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Objectives: Severe polyhydramnios during pregnancy may be associated with long‐term lithium use and presents considerable challenges. This complication, which has been linked to induced nephrogenic diabetes insipidus (NDI), underscores the necessity for cautious management of pregnant women with bipolar disorder. This case report aims to elucidate the relationship between long‐term lithium use, pregnancy, and the development of severe polyhydramnios, emphasizing the importance of diagnosing NDI in order to prevent obstetric and neonatal complications. Methods: We present the case of a 42‐year‐old primigravida undergoing long‐term lithium treatment for bipolar disorder type I, who developed severe polyhydramnios at 34 weeks of gestation. Clinical data including obstetric monitoring and neonatal outcomes were analyzed. Results: This case emphasizes the need for heightened awareness and proactive measures to mitigate the risk associated with lithium treatment during pregnancy. Close monitoring and timely interventions are essential to ensure optimal outcomes for both mother and fetus. Conclusions: Our article puts forth the hypothesis that there is a link between lithium use during pregnancy and the occurrence of polyhydramnios and Nephrogenic Diabetes Insipidus (NDI), which may lead to severe obstetric and neonatal complications. This case report contributes to the limited literature on the subject and gives doctors practical advice that may help them make a better risk‐benefit analysis. Further research is warranted in order to refine risk assessment protocols and management strategies in this complex clinical scenario. [ABSTRACT FROM AUTHOR]

Introduction: Lithium has an irreplaceable role in the treatment of severe mood disorders, but declining renal function associated with its use leads to clinical dilemmas. Although not often applied, and requiring close monitoring and multidisciplinary actions, concurrent lithium and haemodialysis treatment (CLHT) is a feasible option. To our knowledge, however, there are no detailed consensus‐ or evidence‐based treatment guidelines or directives on its delivery. Methods: To fill this gap, we reviewed the literature and surveyed psychiatrists and nephrologists with experience in CLHT using a self‐designed questionnaire. Our goal was to form an integrated picture of the current knowledge and clinical practices of CLHT and formulate practical recommendations for colleagues being confronted with patients with renal dysfunction requiring lithium to help manage their mood disorder. Results: We identified 14 case reports and case series describing CLHT and one systematic review concluding CLHT to be effective. Ten nephrologists and six psychiatrists practising in the Netherlands completed our questionnaire, providing details on collaboration, lithium dosing regimens, serum level evaluations and additional amenities and services they deemed necessary during CLHT delivery. Discussion: We found that CLHT appears to be safe and effective and argue that delivery is a shared responsibility and needs continuous multidisciplinary finetuning. To facilitate delivery, we provide a flowchart for the initiation or reinstatement of lithium therapy in haemodialysis patients and a practical guide for CLHT, including an easy‐to‐use rule of thumb for calculating the lithium target dose. [ABSTRACT FROM AUTHOR]

Background: Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega‐analyses of prospective trials of individual participant‐level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy. Methods: Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega‐analysis). Hierarchical log‐linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores. Results: Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = −2.33, t = −6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = −0.414, t = −6.32, p < 0.001), and a significant improvement in CGI/C across time (b = −0.47, t = −7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62). Conclusion: Findings from this IPD mega‐analysis of bipolar II depression trials suggest a divergence from current evidence‐based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega‐analysis suggests that antidepressant monotherapy may provide superior short‐term effectiveness without clinically meaningful increase in treatment‐emergent hypomanic symptoms compared to lithium monotherapy. [ABSTRACT FROM AUTHOR]

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 thyroidstimulating 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. [ABSTRACT FROM AUTHOR]

Objectives: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well‐characterized individuals with BD in North America, Europe, and Australia. Methods: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta‐analyses with generalized linear mixed methods were conducted to identify prescription patterns. Results: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD‐I (60%; vs. BD‐II = 33%). Cross‐sectionally, mood‐stabilizing anticonvulsants (44%), second‐generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First‐generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD‐II (47%) compared to BD‐I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. Conclusions: Mood‐stabilizing anticonvulsants, second‐generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first‐generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence‐based guidelines to help improve treatment practices in BD. [ABSTRACT FROM AUTHOR]

This article explores the treatment of psoriasis in patients with bipolar disorder who are taking lithium. While lithium can cause or worsen psoriasis, it has traditionally been recommended to discontinue the treatment. However, recent case reports have shown success in using biologic drugs to treat psoriasis without stopping lithium. The article emphasizes the importance of collaboration between psychiatrists and dermatologists in managing this condition. It presents a case study where a patient's psoriasis improved with the introduction of a biologic drug while continuing lithium therapy, suggesting that discontinuing lithium may not be necessary. Further research is needed to develop clinical guidelines in this area. [Extracted from the article]

Background: Clinical guidelines recommend monitoring of creatinine and lithium throughout treatment with lithium. We here assessed the extent to which this occurs in healthcare in Sweden. Methods: This is an observational study of all adults with bipolar disorder starting lithium therapy in Stockholm, Sweden, during 2007–2018. The main outcome was monitoring of blood lithium and creatinine at therapy initiation and/or once annually. The secondary outcome was monitoring of calcium and thyroid‐stimulating hormone (TSH). Patients were followed up until therapy cessation, death, out‐migration, or to the end of 2018. Results: We identified 4428 adults with bipolar disorder who started lithium therapy and were followed up for up to 11 years. Their median age was 39 years, and 63% were women. The median duration on lithium therapy was 4.3 (IQR: 1.9–7.45) years, and the majority who discontinued therapy started another mood stabilizer soon after. Overall, 21% started lithium therapy without assessing the serum/plasma concentration of creatinine. The proportion of people who did not have both lithium and creatinine measured increased from 21% in the first year to 33% in the eleventh year. The proportion with annual testing for TSH or calcium was slightly lower. As few as 16% of patients had both lithium and creatinine tested once annually during their complete time on lithium. Conclusions: In a Swedish community sample, lithium and creatinine monitoring was inconsistent with guideline recommendations that call for measurement of annual biomarker levels. [ABSTRACT FROM AUTHOR]

Objective: This phase 3, randomized, double‐blind, placebo‐controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression. Methods: Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery‐Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale‐Bipolar Version‐Severity Scale (CGI‐BP‐S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality. Results: Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], −2.4; p = 0.02) and CGI‐BP‐S depression subscore (LSMD, −0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, −1.7; p = 0.10) and improvement in the CGI‐BP‐S depression subscore (LSMD, −0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment‐emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin. Conclusions: Lumateperone 42‐mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder. [ABSTRACT FROM AUTHOR]

Objective: The term "mood stabilizer" is controversial in the literature and criticized for being imprecise and overly inclusive, having its retirement suggested to avoid misuse. Nevertheless, it continues to be employed as it may still carry important meaning. Methods: We employed document analysis for reviewing relevant definitions of mood stabilizer employed in the literature. Then, we clarify the meanings associated with the term by employing evolutionary concept analysis. Based on its results, we present a theoretical model for a mood stabilizer and further match it with evidence gathered from published meta‐analyses and other sources for drugs used in the treatment of bipolar disorder. Results: Concept analysis unearthed four attributes of a mood stabilizer that were nested into the following ascending hierarchy: "not worsening," "acute effects," "prophylactic effects," and "advanced effects." "Prophylactic effects" were often considered the core aspect of a legitimate mood stabilizer. Conclusion: The proposed model uses a hierarchy of attributes that take into account the complexity of the term and help to determine whether a drug is a mood stabilizer. Prophylaxis is pivotal to the concept, whose utility lies in implying a drug able to truly treat bipolar disorder, as opposed to merely targeting symptoms. Consistent use of the term could encourage investigation of drugs that modify long‐term outcomes and illness trajectory, instead of simply approaching symptom clusters. [ABSTRACT FROM AUTHOR]

Introduction: Blood test monitoring is essential for the management of lithium treatment and National Institute for Health and Care Excellence guidance recommends 6‐monthly serum testing of thyroid function. We examined conformity to these guidelines and the impact of monitoring outside these intervals. Methods: We extracted serum lithium and thyroid hormone results at one centre between January 2009 and December 2020. We identified 266 patients who started lithium during this period with no history of thyroid abnormality within the previous 2 years and were at risk of developing thyroid abnormalities. We examined the interval between tests, time between onset of lithium testing and first thyroid‐stimulating hormone (TSH) outside the laboratory reference range and assessed impact of testing outside recommended 6‐monthly intervals. Results: The most common testing frequency was 3 months (±1 month), accounting for 17.3% of test intervals. Kaplan‐Meier analysis showed that most thyroid dysfunction manifests within 3 years (proportion with abnormal TSH at 3 years = 91.4%, 19.9% of total patients). In the first 3 months after commencing lithium therapy, eight patients developed subclinical hypothyroidism and had clinical follow‐up data available. Of these, half spontaneously normalized without clinical intervention. In the remaining patients, thyroxine replacement was only initiated after multiple occasions of subclinical hypothyroidism (median = 2 years after initiating lithium, range: 6 months to 3 years). Conclusion: The peak interval at 3 months suggests that thyroid function is frequently checked at the same time as serum lithium, indicating too frequent testing. Our data support the recommended 6‐monthly testing interval and highlight poor adherence to it. [ABSTRACT FROM AUTHOR]

Aim: In order to avoid side effects of lithium doses in some patients, some commonly cultivated mushroom species including A. bisporus have been successfully lithiated, with the potential to provide more acceptable sources of Li. This study assessed the in vitro release (potential bioaccessibility) and possible intake of Li using the action of artificial gastrointestinal juices on lithiated and nonlithiated (control) button mushrooms (Agaricus bisporus) that were subjected to certain modes of culinary processing. Methods: In the in vitro release study, mushrooms were processed using a number of routinely used domestic treatments including rehydrating dried mushrooms, blanching and blanching followed by pickling of fresh or frozen mushrooms. The in vitro digestion procedure used artificial gastrointestinal juices in a two‐stage methodology that was adapted from 'The Bioaccessibility Research Group of Europe' method. The Li concentrations were determined using an inductively coupled argon plasma–dynamic reactive cell–mass spectrometer. Results: Lithium was found to be more bioaccessible from caps of lithiated mushrooms compared with nonlithiated. Releases from the caps and stipes of blanched or blanched and then pickled mushrooms through gastric digestion ranged from 32 ± 2 to 50 ± 1% relative to the dried product and was lower for gastrointestinal digestion, which ranged from 16 ± 1 to 20 ± 1%. Conclusion: Losses of Li sustained through blanching or blanching followed by pickling of fresh mushrooms (41–87% wet weight) combined with limited accessibility during gastrointestinal release (16–55%) result in much lower bioavailability of the dose from lithiated products. A 300‐g meal would provide <5% of the Li (6 mg) required for potential preventative treatments, such as reducing suicide rates and lowering dementia risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article titled "Challenges and missed opportunities in lithium monitoring for bipolar disorder: A reflection on Bosi et al.'s finding" discusses the monitoring of blood lithium levels, creatinine, TSH, and calcium in adults diagnosed with bipolar disorder. The article points out several shortcomings, including a lack of clarity regarding the diagnosis of bipolar disorder in the cohort, the criteria applied to patients who initiated lithium therapy, and the reasons behind therapy transitions. Additionally, the article highlights the need for further clarification on factors leading to decreased monitoring and the continuation of treatment in patients with a diminished glomerular filtration rate. The study also mentions adverse drug effects as a common reason for lithium discontinuation but does not provide specific details. Overall, the article emphasizes the need for more comprehensive understanding and elaboration of the study's findings and implications. [Extracted from the article]

Background: Long‐term management of bipolar disorder (BD), characterized by mood fluctuating between episodes of mania and depression, involves the regular taking of lithium preparations as the most reliable mood stabilizer for bipolar patients. However, despite its effectiveness in preventing and reducing mood swings and suicidality, lithium has a very narrow therapeutic index and it is crucial to carefully monitor lithium plasma levels as concentrations >1.2 mmol/L are potentially toxic and can be fatal. Current methods of lithium therapeutic monitoring involve frequent blood tests, which have several drawbacks related to the invasiveness of the technique, comfort, cost and reliability. Dermal interstitial fluid (ISF) is an accessible and information‐rich biofluid, and correlations have been found between blood and ISF levels of lithium medication. Methods: In the current study, we sought to investigate the optical determination of lithium therapeutic concentrations in samples of ISF extracted from porcine skin utilizing a microneedle‐based approach. Monitoring of lithium levels in porcine ISF was achieved by employing a spectrophotometric method based on the reaction between the chromogenic agent Quinizarin and lithium. Results: The resulting spectra show spectral variations which relate to lithium concentrations of lithium in samples of porcine ISF with a coefficient of determination (R2) of 0.9. This study has demonstrated successfully that therapeutic levels of lithium in micro‐volumes of porcine ISF can be measured with a high level of accuracy utilizing spectroscopic techniques. Conclusions: The results support the future development of a miniaturized and minimally‐invasive device for lithium monitoring in bipolar patients. [ABSTRACT FROM AUTHOR]

Aim: Bipolar disorder (BD) is a mood disorder with a high morbidity and death rate. Lithium (Li), a prominent mood stabilizer, is often used as a first‐line treatment. However, clinical studies have shown that Li is fully effective in roughly 30% of BD patients. Our goal in this study was to use features derived from information theory to improve the prediction of the patient's response to Li as well as develop a diagnostic algorithm for the disorder. Methods: We have performed electrophysiological recordings in patient‐derived dentate gyrus (DG) granule neurons (from a total of 9 subjects) for three groups: 3 control individuals, 3 BD patients who respond to Li treatment (LR), and 3 BD patients who do not respond to Li treatment (NR). The recordings were analyzed by the statistical tools of modern information theory. We used a Support Vector Machine (SVM) and Random forest (RF) classifiers with the basic electrophysiological features with additional information theory features. Results: Information theory features provided further knowledge about the distribution of the electrophysiological entities and the interactions between the different features, which improved classification schemes. These newly added features significantly improved our ability to distinguish the BD patients from the control individuals (an improvement from 60% to 74% accuracy) and LR from NR patients (an improvement from 81% to 99% accuracy). Conclusion: The addition of Information theory‐derived features provides further knowledge about the distribution of the parameters and their interactions, thus significantly improving the ability to discriminate and predict the LRs from the NRs and the patients from the controls. [ABSTRACT FROM AUTHOR]

Objective: Lithium‐induced natriuresis may lead to lithium retention and fluctuation of lithium levels during maintenance therapy. Therefore, the present study was conducted to evaluate the effect of add‐on sodium chloride on serum lithium levels in bipolar disorder. Methods: This RCT was conducted in 60 patients with type I bipolar disorder who were randomized into the control group that received lithium carbonate with the advice not to take additional salt (at the table) and the test group that received sachets of sodium chloride (1 g/d) as an add‐on to lithium carbonate and were advised to restrict their additional salt intake (at the table) to 1 g/d. After baseline assessments, all patients were followed up at 4 weeks, 8 weeks, and 12 weeks when serum lithium, sodium, and potassium were estimated. Serum creatinine and aldosterone were repeated at 12 weeks. The percentage of patients showing fluctuations in serum lithium level (serum lithium <0.6 mEq/L or >0.8 mEq/L) was considered as the primary outcome measure. Results: In the test group, the fluctuation rate in serum lithium (26.7%) was significantly (p = 0.01) lower than that in the control group (63.3%). Serum lithium values varied significantly across sampling times in the control group but not in the test group. There was a significant difference in serum lithium between the groups at 8 and 12 weeks of follow‐up. There were no significant differences in the change in serum sodium, potassium, creatinine, aldosterone, creatinine clearance, and blood pressure within the group and between the groups. A significant positive correlation was found between serum lithium and aldosterone at baseline. Conclusions: Intake of add‐on sodium chloride (1 gm/day) may reduce the fluctuations in serum lithium during the maintenance phase of lithium therapy in type I bipolar disorder. ClinicalTrial.gov Identifier: NCT04222816. [ABSTRACT FROM AUTHOR]

Background: The use of lithium during breast‐feeding has not been comprehensively investigated in humans due to concerns about lithium toxicity. Procedure: We analyzed lithium in the kidneys of nursed pups of lithium medicated mothers, using analytical spectroscopy in a novel rat model. The mothers were healthy rats administered lithium via gavage (1000 mg/day Li2CO3 per 50 kg body weight). Results: Lithium was detected in the breast milk, and in the blood of pups (0.08 mM), of lithium‐exposed dams at post‐natal day 18 (P18), during breast‐feeding. No lithium was detected after breast‐feeding, at P25 (4 days after cessation of nursing). The lithium pups blood had elevated urea nitrogen at P18 and reduced total T4 at P18 and P25, indicating a longer‐term effect on the kidneys and the thyroid gland. Multivariate machine‐learning analysis of spectroscopy data collected from the excised kidneys of pups showed elevated potassium in lithium‐exposed animals both during‐ and after breast‐feeding. The elevated renal potassium was associated with low nephrin expression in the kidneys measured immunohistochemically during breast‐feeding. After lithium exposure is stopped, the filtration of lithium from the kidneys reverses these effects. Our study showed that breastfeeding during lithium use has an effect on the kidneys of the offspring in rats. [ABSTRACT FROM AUTHOR]

Objectives: Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. Methods: Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L. Results: The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. Conclusions: This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research. [ABSTRACT FROM AUTHOR]

Background: Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium. Methods: We compared factors for association with recurrences of BD within 12 months of discontinuing long‐term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium‐discontinuation and prior treatment duration. Results: Among 227 BD subjects who received lithium for 4.47 [CI: 3.89–5.04] years and then discontinued, rapid treatment‐discontinuation, and stopping for medical reasons were strongly associated with new illness‐episodes within 12 months, as were diagnosis (BD‐I > BD‐II), greater morbidity during lithium‐treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment‐discontinuation. Early recurrence was not associated with treatment‐duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD‐I diagnosis remained significantly, independently associated with early illness after lithium‐discontinuation, with no effect of treatment duration. Conclusions: Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD‐I than BD‐II, and following greater morbidity during lithium‐treatment, but not related to dose or duration of preceding treatment exposure. [ABSTRACT FROM AUTHOR]

Medical comorbidities leading to hypernatremia during COVID-19 pandemic in patients with mood disorders on long-term lithium therapy Lithium intoxication accounted for only 1% of all hypernatremia episodes.2 Nevertheless, we must monitor renal function and electrolytes in patients with long-term lithium treatment to identify NDI and hypernatremia. Careful monitoring of the clinical characteristics in patients receiving long-term lithium therapy may help prevent hypernatremia and improve mood disorders exacerbated by the COVID-19 pandemic. COVID-19 may have directly caused hypernatremia, while dehydration may indirectly cause hypernatremia owing to the patients' confinement in a closed ward. [Extracted from the article]

This document is an invited commentary in response to a letter by Professor RH Belmaker regarding the use of lithium as a treatment for bipolar disorder. The authors express gratitude for the opportunity to engage in scholarly conversation and emphasize the importance of robust discussion in expanding knowledge and understanding of complex issues. They agree with Belmaker that there are other treatment options available, but maintain that lithium should be prioritized as the primary maintenance treatment for bipolar type I disorder due to its demonstrated efficacy and relatively favorable side effect profile. The authors also address concerns about the lack of understanding of lithium's mechanism of action and argue that this should not diminish its clinical value. They call for increased emphasis on the evidence supporting lithium's efficacy and the dissemination of knowledge on monitoring and managing side effects to counteract the declining trend in its use for bipolar disorder. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%–40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. Methods: In secondary analyses of a multi‐center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross‐sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. Results: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li‐Rs) showed improvement in circadian symptoms of depression, but non‐responders did not. There was no difference between Li‐Rs and nonresponders in affective, circadian, or total symptoms of mania. Conclusions: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. Clinical Trials Registry: NCT0127253. [ABSTRACT FROM AUTHOR]

Lithium levels are often checked in the inpatient setting when a patient has clear indications of acute kidney injury. Lithium levels can become supratherapeutic in COVID‐19 infection even after normalization of creatinine. Lithium levels should be checked routinely in patients with COVID‐19 infection in order to avoid supratherapeutic levels. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ultimately, electroconvulsive therapy (ECT) was effective, and this is the first published report of treating BD mania with ECT during hemodialysis. Key MessagePharmacologic management of bipolar disorder (BD) in patients on hemodialysis has limited safety and efficacy data. [Extracted from the article]

Background: Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast‐feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well‐understood, affecting its usage and overall health implications. Procedure: We developed a rat lithium and breast‐feeding model at human therapeutic levels to study the effects of lithium exposure through breast‐milk on pups' thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups' thyroid dysfunction. Results: Pups exposed to lithium via breastmilk, even with the dam on a sub‐therapeutic level, experienced weight gain, reduced blood thyroxine (T4), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast‐feeding. Conclusion: These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side‐effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast‐feed. [ABSTRACT FROM AUTHOR]

Objectives: Circadian rhythm disruption is commonly reported in patients with bipolar disorder. Lithium has been suggested to have effects on the circadian clock, the biological basis of the circadian rhythm. The objective of the current review was to review systematically the existing studies on the effect of lithium on circadian rhythm in patients with bipolar disorder. Methods: We systematically searched the scientific literature up to September 2020 for experimental or observational studies which measured circadian rhythm in bipolar patients taking lithium (in comparison with placebo or other active treatments) and carried out a meta‐analysis. Circadian rest‐activity was our primary outcome, but we also collected data about sleep quality and chronotype (Morningness‐Eveningness). The protocol was registered in PROSPERO (CRD42018109790). Results: Four observational studies (n = 668) and one experimental study (n = 29) were included. Results from the meta‐analysis suggest a potential association between lithium and shifts towards morningness (standardized mean difference [SMD]: 0.42, 95% confidence interval [CI]: −0.05 to 0.90). One cohort study with 21 days of follow‐up found that patients treated with lithium had significantly larger amplitude (0.68, 0.01 to 1.36) when compared to anticonvulsants. Conclusion: This review highlights the insufficient evidence to inform us about the effect of lithium on circadian rhythm. However, we found that chronotype can be a potential target for further exploration of biomarkers or biosignatures of lithium treatment in patients with bipolar disorder. Further studies with prospective and longitudinal study design, adopting actigraphy to monitor daily circadian rest‐activity changes are needed. [ABSTRACT FROM AUTHOR]

Objectives: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. Methods: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. Results: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient −0.03, P =.63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. Conclusion: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest. [ABSTRACT FROM AUTHOR]

The letter to the editor discusses the use of lithium as a treatment for bipolar disorder. The author, Robert H. Belmaker, disagrees with the assertion made by Malhi and Bauer in a previous editorial that lithium should be considered the "first line" treatment for bipolar disorder. Belmaker argues that while lithium is effective for some cases of bipolar disorder, it is also effective for other conditions such as unipolar depression and schizoaffective disorder. He emphasizes that the choice of treatment should depend on factors such as side effects and patient adherence, and that there is no overall superiority of lithium compared to other mood stabilizers. Belmaker concludes that lithium is one of many effective treatments for bipolar disorder and should not be considered a "magic bullet" or the gold standard. [Extracted from the article]

Despite its name, only trace amounts of lithium are in both the hot and cold spring waters around Hot Springs National Park. gl Where has lithium gone now? Bipolar Disorder, History, Lithium, Mineral Waters, Uric Acid Diathesis Keywords: Bipolar Disorder; History; Lithium; Mineral Waters; Uric Acid Diathesis EN Bipolar Disorder History Lithium Mineral Waters Uric Acid Diathesis 97 98 2 03/15/23 20230301 NES 230301 Lithium is consistently recommended as first line treatment in bipolar illness in published treatment guidelines. [Extracted from the article]

For instance, in approximately a third of patients with classic bipolar disorder, lithium remains the most suitable therapy. Few, if any other agents, can lay claim to long-term mood stability and prophylaxis over this span of time, not to mention the additional properties alluded to at the outset namely, its anti-suicidal and neuroprotective effects. And in practice, few clinicians would contest the suitability of lithium in the prophylaxis and maintenance treatment of many patients with bipolar disorder. [Extracted from the article]

I read with much interest the article by Hoekstra et al.1 where the authors investigated the trajectory of renal function after discontinuation of lithium in 43 patients receiving chronic lithium therapy with estimated glomerular filtration rate (eGFR) of more than 60 ml/min/1.73 m SP 2 sp at the initiation of lithium therapy in order to know how often and to what extent decline in renal function is reversible after stopping lithium therapy. For example, Pahwa et al.2 reported that among 154 patients who received long-term lithium treatment, 41 patients (27%) developed chronic kidney disease (CKD; eGFR of less than 60 ml/min/ 1.73 m SP 2 sp ). Interestingly, mGFR and lithium treatment duration were strongly correlated in patients with microcysts, but not in patients with no microcysts. [Extracted from the article]

Lithium in drinking water and suicide: A sex difference and dose-response relationship They analyzed data of extremely high levels of lithium concentrations in drinking water, and a dose-response relationship with wide ranges of lithium concentrations in drinking water should be conducted to verify the association. López Steinmetz et al. reported correlations among lithium concentrations in drinking water, mean rates of suicide mortality, and altitude.5 Lithium but not altitude was positively correlated with suicide mortality, presenting rho of 0.76. [Extracted from the article]

A recently published summary of the 2020 clinical practice guidelines for mood disorders from the Royal Australian and New Zealand College of Psychiatrists provides recommendations on management of bipolar disorder.1 The acute phase pharmacotherapy of a depressive episode in patients with bipolar disorder, in the following referred to as treatment of bipolar depression, is especially challenging. We agree that the strong position of lithium as maintenance treatment supports introducing lithium already in the acute treatment phase, whether bipolar depression or mania, in cases where maintenance treatment with lithium is considered relevant and feasible. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. [Extracted from the article]

Objectives The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder ( BD). A region in the first intron of the fat mass- and obesity-associated ( FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index ( BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. Methods The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM- IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5- mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. Results Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p ≤ 0.019), with a mean difference in BMI as high as 7.81 kg/m2. Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p ≤ 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. Conclusions In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles. [ABSTRACT FROM AUTHOR]

In 1/3 of patients with bipolar disorder (BD) called "excellent lithium responders", lithium monotherapy can completely prevent affective recurrences. In their editorial, Malhi et al1 advocate the more frequent use of lithium in patients with mood disorders which concurs with my appeal voiced two years ago.2 Lithium has been universally accepted as the first choice mood-stabilizer for maintenance treatment of bipolar disorder and exerts also anti-suicidal, immunomodulatory, and neuroprotective action. No connection was found between long-term lithium treatment and antithyroid antibodies.3 A serious concern is the possibility of lithium-induced interstitial nephropathy, which can develop after 10-20 years of treatment and leads to increased creatinine concentration and a decreased glomerular filtration rate (GFR). [Extracted from the article]

From a research perspective, although lithium response may comprise a bipolar disorder endophenotype, it is noteworthy that lithium's precise mechanisms of action remain to be established. Arguably, the identification of additional putative pharmacodynamic mechanisms underpinning lithium's efficacy as a mood stabilizer may shed light on the underlying pathophysiology of bipolar disorder and may also inform putative novel neurotherapeutic targets for this complex illness. The serendipitous discovery of lithium's efficacy for the treatment of manic excitement dates back to initial observations by the Danish psychologist Carl Lange in 1886 who theorized that patients with manic-depressive illness had "cerebral gout" for which he suggested lithium salts because lithium could dissolve urate stones. [Extracted from the article]

Make lithium great again - Precisely! 2019; 7 (1). 4 Scott J, Etain B, Bellivier F. Can an integrated science approach to precision medicine research improve lithium treatment in bipolar disorders? Before highlighting factors that may optimise lithium use, we wish to remind readers that lithium is cheap, uniquely effective and a prime candidate for developing precision prescribing in psychiatry. [Extracted from the article]

Malhi and coworker's editorial1 offers several reasons explaining the decline in the use of lithium to treat Bipolar Disorder (BD) against the recommendation of most international guidelines. For instance, lithium monotherapy was superior than valproate monotherapy in preventing both manic and depressive relapses in the BALANCE study,2 a multicentre 2-year randomized open-label trial including 330 patients with type-I BD (BD-I). Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. [Extracted from the article]

B I b ntroduction of lithium carbonate to treat manic excitement in 1949 by John Cade in Melbourne opened a new, revolutionary era in psychiatry with the first clinically effective pharmacological treatment for a major psychiatric disorder. Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters. [Extracted from the article]

Background Although highly controversial, the treatment of obesity with exogenous human chorionic gonadotropin ( HCG) remains popular in the USA. We report the case of a patient whose first manic episode was associated with the use of HCG for weight loss. Case report A 32-year-old female patient was admitted to our psychiatric inpatient unit due to a two-week history of manic symptoms. She had no previous history of manic or hypomanic episodes and had completed a 45-day course of sublingual HCG for weight loss immediately prior to the onset of the manic episode. The patient was treated with lithium carbonate and aripiprazole, and progressed with improvement in the symptoms. Conclusion While it is not possible to definitively link the HCG use to the development of mania, available evidence suggests that HCG may have a contributing role in triggering manic symptomatology. [ABSTRACT FROM AUTHOR]

Objectives The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder ( BAD). Methods In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile Function ( IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist. Results Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time × treatment interaction were observed for total score [Greenhouse-Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse-Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [χ2(1) = 10.800, p = 0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups. Conclusion Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD. [ABSTRACT FROM AUTHOR]

Objective Serum lithium levels may be influenced by mood state. We report on a 58-year-old female patient suffering from rapid cycling bipolar disorder. Her serum lithium levels varied greatly, despite stable medication. Methods The patient was observed over a one-year period. Results The patient received a stable medication of lithium carbonate (450 mg), valproate (1500 mg), and clozapine (200 mg). Investigating mood and serum lithium levels over one year revealed six manic and six depressive phases. The mean lithium serum level was 0.67 mmol/L in the depressive states, 0.39 mmol/L in the manic states ( t = 4.11, p = 0.001 versus depression), and 0.40 mmol/L in the euthymic states ( t = 3.58, p = 0.003 versus depression). Noncompliance was ruled out. The patient gained up to 8 kg during manic phases, accompanied by pretibial edema. Conclusions Changes in serum lithium concentration are probably not caused by altered lithium, but by water metabolism. During mania, body water increases, leading to dilution and therefore a reduction in serum lithium levels. As there is no proof for any other known cause of hypervolemia, we propose the hypothesis that the increase in body water is due to a variant of idiopathic edema. [ABSTRACT FROM AUTHOR]

In my opinion, despite numerous controversies, the concept of ‘mood stabilizer' (MS), if properly defined, may prove useful in clinical practice. The definition of MS should reflect its role in the acute and long term treatment of bipolar disorder.1 Therefore, the first aspect of such a definition should involve reducing or ameliorating manic and/or depressive symptoms during an acute episode. The second aspect of an MS requires prevention of manic and/or depressive recurrences during long- term administration, when a drug is given as monotherapy, and a trial is performed for a duration of at least 1 year. The third, indispensable aspect of an MS is that the drug should not induce or worsen either manic or depressive episodes or mixed states. [ABSTRACT FROM AUTHOR]