Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.

Association between lithium treatment and renal, thyroid and parathyroid function: A cohort study of 6659 patients with bipolar disorder.

OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.

Low and very low lithium levels: Thyroid effects are small but still require monitoring.

AIM: Low doses of lithium, as might be used for mood or dementia prevention, do not carry the same renal, toxicity, and tolerability problems of doses used for prophylaxis or treatment of mania. However, thyroid effects of low doses have not been investigated. Our goal in this study was to assess the changes in thyroid-stimulating hormone (TSH) associated with a broad range of lithium levels, including those well below the therapeutic range for bipolar disorders. METHODS: This study was conducted in a small healthcare system with 19 associated primary care clinics served by a Collaborative Care program of psychiatric consultation. In this retrospective review of electronic records, we searched for patients who had received a lithium prescription and both pre- and post-lithium thyroid-stimulating hormone (TSH) levels. RESULTS: Patients with low lithium levels (<0.5 mEq/L, N = 197) had a mean thyroid-stimulating hormone (TSH) increase of 0.52 mIU/L. Patients with maintenance lithium levels (0.5-0.8 mEq/L; N = 123) had a mean TSH increase of 1.01 mIU/L; and patients with antimanic lithium levels (>0.8 mEq/L; N = 79) had a mean TSH increase of 2.16 mIU/L. The probability of TSH exceeding the upper limit of normal in our laboratory (>4.2 mIU/L) was positively associated with pre-lithium TSH. CONCLUSION: These results suggest that the risk of lithium-induced hypothyroidism is dose-related, and relatively small with very low doses, but thyroid monitoring, including a pre-lithium TSH, is still warranted.

Surgical strategy in lithium-associated hyperparathyroidism: A population-based study.

BACKGROUND: The extent of parathyroidectomy (PTX) recommendation in patients with lithium-associated hyperparathyroidism (LAH) remains controversial. The primary objectives of this study were to analyze extent of surgery, complications, and long-term outcomes. METHODS: A population-based study, including all primary hyperparathyroidism (PHPT) patients who underwent PTX in Sweden between 2008 and 2017. Data on exhibited lithium prescriptions, morbidity, surgical approach, and outcomes were collected from relevant national registers and the Scandinavian Quality Register of Thyroid, Parathyroid, and Adrenal Surgery. Patients with lithium exposure before PTX were defined as having LAH. Descriptive summary statistics and regression models were used to evaluate differences in comorbidities, surgical approach, and outcomes between LAH and PHPT not exposed to lithium (non-LAH). RESULTS: Lithium exposure was significantly more common among PHPT (n = 202, 2.3%) than in controls (n = 416, 0.5%); OR 5.0 (95% CI 4.2-5.9). The risk of LAH correlated to the length of lithium exposure. In the LAH-group, the surgical procedures were more extensive and associated with a higher risk of postoperative bleeding, wound infections, persistent hypercalcemia, and hypocalcemia that remained after adjustment for the higher percentage of multiglandular disease. However, the cumulative risk of re-admission for PHPT was similar the first years after PTX and primarily elevated for patients with >5 years duration of lithium exposure prior to surgery. CONCLUSIONS: The findings support the perception of LAH as a complex entity. We recommend a functionally oriented approach, aimed to obtain and maintain normocalcemia for as long as possible, minimizing the risk of permanent hypoparathyroidism, and accepting some risk of recurrence.

Real-World Clinical Practice Among Patients With Bipolar Disorder and Chronic Kidney Disease on Long-term Lithium Therapy.

PURPOSE: Long-term lithium therapy (LTLT) has been associated with chronic kidney disease (CKD). We investigated changes in clinical characteristics, pharmacotherapeutic treatments for medical/psychiatric disorders, and outcomes among patients with bipolar disorder (BD) and CKD on LTLT in a 2-year mirror-image study design. METHODS: Adult BD patients on LTLT for ≥1 year who enrolled in the Mayo Clinic Bipolar Disorder Biobank and developed CKD (stage 3) were included, and our study was approved by the Mayo Clinic Institutional Review Board. The primary outcome was the time to the first mood episode after CKD diagnosis among the lithium (Li) continuers and discontinuers. Cox proportional hazards models were used to estimate the time to the first mood episode. We tested for differences in other medication changes between the Li continuers and discontinuers group using Mantel-Haenszel χ2 tests (linear associations). RESULTS: Of 38 BD patients who developed CKD, 18 (47%) discontinued Li, and the remainder continued (n = 20). The median age of the cohort was 56 years (interquartile range [IQR], 48-67 years), 63.2% were female, and 97.4% were White. As compared with continuers, discontinuers had more psychotropic medication trials (6 [IQR, 4-6] vs 3 [IQR, 2-5], P = 0.02), a higher rate of 1 or more mood episodes (61% vs 10%, P = 0.002), and a higher risk of a mood episode after CKD diagnoses (Hazard Ratio, 8.38; 95% confidence interval, 1.85-38.0 [log-rank P = 0.001]]. CONCLUSIONS: Bipolar disorder patients on LTLT who discontinued Li had a higher risk for relapse and a shorter time to the first mood episode, suggesting a need for more thorough discussion before Li discontinuation after the CKD diagnosis.

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children.

OBJECTIVE: Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. METHODS: Participants were offspring, aged 8-14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N = 3243). RESULTS: In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. CONCLUSION: We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8-14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings.

Low-level lithium in drinking water and subsequent risk of dementia: Cohort study.

BACKGROUND: Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. AIMS: We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. METHOD: Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. RESULTS: The mean lithium level at all sampling sites was 1.45 µg/L (SD 1.83, range 0.5-18.2) and was 1.26 (SD 0.63, range 0.55-9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04-1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81-1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55-0.68 µg/L) in all deciles except the highest, corresponding with lithium levels 0.68-2.1 µg/L. CONCLUSIONS: Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 µg/L.

An evaluation of the effect of lithium on taxane-induced neuropathy.

PURPOSE: No medications are known to protect against chemotherapy-induced peripheral neuropathy (CIPN). Pre-clinical models suggest that lithium may lessen taxane-induced neuropathy. Our aim was to use clinical data to assess whether concurrent lithium usage decreased the frequency or severity of CIPN in patients receiving taxane chemotherapy. METHODS: A retrospective analysis was performed using the electronic health record at Mayo Clinic to identify all patients prescribed concurrent lithium and paclitaxel. Four controls were matched to each case based on clinical variables. Neuropathy severity was graded from available patient and clinician reports. Rates of any neuropathy, dose reduction for CIPN, and treatment discontinuation for CIPN were compared. Conditional regression analysis was performed with propensity score matching. RESULTS: Six patients, receiving concurrent lithium and paclitaxel, were included in the analysis, and compared to 24 control cases. A similar number of paclitaxel cycles were administered to both groups. Any neuropathy was experienced by 33% (2/6) of patients receiving lithium and 38% (9/24) patients who did not receive lithium (p = 1.000). There was no difference in neuropathy severity (p = 0.8565), rate of chemotherapy dose reduction (17% vs. 17%, p = 1.000), or treatment discontinuation (17% vs 4%, p = 0.3655) for CIPN. In the propensity score analysis, the odds ratio for developing any neuropathy was 0.63 (95% confidence interval, 0.06 to 6.96, p = 0.7079). CONCLUSIONS: Lithium does not appear to significantly lessen the risk of neuropathy for patients receiving paclitaxel. IMPLICATIONS FOR CANCER SURVIVORS: Targeted approaches for preventing CIPN are desperately needed. Despite sound scientific rationale, the current study did not identify neuroprotective properties of lithium.

Safety and efficacy of lithium in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: This study provides a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the safety and efficacy of lithium in amyotrophic lateral sclerosis (ALS) patients. METHODS: PubMed, Web of Science, Cochrane CENTRAL, Scopus, and Your Journals@Ovid were searched up to 9 December 2022. RCTs investigating lithium, either alone or with any supplement, in ALS patients were included. Meta-analysis was performed using RevMan and results are presented in forest plot. RESULTS: Four RCTs with 469 patients met the inclusion criteria and were included in our study. Lithium doses varied among the included studies and one study used a combined therapy of lithium with valproate. Meta-analysis showed no difference between lithium and placebo regarding severe adverse events (odds ratio = 1.13, 95% confidence interval: 0.73 to 1.75, P = 0.58). No significant differences were observed with regard to survival rate between the two groups (hazard ratio = 0.95, 95% confidence interval: 0.65 to 1.37, P = 0.77). There were also no significant differences between the two groups with regard to average changes of revised amyotrophic lateral sclerosis functional rating scale (P = 0.35) and forced vital capacity percentage predicted (P = 0.73). Subgroup analysis showed no significant differences regarding all investigated outcomes either for lithium alone or lithium with valproate. CONCLUSION: Current evidence suggests a safety profile with no benefit of lithium for ALS. However, given the limited number of RCTs and the safety findings, we recommend further well-designed RCTs to investigate lithium and valproate in ALS patients.

Impact of lithium on mortality among older adults with major psychiatric disorders: A 5-year prospective multicenter study.

OBJECTIVE: Prior studies report conflicting results about the association between lithium use and all-cause mortality. In addition, data are scarce on this association among older adults with psychiatric disorders. In this report, we sought to examine the associations of lithium use with all-cause mortality and specific causes of death (i.e., due to cardiovascular disorder, non-cardiovascular disease, accident, or suicide) among older adults with psychiatric disorders during a 5-year follow-up period. METHODS: In this observational epidemiological study, we used data from 561 patients belonging to a Cohort of individuals with Schizophrenia or Affective disorders aged 55-years or more (CSA). Patients taking lithium at baseline were first compared to patients not taking lithium, and then to patients taking (i) antiepileptics and (ii) atypical antipsychotics in sensitivity analyses. Analyses were adjusted for socio-demographic (e.g., age, gender), clinical characteristics (e.g., psychiatric diagnosis, cognitive functioning), and other psychotropic medications (e.g. benzodiazepines). RESULTS: There was no significant association between lithium use and all-cause mortality [AOR=1.12; 95%CI=0.45-2.79; p=0.810] or disease-related mortality [AOR=1.37; 95%CI=0.51-3.65; p=0.530]. None of the 44 patients taking lithium died from suicide, whereas 4.0% (N=16) of patients not receiving lithium did. CONCLUSION: These findings suggest that lithium may not be associated with all-cause or disease-related mortality and might be associated with reduced risk of suicide in this population. They argue against the underuse of lithium as compared with antiepileptics and atypical antipsychotics among older adults with mood disorders.

A Single High Dose of Flufenamic Acid in Rats does not Reduce the Damage Associated with the Rat Lithium-Pilocarpine Model of Status Epilepticus but Leads to Deleterious Outcomes.

BACKGROUND: Epilepsy is one of the most common neurologic diseases, and around 30% of all epilepsies, particularly the temporal lobe epilepsy (TLE), are highly refractory to current pharmacological treatments. Abnormal synchronic neuronal activity, brain glucose metabolism alterations, neurodegeneration and neuroinflammation are features of epilepsy. Further, neuroinflammation has been shown to contribute to dysregulation of neuronal excitability and the progression of epileptogenesis. Flufenamic acid (FLU), a non-steroidal anti-inflammatory drug, is also characterized by its wide properties as a dose-dependent ion channel modulator. In this context, in vitro studies have shown that it abolishes seizure-like events in neocortical slices stimulated with a gamma-aminobutyric acid A (GABAA) receptor blocker. However, little is known about its effects in animal models. Thus, our goal was to assess the efficacy and safety of a relatively high dose of FLU in the lithium-pilocarpine rat model of status epilepticus (SE). This animal model reproduces many behavioral and neurobiological features of TLE such as short-term brain hypometabolism, severe hippocampal neurodegeneration and inflammation reflected by a marked reactive astrogliosis. METHODS: FLU (100 mg/kg, i.p.) was administered to adult male rats, 150 min before SE induced by pilocarpine. Three days after the SE, brain glucose metabolism was assessed by 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) positron emission tomography (PET). Markers of hippocampal integrity, neurodegeneration and reactive astrogliosis were also evaluated. RESULTS: FLU neither prevented the occurrence of the SE nor affected brain glucose hypometabolism as assessed by [18F]FDG PET. Regarding the neurohistochemical studies, FLU neither prevented neuronal damage nor hippocampal reactive astrogliosis. On the contrary, FLU increased the mortality rate and negatively affected body weight in the rats that survived the SE. CONCLUSIONS: Our results do not support an acute anticonvulsant effect of a single dose of FLU. Besides, FLU did not show short-term neuroprotective or anti-inflammatory effects in the rat lithium-pilocarpine model of SE. Moreover, at the dose administered, FLU resulted in deleterious effects.

Antiepileptogenic Effects of Anakinra, Lamotrigine and Their Combination in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Case Reports: Exposure to SARS-CoV-2, Acute Kidney Injury, and Lithium Toxicity.

PURPOSES: The aims of the study were to review 3 cases of lithium toxicity among individuals with bipolar disorder who were diagnosed with COVID-19 and to review the literature discussing the implications of COVID-19 and exposure to SARS-CoV-2 relative to medical use of lithium in management of bipolar disorder. METHODS: This is a case review of medical and psychiatric notes of 3 individuals with bipolar disorder, managed with lithium, who developed COVID-19. This study discussed these cases in context of previous case reports and relevant literature pertaining to lithium and exposure to SARS-CoV-2. FINDINGS: Infection with SARS-CoV-2 along with symptoms of COVID-19 and mental state changes in three individuals were temporally associated with lithium levels in the toxic range. IMPLICATIONS: Exposure to SARS-CoV-2 or symptoms suggestive of COVID-19 should result in increased clinical monitoring of individuals taking lithium. Those taking lithium and providers are advised to have a low clinical threshold for requesting lithium levels and kidney function estimates for the duration of the COVD-19 pandemic.

Renal function after withdrawal of lithium.

OBJECTIVES: Patients on chronic lithium therapy sometimes develop chronic kidney disease. For clinical decision-making, it is important to know whether discontinuation of lithium can lead to improvement of renal function. We studied the trajectory of renal function in a population previously on chronic lithium therapy. METHODS: From a large database of patients on chronic lithium therapy, we selected a group of patients who stopped using lithium and whose creatinine values at least half a year after lithium withdrawal were available. We measured the slope of renal function (eGFR) before and after discontinuation of lithium. We compared the subgroup of patients with improvement of the renal function with those who showed further deterioration of the eGFR. RESULTS: eGFR slope significantly improved after discontinuation of lithium. Of patients with chronic kidney disease stage 3 or more (eGFR<60 ml/min), the vast majority showed an increase of eGFR or a decrease in the rate of decline after lithium withdrawal. The group of patients with further deterioration of the renal function had a mean eGFR of 32 ml/min, which was significantly lower than the patients with an improvement of the kidney function. CONCLUSIONS: Discontinuation of lithium leads in the majority of patients to improvement in renal function or at least less rapid deterioration.

Prevalence of impaired kidney function in patients with long-term lithium treatment: A systematic review and meta-analysis.

OBJECTIVES: Although lithium renal effects have been extensively investigated, prevalence rates of chronic kidney disease (CKD) in lithium-treated patients vary. Our aim was to provide prevalence estimates and related moderators. METHODS: We performed a systematic review in PubMed/Embase until November 01, 2021, conducting a random effects meta-analysis of studies evaluating CKD prevalence rates in lithium-treated patients calculating overall prevalence ±95% confidence intervals (CIs). Meta-regression analyses included sex, age, body mass index, smoking, hypertension, diabetes, cardiovascular disease, lithium-treatment dose, duration, and blood levels. Subgroup analyses included sample size, diagnoses, and study design. Pooled odds ratios (OR) were estimated for studies including patients receiving nonlithium treatment. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: Five, nine, and six trials were rated as high, fair, and low quality, respectively. In 20 studies (n = 25,907 patients), we estimated an overall prevalence of 25.5% (95% CI = 19.8-32.2) of impaired kidney function; despite lack of differences (p = 0.18), prevalence rates were higher in elderly samples than mixed samples of elderly and nonelderly (35.6%, 95% CI = 21.4-52.9, k = 2, n = 3,161 vs. 25.1%, 95% CI = 19.1-31.3, k = 18, n = 22,746). Prevalence rates were associated with longer lithium treatment duration (p = 0.04). Cross-sectional studies provided lower rates than retrospective studies (14.5%, 95% CI = 13.5-15.5, k = 6, n = 4,758 vs. 29.5%, 95% CI = 22.1-38.0, k = 12, n = 17,988, p < 0.001). Compared with 722,529 patients receiving nonlithium treatment, the OR of impaired kidney function in 14,187 lithium-treated patients was 2.09 (95% CI = 1.24-3.51, k = 8, p = 0.005). CONCLUSIONS: One-fourth of patients receiving long-term lithium may develop impaired kidney function, although research suffers from substantial heterogeneity between studies. This risk may be twofold higher compared with nonlithium treatment and may increase for a longer lithium treatment duration.

Modafinil exerts anticonvulsive effects against lithium-pilocarpine-induced status epilepticus in rats: A role for tumor necrosis factor-α and nitric oxide signaling.

BACKGROUND: Status epilepticus (SE) is a continuous episode of seizures which leads to hippocampal neurodegeneration, severe systemic inflammation, and extreme damage to the brain. Modafinil, a psychostimulant and wake-promoting agent, has exerted neuroprotective and anti-inflammatory effects in previous preclinical studies. The aim of this study was to assess effects of modafinil on the lithium-pilocarpine-induced SE rat model and to explore possible involvement of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) pathways in this regard. METHODS: Status epilepticus was provoked by injection of lithium chloride (127 mg/kg, intraperitoneally [i.p]) and pilocarpine (60 mg/kg, i.p.) in rats. Animals received different modafinil doses (50, 75, 100, and 150 mg/kg, i.p.) and SE scores were documented over 3 hours of duration. Moreover, the role of the nitrergic pathway in the effects of modafinil was evaluated by injection of the non-selective NO synthase (NOS) inhibitor L-NG-Nitro arginine methyl ester (L-NAME, 10 mg/kg, i.p.), the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg, i.p.), and the selective inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) 15 min before saline/vehicle or modafinil. The ELISA method was used to quantify TNF-α and NO metabolite levels in the isolated hippocampus. RESULTS: Modafinil at 100 mg/kg significantly decreased SE scores (P < 0.01). Pre-treatment with L-NAME, 7-nitroindazole, and aminoguanidine significantly reversed the anticonvulsive effects of modafinil. Status epilepticus-induced animals showed significantly higher NO metabolite and TNF-α levels in their hippocampal tissues, an effect that was reversed by modafinil (100 mg/kg, i.p.) treatment. Administration of NOS inhibitors resulted in excessive NO level reduction but an escalation of TNF-α level in modafinil-treated SE-animals. CONCLUSION: Our study revealed anticonvulsive effects of modafinil in the lithium-pilocarpine-induced SE rat model via possible involvement of TNF-α and nitrergic pathways.

Investigating the protective role of metformin on lithium-induced hypothyroidism.

Induction of oxidative stress events has been shown to be associated with lithium (Li) hypothyroidism induction. Metformin (MET) is a commonly used antidiabetic drug with multiple properties including antiproliferative activity, antioxidant potency, and is used in polycystic ovarian syndrome treatment. Here, in this study, we aimed to investigate the effect of different doses of MET on Li-induced hypothyroidism for elucidating its mechanism of action. The obtained results demonstrated the oxidative stress reduction in thyroid tissues upon MET treatment. Besides this, the biochemical analysis revealed a significant reduction in T3 and TSH levels (down to 2 ng/ml and 0.05 µU/ml, respectively) in coordination with an observable reduction in T4 level (up to 2.1 ng/ml). Also, a significant reduction in Li-related tissue damages including changes in the morphology and the size of follicles, rate of vascularity, detachment of follicular cells, inflammatory cells infiltration, and follicular cells hypertrophy and disruption was observed. Ultimately, regarding the significant improvement in thyroid tissues and valuable antioxidant activity determined in tissues treated with MET, it is concluded that MET co-administration with Li can significantly reduce the negative effects of Li and enhance the efficacy of Li therapy.

Electroconvulsive therapy combined with lithium developed reversible pure anomic aphasia: a case report.

BACKGROUND: Electroconvulsive therapy (ECT) combined with mood stabilizers is an effective method of treatment for manic episodes; however, there are controversial views on its side effects. CASE PRESENTATION: A 53-year-old man was diagnosed with bipolar disorder during a manic episode, and had previous conditions such as hypertension, and diabetes. He developed reversible delirium and anomic aphasia during combined treatment with lithium and ECT (Li-ECT). No other neurological symptoms or signs happened during the one-month follow-up period. CONCLUSIONS: The anomic aphasia appeared after ECT was reversible. Li-ECT should be administered with caution to middle- and older-aged patients with comorbidities, and serum Li levels should be closely monitored during the treatment period.

Lithium use during breastfeeding was safe in healthy full-term infants under strict monitoring.

AIM: Previous studies on breastfeeding during lithium therapy have shown conflicting results. The aim of this study was to evaluate the safety when practising thorough follow-up of the infants. METHOD: This retrospective study focused on women with lithium medication, and their breastfed infants born between 2006 and 2021 in Stockholm, Sweden. Information about infant serum lithium concentrations and clinical status was collected from medical records. RESULTS: In total, 30 infants exposed to lithium through breastmilk, 21 girls and 9 boys, were included. The median age at follow-up was 40 days (range 8-364 days). The median lithium serum concentration was 0.10 mmol/L in the second week of life (range <0.05-0.7 mmol/L), 0.08 in week 2-4 (range <0.05-1.2), 0.06 in the second month of life (range <0.05-0.2) and 0.07 after 2 months of age (range <0.05-0.2). Unexpectedly high lithium concentrations were found in two infants in the first month of life. Apart from poor weight gain, no adverse effects were found. CONCLUSION: Serum lithium concentrations in breastfed infants were stabilised at barely measurable levels after the first weeks of life. Before that, concentrations higher than the mothers were found. Lithium treatment during breastfeeding can be considered safe under strict follow-up.

Genetic background determines renal response to chronic lithium treatment in female mice.

Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose, and duration of treatment are important risk factors, whereas genetic background might also play an important role. To investigate the role of genetics, female mice of 29 different inbred strains were treated for 1 year with control or lithium chow and urine, blood, and kidneys were analyzed. Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, whereas in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, whereas eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, whereas the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary ß2-microglobulin (ß2M) levels, an indicator of proximal tubule damage. Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary ß2M levels indicates that ß2M is a promising biomarker for chronic renal damage induced by lithium.