrist Carl Lange. However, since this discovery was based on incorrect premises, namely, on the theory of «brain urine acid diathesis» as the cause of mental illness, it was not accepted, ignored and even ridiculed by colleagues. The rediscovery of the anti-manic effect of lithium salts by John Cade in 1948 is one of the greatest discoveries of psychiatry of the 20th century.The mechanisms of lithium therapeutic action are complex, diverse and not fully understood to this day. Initially, John Cade suggested that this effect of lithium is associated with its deficiency in patients with bipolar disorder and that exogenous lithium aids in compensation of such deficiency, or that patients with bipolar disorder suffer from some congenital disorder of lithium metabolism, thus requiring higher daily lithium doses than healthy people. However, it was soon shown that this was not the case.Despite the emergence of a significant number of alternative mood stabilizers, lithium remains relevant in psychiatry to this day.

Experimental Pharmacology in Transgenic Rodent Models of Alzheimer's Disease.

This Mini Review discusses the merits and shortfalls of transgenic (tg) rodents modeling aspects of the human Alzheimer’s disease (AD) pathology and their application to evaluate experimental therapeutics. It addresses some of the differences between mouse and rat tg models for these investigations. It relates, in a condensed fashion, the experience of our research laboratory with the application of anti-inflammatory compounds and S-adenosylmethionine (SAM) at the earliest stages of AD-like amyloid pathology in tg mice. The application of SAM was intended to revert the global brain DNA hypomethylation unleashed by the intraneuronal accumulation of amyloid-β-immunoreactive material, an intervention that restored levels of DNA methylation including of the bace1 gene. This review also summarizes experimental pharmacology observations made in the McGill tg rat model of AD-like pathology by applying “nano-lithium” or a drug with allosteric M1 muscarinic and sigma 1 receptor agonistic properties (AF710B). Extremely low doses of lithium (up to 400 times lower than used in the clinic) had remarkable beneficial effects on lowering pathology and improving cognitive functions in tg rats. Likewise, AF710B treatment, even at advanced stages of the pathology, displayed remarkable beneficial effects. This drug, in experimental conditions, demonstrated possible “disease-modifying” properties as pathology was frankly diminished and cognition improved after a month of “wash-out” period. The Mini-Review ends with a discussion on the predictive value of similar experimental pharmacological interventions in current rodent tg models. It comments on the validity of some of these approaches for early interventions at preclinical stages of AD, interventions which may be envisioned once definitive diagnosis of AD before clinical presentation is made possible.

ATORVASTATIN IN THE TREATMENT OF LITHIUM-INDUCED NEPHROGENIC DIABETES INSIPIDUS: THE PROTOCOL OF A RANDOMIZED CONTROLLED TRIAL

Introduction Lithium is the gold-standard treatment for bipolar disorder, is highly effective in major depressive disorder, and is being investigated for therapeutic benefits in dementia, stroke, and even cancer. Approximately 350,000 Canadians use lithium and more could benefit. Despite this, clinicians are avoiding lithium, largely due to fear of renal toxicity, including irreversible chronic kidney disease (CKD). Nephrogenic Diabetes Insipidus (NDI) occurs in 20% of lithium users and independently predicts a 2-3 times increased risk of CKD. To date, amiloride is the only medication with randomized controlled trial (RCT) evidence for treating NDI, however it can increase lithium toxicity risk. There is a need for novel, well-tolerated treatments for NDI. We recently found that statins are associated with lower NDI risk in a cross-sectional study (n=71 lithium users). 0% (0/17) of statin users compared to 20.4% (11/54) of non-users had NDI (p=0.055), with atorvastatin 10-40mg/day being the main statin used. Mice studies from our collaborators have also been promising. We present the protocol for a pilot human RCT of statins in NDI to guide a larger confirmatory RCT. Methods We propose a 12-week, double-blind placebo-controlled pilot RCT of atorvastatin in patients with lithium-induced NDI. We will recruit 60 psychiatric patients, aged 18-85, who are on a stable lithium dose for ≥2 months and who have NDI, defined as a 10-hour fluid restriction urine osmolality (UOsm) Results The protocol of this study will be presented. Results will be ready in late 2019. Conclusions Atorvastatin is found to be useful in treating NDI, lithium could be used more safely in patients with a reduced subsequent risk of CKD, as well as hypernatremia, and acute kidney injury (AKI). This could also allow many additional patients with bipolar disorder, depression, and other psychiatric/neurological conditions to benefit from lithium. This could also potentially prevent medical health service utilization related to psychiatric, neurological, and renal disease, saving significant health costs. This research was funded by Kidney Foundation of Canada

Dose optimization of lithium to increase the uptake and retention of I-131 in rat thyroid

The present study was undertaken to optimize the dose of lithium, with an aim to increase the retention of I-131 in the thyroid follicles while maintaining the euthyroid state. 24 female Wistar rats weighing 110 ± 20g were segregated into four groups. Animals in group I were fed standard laboratory feed and water throughout the period of experimentation. Animals in group II, III and IV were additionally fed with lithium in the form of lithium carbonate orally, at a dose of 10mg/kg body weight, 20mg/kg body weight, 30mg/kg body weight respectively. The dose of lithium was started 1 week prior to radioiodine administration and continued thereafter for another 8 days. After 7 days of lithium treatment, 0.48MBq of carrier-free I-131 was injected intraperitoneally into each rat, of the four groups. I-131 thyroidal uptake and biokinetics, as well as serum TSH, T3, T4 levels were estimated in all the treatment groups. A significant increase in the thyroid and whole body counts was observed after 4 and 24h of I-131 aministration in lithium treated rats, compared to control animals. An increase in thyroidal effective t1/2 and serum TSH levels, along with decrease in the levels of serum T3 and T4 was observed with a dose of 20mg/kg or higher. In Conclusion, a Lithium dose of 10mg/kg body weight in rats could increase the uptake of I-131 in the thyroid, without disturbing the control circulating levels of thyroid hormones.