Plasma Lithium Concentrations Research Articles

Low exposition to lithium prevents nephrogenic diabetes insipidus but not microcystic dilations of the collecting ducts in long-term rat model.

Lithium induces nephrogenic diabetes insipidus (NDI) and microcystic chronic kidney disease (CKD). As previous clinical studies suggest that NDI is dose-dependent and CKD is time-dependent, we investigated the effect of low exposition to lithium in a long-term experimental rat model. Rats were fed with a normal diet (control group),with the addition of lithium (Li+ group), or with lithium and amiloride (Li+/Ami group) for 6 months, allowing obtaining low plasma lithium concentrations (0.25 ± 0.06 and 0.43 ± 0.16 mmol/L, respectively). Exposition to low concentrations of plasma lithium levels prevented NDI but not microcystic dilations of kidney tubules, which were identified as collecting ducts (CDs) on immunofluorescent staining. Both hypertrophy, characterized by an increase in the ratio of nuclei per tubular area, and microcystic dilations were observed. The ratio between principal cells and intercalated cells was higher in microcystic than in hypertrophied tubules. There was no correlation between AQP2 messenger RNA levels and cellular remodeling of the CD. Additional amiloride treatment in the Li+/Ami group did not allow consistent morphometric and cellular composition changes compared to the Li+ group. Low exposition to lithium prevented overt NDI but not microcystic dilations of the CD, with differential cellular composition in hypertrophied and microcystic CDs, suggesting different underlying cellular mechanisms.

Achieving and Maintaining Effective Plasma Concentration of Lithium After Oral Administration

The aim of the study. To study the achievability and contingency to maintain an effective plasma lithium concentration in the perioperative period in patients undergoing carotid endarterectomy (CEAE) with oral intake of lithium carbonate pills.Materials and methods. It was a prospective study, as a preparatory stage of the multicenter «BINOS» (NCT05126238) RCT. The sample included 15 patients undergoing elective CEAE. In the course of this study, patients were administered oral lithium carbonate, 900 mg per day during 4 perioperative days: two days before the procedure, in the day of surgery and in the 1st postoperative day. Plasma lithium concentration was monitored every 24 hours during all 4 days from the onset of treatment.Results. Increased plasma lithium concentrations were found in blood samples taken at 48 hours (0.68 mmol/l [0.53–0.84, P = 0.004) and 72 hours (0.68 mmol/l [0.62–0.90, P < 0.001), as compared with the initial values (0.14 mmol/l [0.11–0.17).While during the period between 48 and 72 hours from the onset of treatment the plasma lithium concentration remained in the therapeutic range (0.4–1.2 mmol/l) in 100% of patients.Conclusion. Oral intake of lithium carbonate pills at a dose of 900 mg/day during 2 preoperative days provided an effective and safe plasma lithium concentration in 100% of patients enrolled in the study.

Early Postnatal Outcome and Care after in Utero Exposure to Lithium: A Single Center Analysis of a Belgian Tertiary University Hospital.

Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36–39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56–0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87–1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8–12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed.

Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden

Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin-aldosterone-angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; β=-0·053 [95% CI -0·071 to -0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.

Lithium placental passage at delivery and neonatal outcomes: A retrospective observational study

Introduction Lithium is an effective mood stabilizer and is widely used as a first-line treatment for bipolar disorder in the perinatal period. Several guidelines have provided clinical advice on dosing strategy (dose reduction versus stop lithium) in the peripartum period to minimize the risk of neonatal complications. An association has been observed between high neonatal lithium concentrations (&gt; 0.64 mEq/L) and lower 1-min Apgar scores, longer hospital stays, and central nervous system and neuromuscular complications.ObjectivesTo quantify the rate of lithium placental passage at delivery. To assess any association between plasma concentration of lithium at delivery and neonatal outcome.Methods In this retrospective observational cohort study, we included women treated with llithium at least in late pregnancy. Maternal (MB) and umbilical cord (UC) lithium blood level measurement were collected at delivery. Lithium serum concentrations were determined by means of an AVL 9180 electrolyte analyzer. The limit of quantification (LoQ) was 0.20 mEq/L and detection limit was 0.10 mEq/L. From the medical records, we extracted information on neonatal outcomes (preterm birth, birth weight, Apgar scores, pH-values, and admision to NICU) and complications categoriced by organ system: respiratory, circulatory, hematological, gastro-intestinal, metabolic, neurological, and immune system (infections).ResultsUmbilical cord and maternal lithium blood levels were strongly correlated: mean (SD) range UC/MR ratio 1.15 (0.24). Umbilical cord lithium levels ranged between 0.20 to 1.42 mEq/L. We observed no associations between umbilical cord lithium blood levels at delivery and neonatal outcomes.ConclusionsIn our study, newborns tolerated well a wide range of lithemias, between 0.20 and 1.42 mEq/L.

Infant exposure to lithium through breast milk

IntroductionWomen who take lithium during pregnancy and continue after delivery may opt to breastfeed, formula feed, or mix these options.ObjectivesTo evaluate the neonatal lithium plasma concentrations and nursing infant outcomes based on these three feeding trajectories.MethodsWe followed 24 women with bipolar disorder on lithium monotherapy during late pregnancy and postpartum (8 per trajectory). Lithium serum concentrations were determined by an AVL 9180 electrolyte analyser with a 0.10 mEq/L detection limit and a 0.20 mEq/L limit of quantification (LoQ).ResultsThe mean ratio of lithium concentration in the umbilical cord to maternal serum being 1.12 (0.17). We used the Turnbull estimator for interval-censored data to estimate the probability that the LoQ was reached as a function of time. The median times to LoQ was 6–8, 7–8, and 53–60 days for formula, mixed, and breastfeeding, respectively. Generalised log-rank testing indicated that the median times to LoQ differed by feeding trajectory (p = 0.037). Multivariate analysis confirmed that the differences remained after adjusting for serum lithium concentrations at birth (formula, p = 0.015; mixed, p = 0.012). We did not found any acute observable growth or developmental delays in any of the neonates/infants.ConclusionsLithium did not accumulate in the infant under either exclusive or mixed-breastfeeding. Lithium concentrations declined in all trayectories. The time needed to reach the LoQ was much longer for those breastfeeding exclusively. Lithium transfer via breastmilk is much less than via the placenta. We did not found any acute observable growth or developmental delays in any infant during follow-up.DisclosureNo significant relationships.

Effect of a New Lithium Preparation on the Behavior of CBA/CaLac Mice in an Experimental Conflict Model.

The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.

Estimation of lithium clearance in patients with bipolar disorder.

Lithium is an effective agent approved for the treatment of bipolar disorder. It has narrow therapeutic window and significant variability in its pharmacokinetic. The aim of this study is to determine the population pharmacokinetics of lithium in patients with bipolar disorder in Saudi Arabia and to identify the factors that explain variability. A retrospective chart review was performed on patients with bipolar disorder who received oral lithium. The population pharmacokinetic models were developed using Monolix 4.4. After the appropriate base model was established, five covariates were tested, namely age, sex, weight, serum creatinine, and creatinine clearance. The analysis included a total of 170 lithium plasma concentrations from 31 patients. The data were adequately described by a two-compartment open model with linear absorption and elimination. The average parameter estimates for lithium CL/F, V1/F, V2/F, and Q/F were estimated. The inter-individual variability (coefficients of variation) in CL was 42%. The most significant covariate on lithium CL was found to be creatinine clearance. The population pharmacokinetic model of lithium in patients with bipolar disorder in Saudi Arabia was established. Our findings showed that creatinine clearance is the most significant covariate on lithium clearance. Further studies are required to understand the factors that may influence the pharmacokinetics of lithium and assist in drug dosage decisions.

Seasonal and temperature effect on serum lithium concentrations

Lithium remains the gold standard treatment for bipolar disorder. However, it has a very narrow therapeutic index (0.6-0.8 mmol/L). It has been suggested that high environmental temperature can lead to dehydration, elevated plasma lithium concentration and then lithium toxicity. We aimed to investigate the effect of seasonal and short-term changes in temperature on serum lithium concentrations in Sydney, Australia. We retrospectively analysed data from all patients who had serum lithium concentrations taken from the Prince of Wales and Sutherland Hospitals between 2008 and 2018. Temperature data came from the Bureau of Meteorology. We examined correlations between lithium concentrations and the preceding 5 days maximum temperatures, month and season. We also performed a longitudinal analysis of the effect of temperature and seasons within selected patients who had repeated levels. A total of 11,912 serum lithium concentrations from 2493 patients were analysed. There was no significant association between higher lithium concentration and preceding higher temperatures (r = -0.008, p = 0.399). There was also no important seasonal or monthly variation, across all patients or in the smaller cohort with longitudinal data (n = 123, r = 0.008, 95% confidence interval: [-0.04, 0.06]). There were no clinically important differences in serum lithium concentration related to seasons, months or temperatures, which suggests that patients on lithium are able to adequately maintain hydration during hot weather in Sydney.

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.

Effect of acetazolamide on lithium reabsorption and lithium-induced GSK3β phosphorylation in rat kidney.

Lithium promotes the phosphorylation of glycogen synthase kinase-3β (GSK3β), and this reaction protects against acute kidney injury mediated by renal apoptosis. Lithium is considered to be reabsorbed by sodium-phosphate cotransporters and sodium-proton exchanger NHE3. This study evaluated the relation between the lithium reabsorption and the phosphorylation of GSK3β, by using acetazolamide, an NHE3 inhibitor. In rats infused with lithium chloride, the plasma concentration of lithium was 4.77 mEq/l, and the renal clearance of lithium and its fractional excretion were calculated to be 2.29 ml/min/kg and 0.405, respectively. Coadministration of acetazolamide decreased creatinine clearance and the reabsorption rate of lithium, increased the fractional excretion of lithium, and did not affect its plasma concentration. Western blot analysis exhibited the facilitation of GSK3β phosphorylation in the kidney cortex by lithium infusion, and acetazolamide inhibited the lithium-induced phosphorylation of GSK3β. Lithium did not affect GSK3β phosphorylation in the liver and did not affect Akt in the kidney cortex and liver. These data show that lithium reabsorption contributes to GSK3β phosphorylation in the kidney cortex.

Methodology for rapid assessment of blood lithium levels in ultramicro volumes of blood plasma for applications in personal monitoring of patients with bipolar mood disorder.

Bipolar disorder (BD) is a common mental health condition, characterized by extreme changes in mood, energy, and behavior. BD is often managed through mood-stabilizing medications, of which lithium formulations remain the most reliable and effective at reducing the risk of suicide. To achieve adequate and consistent efficacy, lithium concentrations need to be maintained within a narrow therapeutic range (0.4 to 1.2 mmol / L). Because of its narrow therapeutic index, long-term lithium therapy is associated with serious side effects and risks of toxicity. It is believed that the availability of a personal blood lithium analyzer would benefit patients who are on lithium treatment. We detail the results of a spectrophotometric method performed on ultramicro volumes to determine blood plasma lithium concentrations as compared with reference measurements of flame photometry, and validated in samples of unknown lithium content. Applying multiple linear regression, lithium concentrations could be determined in a rapid manner using full-range spectra or triwavelength data. Both techniques highly correlated with reference standards and could predict lithium levels accurately (R2 = 0.794214 and RMSEP = 0.209584, and R2 = 0.863921 and RMSEP = 0.167524, respectively). Therefore, this method can be a useful for rapid assessment of blood lithium in nonlaboratory settings i.e., general practices, hospital clinics, and community health centers by healthcare professionals and/or by patients. Future work will now focus on completion of a miniaturized and integrated system that will deliver a portable and personal lithium-monitoring device.

Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2T.

Lithium is the first-line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood-brain barrier remain poorly understood. The contribution of lithium-7 magnetic resonance imaging (7 Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo-spin-echo imaging sequence at 17.2T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B1 inhomogeneities and differential T1 and T2 weighting. Our MRI-derived lithium concentrations were validated by comparison with inductively coupled plasma-mass spectrometry (ICP-MS) measurements ([Li]MRI =1.18[Li]MS , R=0.95). Overall, a sensitivity of 0.03mmol/L was achieved for a spatial resolution of 16μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain-to-plasma lithium ratio was 0.34±0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90.

Simulating therapeutic drug monitoring results for dose individualisation to maintain investigator blinding in a randomised controlled trial

BackgroundTherapeutic drug monitoring (TDM) is essential practice when dosing drugs with a narrow therapeutic index in order to achieve a plasma drug concentration within a narrow target range above the efficacy concentration but below the toxicity concentration. However, TDM with dose individualisation is challenging during a double-blind clinical trial with laboratory staff and investigators blinded to treatment arm allocation.MethodsDrug concentrations were simulated for participants in the placebo arm by an unblinded independent statistician, utilising the measured values from the treatment arm participants. Simulated and actual concentrations were re-blinded and passed on to a dose-adjusting investigator, who made dose adjustment recommendations but was not directly responsible for clinical care of participants.ResultsA total of 257 sham lithium plasma concentrations were simulated utilising 242 true lithium plasma concentrations in real time as the trial progressed. The simulated values had a median (interquartile range) of 0.59 (0.46, 0.72) compared to 0.53 (0.39, 0.72) in the treatment arm. Blinding of the laboratory staff and dose-adjusting investigator was maintained successfully.ConclusionsWe succeeded in simulating sham lithium plasma concentrations while maintaining blinding. Our simulated values have a smaller range than the observed data, which can be explained by the challenges with respect to drug adherence and dose timing that were experienced.Trial registrationPan African Clinical Trials Registry, PACTR201310000635418. Registered on 30 August 2013.

The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines

BackgroundLithium is an effective mood stabilizer that is used principally for the management of bipolar disorder (BD). Its administration is complex and often requires sophisticated management and assiduous monitoring. When considering the use of lithium therapy for bipolar disorder, clinicians are advised to refer to recommendations outlined in clinical practice guidelines (CPGs); but because of varying emphases placed by different international CPGs, recommendations addressing the practical use of lithium lack consistency. MethodIn order to inform clinicians of optimal lithium therapy for bipolar disorder, we compared and synthesized recommendations for the treatment of bipolar disorder made by recognized CPGs internationally. We conducted a search of the literature and extracted guidance across multiple clinical issues, including clinical indications, disorder subtypes, additional uses, special populations, practical aspects, and side effects. ResultsCollectively, CPGs consider lithium most robustly as a first-line intervention for maintenance treatment of bipolar disorder and strongly for the treatment of mania, with relatively modest support for the management of acute bipolar depression. Additionally, there is consensus across the CPGs that lithium tangibly reduces the risk of suicide. Generally, CPGs provide guidance on the many facets of initiating and maintaining patients on lithium therapy, but individually the CPGs varied in terms of depth and practical guidance they provide across these areas. However, consensus was established across many key areas of practice such as the ideal lithium plasma concentration for maintenance and monitoring (0.6–0.8mmol/L), along with the need for regular monitoring of renal and endocrine function. However, with more complex aspects (e.g., atypical presentations) and in special populations (e.g., youth; pregnancy and post-partum; older adults), guidance varied considerably and clear consensus recommendations were more difficult to achieve. In younger adults desirable plasma lithium levels of 0.6–0.8mmol/L can perhaps be achieved with comparatively lower doses and in the very elderly it may be prudent to target lower plasma levels in the first instance. These are important practical points for consideration that, along with many others offered throughout the article, should assist clinicians in dissecting the more complex aspects of management with greater precision. LimitationsThis review was limited to CPGs written in English. CPGs are themselves limited by reliance on evidence that often has little resemblance to real-world presentations. An important area that is not sufficiently addressed in the CPGs is clear guidance on the cessation of lithium therapy. ConclusionsFurther research is needed on many aspects of lithium therapy and this alongside existing knowledge needs to be used more consistently to inform CPGs, which should also incorporate empirical evidence and clinical experience. The recommendations in this paper provide a useful synthesis of guidance available currently.

Electroencephalographic patterns of lithium poisoning: a study of the effect/concentration relationships in the rat

Lithium overdose may result in encephalopathy and electroencephalographic abnormalities. Three poisoning patterns have been identified based on the ingested dose, previous treatment duration and renal function. Whether the severity of lithium-induced encephalopathy depends on the poisoning pattern has not been established. We designed a rat study to investigate lithium-induced encephalopathy and correlate its severity to plasma, erythrocyte, cerebrospinal fluid and brain lithium concentrations previously determined in rat models mimicking human poisoning patterns. Lithium-induced encephalopathy was assessed and scored using continuous electroencephalography. We demonstrated that lithium overdose was consistently responsible for encephalopathy, the severity of which depended on the poisoning pattern. Acutely poisoned rats developed rapid-onset encephalopathy which reached a maximal grade of 2/5 at 6h and disappeared at 24h post-injection. Acute-on-chronically poisoned rats developed persistent and slightly fluctuating encephalopathy which reached a maximal grade of 3/5. Chronically poisoned rats developed rapid-onset but gradually increasing life-threatening encephalopathy which reached a maximal grade of 4/5. None of the acutely, 20% of the acute-on-chronically and 57% of the chronically lithium-poisoned rats developed seizures. The relationships between encephalopathy severity and lithium concentrations fitted a sigmoidal Emax model based on cerebrospinal fluid concentrations in acute poisoning and brain concentrations in acute-on-chronic poisoning. In chronic poisoning, worsening of encephalopathy paralleled the increase in plasma lithium concentrations. The severity of lithium-induced encephalopathy is dependent on the poisoning pattern, which was previously shown to determine lithium accumulation in the brain. Our data support the proposition that electroencephalography is a sensitive tool for scoring lithium-related neurotoxicity.

Lithiumeter: Version 2.0.

The Lithiumeter was developed as a visual and practical guide for determining lithium levels in the management of bipolar disorder (BD). It appears to have been well received, as evidenced by its increasing popularity amongst doctors as a deskside clinical aide, and adoption and reproduction of the schematic in clinical guidelines and texts. However, since its publication 5years ago, key basic neuroscience and clinical research developments pertaining to lithium have significantly advanced our understanding, necessitating further refinement of guidance concerning the practicalities of lithium therapy. Literature concerning the indications for, and therapeutic levels of, lithium and the associated acute and chronic risks of therapy was scrutinized as part of updating clinical practice guidelines. We have reviewed these updates and identified significant areas of change with respect to the previous Lithiumeter (version 1.0). Since 2011, updated clinical practice guidelines have narrowed the indicated plasma lithium concentration for maintenance therapy, suggesting that additional guidance is necessary for optimizing treatment. Relevant updated clinical guidance was integrated to constitute the Lithiumeter 2.0, which provides a more comprehensive overview of the practical aspects of lithium therapy while maintaining a focus on optimization of lithium levels, such as differential titration of lithium depending on the current mood state. The Lithiumeter 2.0 is an update that clinicians will find useful for their practice. By addressing some of the issues faced in clinical practice, translational clinical research will continue to inform the Lithiumeter in future updates.

Take care when using lithium with other drugs, as clinically relevant interactions may occur

Relatively minor changes in plasma concentrations of lithium can have significant clinical ramifications. Although controlled studies of drug interactions with lithium are limited, accumulated evidence implicates drugs from several classes in the development of lithium toxicity. Consequently, clinicians treating patients with mood disorders need to take a cautious approach when combining lithium with any other medication. This is particularly pertinent in the treatment of elderly patients and those with medical comorbidities.

Lithium Poisoning.

Lithium is a commonly prescribed treatment for bipolar affective disorder. However, treatment is complicated by lithium's narrow therapeutic index and the influence of kidney function, both of which increase the risk of toxicity. Therefore, careful attention to dosing, monitoring, and titration is required. The cause of lithium poisoning influences treatment and 3 patterns are described: acute, acute-on-chronic, and chronic. Chronic poisoning is the most common etiology, is usually unintentional, and results from lithium intake exceeding elimination. This is most commonly due to impaired kidney function caused by volume depletion from lithium-induced nephrogenic diabetes insipidus or intercurrent illnesses and is also drug-induced. Lithium poisoning can affect multiple organs; however, the primary site of toxicity is the central nervous system and clinical manifestations vary from asymptomatic supratherapeutic drug concentrations to clinical toxicity such as confusion, ataxia, or seizures. Lithium poisoning has a low mortality rate; however, chronic lithium poisoning can require a prolonged hospital length of stay from impaired mobility and cognition and associated nosocomial complications. Persistent neurological deficits, in particular cerebellar, are described and the incidence and risk factors for its development are poorly understood, but it appears to be uncommon in uncomplicated acute poisoning. Lithium is readily dialyzable, and rationale support extracorporeal treatments to reduce the risk or the duration of toxicity in high-risk exposures. There is disagreement in the literature regarding factors that define patients most likely to benefit from treatments that enhance lithium elimination, including specific plasma lithium concentration thresholds. In the case of extracorporeal treatments, there are observational data in its favor, without evidence from randomized controlled trials (none have been performed), which may lead to conservative practices and potentially unnecessary interventions in some circumstances. More data are required to define the risk-benefit of extracorporeal treatments and their use (modality, duration) in the management of lithium poisoning.

Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3β by lithium in the rat kidney cortex

Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3β in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3β in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3β. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3β in the rat kidney cortex.