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Lithium Carbonate is an effective treatment for affective disorders, but has a range of side effects. This case report highlights a rare side effect of Raynaud’s phenomenon following initiation of Lithium therapy in a patient with recurrent depressive disorder. He was commenced on Lithium therapy to treat severe treatment resistant depression with psychotic symptoms when alternative treatments trialled were ineffective. He had no other risk factors or known aetiological causes for development of Raynaud’s phenomenon. Symptoms resolved on discontinuation of Lithium and re-emerged on recommencement. Previous case series have shown Lithium effectively treating vasospastic disorders such as cluster headache and Raynaud’s phenomenon. However, a paradoxical reaction to those previously described was induced in this case.

In 2019 in the US, 7,085 toxic lithium exposures were documented. This refers to substantial exposures that may have resulted in a clinical outcome of at least moderate severity. Of these, 22% resulted in serious clinical consequences, including 4 deaths. Lithium has a narrow therapeutic index and a wide range of toxicities. It is an effective and widely prescribed therapy for bipolar disorder and is also used off label for other psychiatric disorders. It is available in both immediate-release and sustained-re lease preparations. The recommended therapeutic range varies with patient age, owing to age-related changes in renal function and increased prevalence of polypharmacy and drug interactions. Lithium is an inorganic monovalent cation with a small molecular weight of 7 Da. It is rapidly absorbed, not protein bound, has a low volume of distribution between 0.6 and 0.9 L/kg, and is freely excreted unchanged via the kidneys. Here, Kobylianskii et al examine the case of 54-year-old woman with chronic lithium toxicity.

Background Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. Methods Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. Results The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW 0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a ≥50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies. Conclusions When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.

Background Hyperthyroidism poses challenges, and common treatments like Radioactive Iodine (RAI) have limitations, prompting exploration of adjunctive approaches. This meta-analysis evaluates the combined impact of RAI and Lithium carbonate (LiCO3) on cure rates and thyroid hormone levels. Methods We systematically searched Cochrane Library, PubMed, Scopus, and Web of Science for studies comparing LiCO3 combined with RAI to RAI alone. Pooled results analyzed cure rates and Free T3/T4 changes. A subgroup analysis was conducted based on LiCO3 dosage and treatment duration, while meta-regression was performed to assess covariates such as the patient’s age, RAI dose, and lithium dose. The risk of bias was evaluated using ROB2, ROBINS-1, and NOS, while the statistical analyses were conducted using Revman software 5.4.1. Results Analysis of 14 studies involving 2047 patients revealed a significantly increased cure rate with RAI and LiCO3 compared to RAI alone (RR 1.12, 95% CI [1.03,1.23], p  = 0.01). Subgroup analysis revealed higher cure rates with short-duration intensified doses of LiCO3, while short-duration diluted doses reduced cure rates. No significant differences were noted in euthyroid and hypothyroid states. Changes in free T3 showed no significant difference between the arms at 7 days and the most common time point. A significant decrease in free T4 favored RAI with LiCO3 at 7 days (MD -4.90, 95% CI [-7.91, -1.89], p  = 0.001), and the most common time point (MD -3.83, 95% CI [-7.45, -0.20], p  = 0.04). Meta-regression analysis indicated better cure rates in older patients ( p  < 0.001) and lower total lithium doses ( p  < 0.001). Conclusion Treatment with RAI combined with LiCO3 significantly enhanced cure rates, particularly when using short-duration intensified doses of LiCO3. Additionally, LiCO3 effectively reduced T4 levels without altering T3 levels. Future research is needed to validate our findings. Clinical trial number Not applicable.

Objective Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and serious side effect of many cytotoxic drugs, including paclitaxel. Despite the identification of treatment options in animal models, clinical trials for the treatment or prevention of CIPN have been negative. Major challenges for successful clinical translation of preclinical data include a lack of reproducibility and randomization, small sample sizes and insufficient statistical tests. We therefore conducted a confirmatory, preclinical multicenter randomized controlled replication trial to test the safety and efficacy of three drugs for preventing paclitaxel-induced polyneuropathy: (1) nilotinib, (2) lithium carbonate and (3) interleukin-6-neutralizing antibodies. We preregistered the data analysis plan as well as the two-step study protocol: the optimal doses of the three compounds were assessed first and then tested in a mouse breast cancer xenograft model to compare safety and efficacy. Results Unfortunately, toxicity of intraperitoneally administered nilotinib in combination with paclitaxel was observed, and higher-than-expected tumor growth resulted in a lack of power when the trial was analyzed. Thus, although lithium carbonate and IL-6-neutralizing antibodies tended toward neuroprotection, the differences between these groups were not statistically significant. However, the PINPRICS study ultimately still provides important lessons with regard to the planning and conduction of multicenter preclinical trials.

Reddy and Reddy (2014) discuss the optimal timing for lithium levels in patients taking once-daily extended-release lithium formulations. They argue for blood sampling 24 h after the previous dose rather than the standard 12 h. I interpret the data quite differently. The authors start with the assumption that the clinician wants a trough level. I disagree. What one wants is to be able to compare a patient's lithium level to the large body of published knowledge about lithium dosing. Almost all of that data comes from standard 12-h blood draws with plain (immediate-release) lithium carbonate or lithium citrate. So, the real question of interest is, with extended-release lithium formulations, at what time point does one draw the lithium level to compare most accurately with a standard 12-h blood draw with plain lithium carbonate? The answer is not obvious because extended-release formulations affect only the absorption and not the excretion of lithium. Their primary benefit is reducing the transient peak lithium serum concentration, not delaying the (already relatively slow) elimination of lithium. Emami and colleagues (2004) provide the needed data. First they show that 90% of the administered dose of a commercial extended-release formulation (Eskalith CR ®) is absorbed by 4 h after a dose, and ~100% is absorbed by 8 h (their Figure 2A). Second, they show that at 12 h after a dose, the blood levels for immediate and extended release formulations are essentially identical (their Figure 3).  Thus 12 h after the previous dose is the ideal time for drawing blood levels for extended-release lithium tablets.

RationaleTreatment of bipolar disorder (BPD) with lithium and olanzapine concurrent administration is a major medicine issue with the elusive neurobiological mechanisms underlying the cognitive function.ObjectiveTo clarify the precise mechanisms involved, the possible role of the hippocampus (HPC) and prefrontal cortical (PFC) NMDA receptors and CAMKII-CREB signaling pathway in the interactive effects of lithium and olanzapine in memory consolidation was evaluated. The dorsal hippocampal CA1 regions of adult male Wistar rats were bilaterally cannulated and a step-through inhibitory avoidance apparatus was used to assess memory consolidation. The changes in p-CAMKII/CAMKII and p-CREB/CREB ratio in the HPC and the PFC were measured by Western blot analysis.ResultsPost-training administration of lithium (20, 30, and 40 mg/kg, i.p.) dose-dependently decreased memory consolidation whereas post-training administration olanzapine (2 and 5 mg/kg, i.p.) increased memory consolidation. Post-training administration of certain doses of olanzapine (1, 2, and 5 mg/kg, i.p.) dose-dependently improved lithium-induced memory impairment. Post-training administration of ineffective doses of the NMDA (10−5 and 10−4 μg/rat, intra-CA1) plus an ineffective dose of olanzapine (1 mg/kg, i.p.) dose-dependently improved the lithium-induced memory impairment. Post-training microinjection of ineffective doses of the NMDA (10−5 and 10−4 μg/rat, intra-CA1) dose-dependently potentiated the memory improvement induced by olanzapine (1 mg/kg, i.p.) on lithium-induced memory impairment which was associated with the enhancement of the levels of p-CAMKII and p-CREB in the HPC and the PFC. Post-training microinjection of ineffective doses of the noncompetitive NMDA receptor antagonist, MK-801 (0.0625 and 0.0125 μg/rat, intra-CA1), dose-dependently decreased the memory improvement induced by olanzapine (5 mg/kg, i.p.) on lithium-induced memory impairment which was related to the reduced levels of HPC and PFC CAMKII-CREB.ConclusionThe results strongly revealed that there is a functional interaction among lithium and olanzapine through the HPC and the PFC NMDA receptor mechanism in memory consolidation which is mediated with the CAMKII-CREB signaling pathway.

Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li CO ). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li CO . Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

In any animal model of human disease a positive control therapy that demonstrates efficacy in both the animal model and the human disease can validate the application of that animal model to the discovery of new therapeutics. Such a therapy has recently been reported by Fornai et al. using chronic lithium carbonate treatment and showing therapeutic efficacy in both the high-copy SOD1G93A mouse model of familial amyotrophic lateral sclerosis (ALS), and in human ALS patients. Seeking to verify this positive control therapy, we tested chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using the high-copy (average 23 copies) SOD1G93A mouse (n = 27-28/group). Lithium-treated mice received single daily 36.9 mg/kg i.p. injections from 50 days of age through death. This dose delivered 1 mEq/kg (6.94 mg/kg/day lithium ions). Neurological disease severity score and body weight were determined daily during the dosing period. Age at onset of definitive disease and survival duration were recorded. Summary measures from individual body weight changes and neurological score progression, age at disease onset, and age at death were compared using Kaplan-Meier and Cox proportional hazards analysis. Our study did not show lithium efficacy by any measure. Rigorous survival study design that includes sibling matching, gender balancing, investigator blinding, and transgene copy number verification for each experimental subject minimized the likelihood of attaining a false positive therapeutic effect in this standard animal model of familial ALS. Results from this study do not support taking lithium carbonate into human clinical trials for ALS.

Bipolar disorder is a recurrent chronic illness distinguished by periods of mania and depression. Lithium has been used for about 60 years as a ‘mood stabilizer’ for bipolar disorder with proven efficacy in preventing relapse of both mania and depression. Despite its long history and ongoing use in current management of bipolar disorder, the optimal dosing of lithium is still the subject of ongoing debate. This article aims to evaluate different dosing schedules, in the light of the unique pharmacokinetic and pharmacodynamic properties of lithium, as well as its adverse-effect and toxicity profiles. This is all the more important given the narrow therapeutic index of lithium. Current recommendations mostly advocate that lithium be administered in multiple daily doses. However, single daily or alternate daily schedules may be viable options for administration. Multiple daily schedules are thought to be advantageous in maintaining more constant plasma lithium concentrations than single daily regimens, which are associated with significant fluctuations throughout the day. When comparing these two schedules with respect to plasma lithium concentrations, adverse-effect profiles and recurrence of symptoms, there are no significant differences between the two regimens. In fact, a single daily regimen may have added advantages in reducing the risk of long-term renal damage and increasing compliance. The evidence for alternate daily dosing is somewhat varied with regard to symptom recurrence; however, this schedule has been shown to be associated with decreased adverse effects, and further research into this issue is therefore warranted. Presently, therefore, clinicians should consider single daily administration of lithium to potentially minimize adverse effects and enhance compliance.