Search

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: Lithium is effective in the long-term treatment of bipolar disorder. Concerns have been raised about non-responsiveness after discontinuation and resuming previously effective lithium prophylaxis. We reviewed the available literature on this so-called lithium-discontinuation-induced treatment refractoriness (LDITR). Results: We found 11 case reports and six cohort studies including 403 patients addressing LDITR, and one nation-wide register study providing some additional data on LDITR. Pooling all cohort studies, the percentages of non-responders during re-treatment with lithium ranged from 3.6 to 27.7%, with an average of 17.3%. Non-responsiveness was associated with longer duration of lithium treatment before discontinuation, longer duration of bipolar disorder before start of lithium, faster tapering off lithium, and longer duration of discontinuation. Conclusions: There may be a subgroup in whom lithium discontinuation-induced treatment refractoriness exists. However, the vast majority of people respond when lithium is restarted. Moreover, it may be necessary to continue lithium beyond the first relapses to restore long-term prophylactic efficacy. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to determine whether the clinical profiles of bipolar disorder (BD) patients could be differentiated more clearly using the existing classification by diagnostic subtype or by lithium treatment responsiveness. Methods: We included adult patients with BD‐I or II (N = 477 across four sites) who were treated with lithium as their principal mood stabilizer for at least 1 year. Treatment responsiveness was defined using the dichotomized Alda score. We performed hierarchical clustering on phenotypes defined by 40 features, covering demographics, clinical course, family history, suicide behaviour, and comorbid conditions. We then measured the amount of information that inferred clusters carried about (A) BD subtype and (B) lithium responsiveness using adjusted mutual information (AMI) scores. Detailed phenotypic profiles across clusters were then evaluated with univariate comparisons. Results: Two clusters were identified (n = 56 and n = 421), which captured significantly more information about lithium responsiveness (AMI range: 0.033 to 0.133) than BD subtype (AMI: 0.004 to 0.011). The smaller cluster had disproportionately more lithium responders (n = 47 [83.8%]) when compared to the larger cluster (103 [24.4%]; p = 0.006). Conclusions: Phenotypes derived from detailed clinical data may carry more information about lithium responsiveness than the current classification of diagnostic subtype. These findings support lithium responsiveness as a valid approach to stratification in clinical samples. [ABSTRACT FROM AUTHOR]

Background: Lithium stands as the gold standard in treating bipolar disorders (BD). Despite numerous clinical factors being associated with a favorable response to lithium, comprehensive studies examining the collective influence of clinical variables alongside psychopathological dimensions are lacking. Our study aims to enhance comprehension of lithium response in individuals with BD by integrating clinical variables with psychopathological traits and early adverse events. Methods: We assessed 201 patients with BD for clinical characteristics, childhood trauma, temperament traits, impulsivity, and aggression. Lithium response was evaluated using the gold standard Alda scale, and predictors of lithium response were estimated through a multivariate model. Results: On the total sample, 61 (30.3%) patients were lithium responders according to the Alda scale. Comparatively, lithium responders, in contrast to non-responders, demonstrated a higher prevalence of the mania-depression-interval (MDI) cycle, a more frequent diagnosis of BD type I, and reported an earlier age of onset. They also exhibited less lifetime substance abuse, emotional, physical, and sexual abuse, while scoring higher on hyperthymic and irritable temperament scales. In multivariate analyses, only the MDI cycle (OR,3.47; 95%CI,1.61–7.50) hyperthymic (OR,1.20; 95%CI,1.02–1.41) and irritable temperament (OR,1.28; 95%CI,1.08–1.52) persisted as significant predictors of a positive response to lithium treatment, while emotional (OR,0.87; 95%CI,0.76–0.98) and physical abuse (OR,0.83; 95%CI,0.70–0.98) were predictors of non-response. Conclusions: In evaluating lithium response in BD, our study highlights the importance of considering clinical variables alongside temperament and childhood adversities. The assessment of hyperthymic and irritable temperament, emotional and physical abuse together with the type of cycle is of particular importance. Furthermore, our findings underscore the significance of systematically assessing the type of cycle in patients with BD through the use of life charts. [ABSTRACT FROM AUTHOR]

Rationale: In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment. Objectives: We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes. Results: We genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers. Conclusions: Our study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium's immunomodulatory potential. [ABSTRACT FROM AUTHOR]

Background: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient. Main body: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described. Conclusions: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients. [ABSTRACT FROM AUTHOR]

Introduction: Dementia is a neurodegenerative disease with insidious onset and progressive progression, of which the most common type is Alzheimer's disease (AD). Lithium, a trace element in the body, has neuroprotective properties. However, whether lithium can treat dementia or AD remains a highly controversial topic. Therefore, we conducted a meta-analysis. Methods: A systematic literature review was conducted on PubMed, Embase, and Web of Science. Comparison of the effects of lithium on AD or dementia in terms of use, duration, and dosage, and meta-analysis to test whether lithium therapy is beneficial in ameliorating the onset of dementia or AD. Sensitivity analyses were performed using a stepwise exclusion method. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. We determined the relative risk (RR) between patient groups using a random-effects model. Results: A total of seven studies were included. The forest plot results showed that taking lithium therapy reduced the risk of AD (RR 0.59, 95% confidence interval [CI]: 0.44–0.78) and is also protective in reducing the risk of dementia (RR 0.66, 95% CI: 0.56–0.77). The duration of lithium therapy was able to affect dementia incidence (RR 0.70, 95% CI: 0.55–0.88); however, it is unclear how this effect might manifest in AD. It is also uncertain how many prescriptions for lithium treatment lower the chance of dementia development. Conclusion: The duration of treatment and the usage of lithium therapy seem to lower the risk of AD and postpone the onset of dementia. [ABSTRACT FROM AUTHOR]

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

The use of adjunctive therapy for bipolar disorder is increasingly considered to increase the efficacy of standard treatments. In this randomized clinical trial, we evaluated the effect of vitamins B1 and B6 in separate treatment arms on mood symptoms, cognitive status, and sleep quality in hospitalized patients with bipolar disorder in manic episodes. In addition to receiving standard lithium treatment, participants (N = 66) were randomized to one of three conditions: 100 mg of vitamin B1, 40 mg of vitamin B6, or placebo. Outcomes were assessed one and 8 weeks of daily treatment, including the Young Mania Rating Scale (YMRS), Pittsburgh Sleep Quality Scale (PSQI), and Mini-Mental State Examination (MMSE). This study was performed between December 2020 and September 2021 based on the registration code number IRCT20200307046712N1. Vitamin B6 had a significant effect (P value < 0.025 as significant) on mood improvement compared to placebo (F (1, 27.42) = 30.25, P < 0.001, r = 0.72), but vitamin B1 had no significant effect on mood improvement compared to Placebo (F (1/35.68) = 4.76, P = 0.036, r = 0.34). The contrasts between groups on PSQI showed a significant effect (P value < 0.025 as significant) of vitamin B6 over placebo for sleep status improvement (F (1/32.91) = 16.24, P < 0.001, r = 0.57) and also a significant effect of vitamin B1 over placebo (F (1/41.21) = 13.32, P < 0.001, r = 0.49). The use of vitamin B6 as an adjunctive therapy to lithium can be associated with the improvement of mood symptoms in patients with bipolar disorder in the midst of a manic episode. • The use of vitamin B6 as an adjunctive therapy to lithium can be associated with the improvement of mood symptoms in patients with bipolar disorder in manic episodes. • Vitamin B6, as well as vitamin B1 as adjunctive therapy, can improve sleep quality in patients with bipolar disorder in manic episodes. [ABSTRACT FROM AUTHOR]

This article examines the scientific career of Edward Trautner, who did pioneering research in the 1950s on lithium treatment for psychiatric disorders. Trautner was the first scientist to study the mechanism of action of lithium as a psychiatric medication. His research established that lithium could be used safely and rationally, and anticipated by a decade the large volume of research in the 1960s and 1970s that led to international acceptance of lithium treatment for mood disorders. Trautner was a pioneer of biological psychiatry who considered pharmacology to be a useful therapeutical tool rather than a permanent cure for putative chemical imbalances. His research involved cross-disciplinary collaborations that combined clinical and laboratory research in the disciplines of psychiatry, physiology, biochemistry, teratology, and even oncology. Trautner himself had a multidisciplinary background that included publications in literature and philosophy. [ABSTRACT FROM AUTHOR]

As in type 1 diabetes, the loss of pancreatic ß-cells leads to insulin deficiency and the subsequent development of hyperglycemia. Exercise has been proposed as a viable remedy for hyperglycemia. Lithium, which has been used as a treatment for bipolar disorder, has also been shown to improve glucose homeostasis under the conditions of obesity and type 2 diabetes by enhancing the effects of exercise on the skeletal muscles. In this study, we demonstrated that unlike in obesity and type 2 diabetic conditions, under the condition of insulin-deficient type 1 diabetes, lithium administration attenuated pancreatic a-cell mass without altering insulin-secreting ß-cell mass, implying a selective impact on glucagon production. Additionally, we also documented that lithium downregulated the hepatic gluconeogenic program by decreasing G6Pase protein levels and upregulating AMPK activity. These findings suggest that lithium's effect on glucose metabolism in type 1 diabetes is mediated through a different mechanism than those associated with exerciseinduced metabolic changes in the muscle. Therefore, our research presents the novel therapeutic potential of lithium in the treatment of type 1 diabetes, which can be utilized along with insulin and independently of exercise. [ABSTRACT FROM AUTHOR]

Background: Lithium is an essential psychopharmaceutical, yet side effects and concerns about severe renal function impairment limit its usage. Aims: Our objectives were to quantify the occurrence of chronic kidney disease stage 4 or higher (CKD4 +) within a lithium-treated population, using age- and time-specific cumulative incidence and age-specific lifetime risk as measures of disease occurrence. Additionally, we aimed to investigate the association between the duration of lithium treatment and the risk of CKD4 +. Methods: We identified patients from the Sahlgrenska University Hospital's laboratory database. We conducted a retrospective cohort study employing cumulative incidence functions that account for competing deaths to estimate cumulative and lifetime risk of CKD4 +. A subdistribution hazards model was employed to explore baseline covariates. For measuring the association between the duration of lithium treatment and CKD4 + occurrence, we used a matched 1:4 case–control study design and logistic regression. Results: Considering a 90-year lifetime horizon, the lifetime risk of CKD4 + for patients initiating lithium treatment between ages 55 and 74 ranged from 13.9% to 18.6%. In contrast, the oldest patient group, those starting lithium at 75 years or older, had a lower lifetime risk of 5.4%. The 10-year cumulative risk for patients starting lithium between ages 18 and 54 was minimal, ranging from 0% to 0.7%. Pre-treatment creatinine level was a predictive factor, with a hazard ratio of 4.6 (95% CI 2.75–7.68) for values within the upper third of the reference range compared to the lower third. Moreover, twenty or more years of lithium exposure showed a strong association with an increased risk of CKD4 + compared to 1–5 years of lithium use, with an odds ratio of 6.14 (95% CI 2.65–14.26). Conclusions: The risk of CKD4 + among lithium-treated patients exhibited significant age-related differences. Patients under 55 years old had negligible 10-year risk, while the lifetime risk for those aged 75 and older was limited. Duration of lithium treatment, especially exceeding 20 years, emerged as a significant risk factor. For individual risk assessment and prediction, consideration of age, pre-treatment creatinine levels, and the chosen time horizon for prediction is essential. [ABSTRACT FROM AUTHOR]

For over half a century, it has been widely known that lithium is the most efficacious maintenance treatment for bipolar disorder. Despite thorough research on the long-term effects of lithium on renal function, a number of important questions relevant to clinical practice remain. The risk of polyuria, reflecting renal tubular dysfunction, is seen in a substantial proportion of patients treated with long term lithium therapy. The duration of lithium may be the most important risk factor for lithium-induced polyuria. Most, but not all, studies find that lithium is associated with higher rates of chronic kidney disease compared to either age matched controls or patients treated with other mood stabilizers. Age, duration of lithium therapy and medical disorders such as hypertension and diabetes mellitus are risk factors for chronic kidney disease in lithium-treated patients. The relationship between polyuria and chronic kidney disease is inconsistent but poorly studied. Although not all studies agree, it is likely that lithium may increase the risk for end stage renal disease but in a very small proportion of treated patients. Patients whose renal function is relatively preserved will show either no progression or improvement of renal function after lithium discontinuation. In contrast, patients with more renal damage frequently show continued deterioration of renal function even after lithium discontinuation. Optimal management of lithium treatment requires obtaining a baseline measure of renal function (typically estimated glomerular filtration rate [eGFR]) and regular monitoring of eGFR during treatment. Should the eGFR fall rapidly or below 60 ml/minute, patients should consider a consultation with a nephrologist. A decision as to whether lithium should be discontinued due to progressive renal insufficiency should be made using a risk/benefit analysis that takes into account other potential etiologies of renal dysfunction, current renal function, and the efficacy of lithium in that individual patient. [ABSTRACT FROM AUTHOR]

Background: The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. Methods: Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. Results: We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). Conclusions: Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases. [ABSTRACT FROM AUTHOR]

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

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]

Background: Lithium is widely used as treatment of acute mania and as prophylactic therapy for bipolar disorder. International and national guidelines also consider lithium as a possible treatment of acute bipolar depression. Research on the use of lithium in bipolar depression, however, seems to be limited compared to the data available for its efficacy in the other phases of bipolar disorder. Objective: To provide a systematic review of the evidence for lithium in the treatment of acute bipolar depression and provide directions for further research. Method: A systematic review of clinical studies investigating the use of lithium in bipolar depression was performed using preferred reporting items for systematic reviews and meta‐analyses guidelines in Pubmed, Embase and Psychinfo using the medical subjects headings and free text terms "lithium," "bipolar depression," "dosage," "serum concentration" and "bipolar disorders." Results: This review included 15 studies with a total of 1222 patients, between the age of 18 and 65, suffering from bipolar depression of which 464 were treated with lithium. There are currently only limited and low‐quality data on the efficacy of lithium as a treatment of bipolar depression. It appears that there have been no placebo controlled randomized controlled trials with lithium concentrations that are considered to be therapeutic. The older studies suffered from limitations such as small sample sizes, insufficient treatment lengths, and insufficient monitoring of serum concentrations. Conclusion: In contrast to data for the treatment of mania and prophylaxis, robust data on the efficacy of lithium in bipolar depression is currently lacking, making it impossible to make conclusions regarding efficacy or inefficacy, for which further research is needed. [ABSTRACT FROM AUTHOR]

Rationale: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown. Objective: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this. Method: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport. Results: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone. Conclusions: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed. [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]

Lithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients' experiences, knowledge and attitudes about lithium may improve its clinical use. Online anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). Among 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients' survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium. Cross-sectional design with predominantly English-speaking participants from Brazil and North America. There is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use. • Despite being the gold-standard treatment for bipolar disorder, lithium is still underused. • Clinicians reported good confidence in managing lithium but may not comply with monitoring practices. • Most patients found lithium useful but did not receive enough information about the treatment. • Clinicians and patients are receptive about improving their lithium literacy. [ABSTRACT FROM AUTHOR]

Background: Lithium has long been considered the gold-standard pharmacological treatment for the maintenance treatment of bipolar disorders (BD) which is supported by a wide body of evidence. Prior research has shown a steady decline in lithium prescriptions during the last two decades. We aim to identify potential factors explaining this decline across the world with an anonymous worldwide survey developed by the International Society for Bipolar Disorders (ISBD) Task Force "Role of Lithium in Bipolar Disorders" and distributed by diverse academic and professional international channels. Results: A total of 886 responses were received of which 606 completed the entire questionnaire while 206 completed it partially. Respondents were from 43 different countries comprising all continents. Lithium was the most preferred treatment option for the maintenance of BD patients (59%). The most relevant clinical circumstances in which lithium was the preferred option were in patients with BD I (53%), a family history of response (18%), and a prior response during acute treatment (17%). In contrast, Lithium was not the preferred option in case of patients´ negative beliefs and/or attitudes towards lithium (13%), acute side-effects or tolerability problems (10%) and intoxication risk (8%). Clinicians were less likely to prefer lithium as a first option in BD maintenance phase when practising in developing economy countries [X2 (1, N = 430) = 9465, p = 0.002) ] and private sectors [X2 (1, N = 434) = 8191, p = 0.004)]. Conclusions: Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders appear to be affected by both the patients' beliefs and the professional contexts where clinicians provide their services. More research involving patients is needed for identifying their attitudes toward lithium and factors affecting its use, particularly in developing economies. [ABSTRACT FROM AUTHOR]

Due to a narrow therapeutic index, prolonged lithium treatment and overdose may result in neurotoxicity. Neurotoxicity is deemed reversible with lithium clearance. However, echoing the report of syndrome of irreversible lithium‐effectuated neurotoxicity (SILENT) in rare severe poisonings, lithium‐induced histopathological brain injuries including extensive neuronal vacuolization, spongiosis and ageing‐like neurodegenerative changes were described in the rat following acute toxic and pharmacological exposure. We aimed to investigate the histopathological consequences of lithium exposure in rat models mimicking prolonged treatment and all three patterns of acute, acute‐on‐chronic and chronic poisonings observed in humans. We performed histopathology and immunostaining‐based analyses using optic microscopy of brains obtained from male Sprague–Dawley rats randomly assigned to lithium or saline (controls) and treated according to the therapeutic or to the three poisoning models. No lesion was observed in any brain structure in any of the models. Neuron and astrocyte counts did not differ significantly between lithium‐treated rats and controls. Our findings support that lithium‐induced neurotoxicity is reversible and brain injury not a common feature of toxicity. [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: Modern lithium management guidelines were introduced to improve the renal prognosis of lithium patients. Aims: To examine whether prospects for severe renal impairment (defined as chronic kidney disease at least stage 4 (CKD4)), in long-term lithium patients, have changed over time after the introduction of lithium monitoring guidelines. Methods: The time to and hazard for CKD4 were compared between three patient cohorts who started long-term lithium in three consecutive decades: 1980s, 1990s and 2000s. The follow-up time was 10 years after completion of 1-year treatment. The data were collected from Sahlgrenska University Hospital's laboratory database. Results: In all, 2169 patients were included: 623 in Cohort 1 (started lithium during 1980s), 874 in Cohort 2 (1990s) and 672 in Cohort 3 (2000s). Compliance with lithium monitoring guidelines improved, and mean serum lithium decreased, through the cohorts. In all, 22 patients developed CKD4 during follow-up. The time to CKD4 was the same in all three cohorts (overall: 10.96 years, 95% confidence interval: 10.94–11 years). Age and serum creatinine concentration at start were significant risk factors, while sex had no prognostic value. After adjusting for the significant covariates, there was no statistically significant difference in the hazard for CKD4 between the three cohorts. Conclusion: The risk for severe renal damage during the first decade of long-term lithium is low, but has not changed over time. Our data suggest that improved compliance with lithium guidelines is not reflected in less risk for severe renal damage. [ABSTRACT FROM AUTHOR]

A patient with schizoaffective disorder and receiving long‐term treatment with lithium developed prolonged delirium. She had recently been diagnosed with stage IVB endometrial cancer and presented a deteriorating general condition. Toxic levels of lithium were measured in serum. After hemodialysis, lithium levels gradually decreased and the symptoms disappeared completely. [ABSTRACT FROM AUTHOR]

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]

Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3β (GSK3β) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3β, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3β protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3β and possibly associated with a decrease in muscle injury. [ABSTRACT FROM AUTHOR]

Background: Lithium is one of the most consistently effective treatment for mood disorders. However, patients may show a high level of heterogeneity in treatment response across the lifespan. In particular, the benefits of lithium use may vary in special clinical conditions. The aim of this study was to test this hypothesis by conducting an umbrella review on the efficacy and safety of lithium in childhood and adolescence, peripartum and old age. Methods: We applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (PRISMA) to identify systematic reviews/meta-analyses on the efficacy and/or safety of lithium in mood disorders in special clinical conditions: (i) childhood and adolescence; (ii) peripartum (pregnancy, postpartum and lactation); (iii) old age. The Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool was used to assess the risk of bias. Overlap in primary studies across systematic reviews was calculated through the Corrected Covered Area (CCA). Results: We included 20 independent studies, for a total of 8209 individuals treated with lithium. Regarding paediatric age, efficacy and safety results suggested that lithium may be superior to placebo in bipolar disorders (BD) and not associated with serious adverse events. Nevertheless, primary available data are very limited. Efficacy in paediatric major depressive disorder (MDD) is not clear. During peripartum, lithium use was superior to non-lithium in preventing mood episodes and it was associated with low risk of congenital anomalies and with normal child neurodevelopment. Regarding old age, limited evidence supported lithium as an effective treatment in BD and resistant MDD; low doses should be used in this population. Systematic reviews on paediatric age showed the lowest risk of bias (80% of the studies at low risk). The CCA range of included studies was 13–47%. Conclusions: This umbrella review supports the use of lithium across the lifespan, including special clinical condition. Nevertheless, more studies with increased methodological homogeneity are needed. [ABSTRACT FROM AUTHOR]

Background: Lithium is well recognized as the first-line maintenance treatment for bipolar disorder (BD). However, besides therapeutic benefits attributed to lithium therapy, the associated side effects including endocrinological and renal disorders constitute important parameters in prescribing patterns and patient adherence. The objectives of this study is to (i) determine whether long-term lithium therapy is associated with a decrease in renal function, hyperparathyroidism and hypercalcemia and (ii) identify risk factors for lithium-induced chronic kidney disease (CKD). Methods: We conducted a single-centered cohort study of adult patients (≥ 18 years) treated with lithium, who were enrolled at Rennes University Hospital in France between January 1, 2018 and June 1, 2020. Required data were collected from the patient's medical records: demographics characteristics (age, sex, body mass index), biologic parameters (GFR, lithium blood level, PTH and calcium), medical comorbidities (hypertension and diabetes), lithium treatment duration and dosage, and length of hospitalization. Results: A total of 248 patients were included (mean age: 60.2 ± 16.5 years). Duration of lithium treatment correlated with (i) deterioration of renal function estimated at − 2.9 mL/min/year (p < 0.0001) and (ii) the development of hyperparathyroidism (p < 0.01) and hypercalcemia (p < 0.01). We also noted that patients with lithium blood level > 0.8 mEq/mL had significantly lower GFR than patients with lithium blood level < 0.8 mEq/mL (61.8 mL/min versus 77.6 mL/min, respectively, p = 0.0134). Neither diabetes mellitus nor hypertension was associated with more rapid deterioration of renal function. Conclusion: This study suggests that the duration of lithium treatment contribute to the deterioration of renal function, raising the question of reducing dosages in patients with a GFR < 60 mL/min. Overdoses has been identified as a risk factor for CKD, emphasizing the importance of regular re-evaluation of the lithium dose regimen. Also, long-term lithium therapy was associated with hyperparathyroidism and hypercalcemia. Particular vigilance is required on these points in order to limit the occurrence of endocrinological and renal lithium adverse effects. [ABSTRACT FROM AUTHOR]

Lithium has proven its efficacy in treating bipolar disorder. Severe side effects caused by lithium, including renal and endocrine outcomes, have already been amply documented. The impact of lithium on sexual function, however, is less well known. A 33-year-old man, with no past medical history, diagnosed with bipolar disorder, developed premature ejaculation after short-term use of lithium. The dose of lithium was reduced, leading to a rapid clinical resolution. Retrospectively, lithium-induced premature ejaculation was deemed the most likely diagnosis. Premature ejaculation is a rare side effect of lithium. Changing the time of medication administration and lowering dose could be considered as alternatives. Given lithium's pharmacological profile, it is likely that the pathophysiologic mechanism behind premature ejaculation is altered levels or altered serotonin receptor sensitivity in the ejaculatory modulating centers of the central nervous system. Given the reluctance to spontaneously report sexual adverse effects, clinicians should be aware of this possible side effect. [ABSTRACT FROM AUTHOR]

Lithium remains the drug of first choice for prophylactic treatment of bipolar disorder, preventing the recurrences of manic and depressive episodes. The longitudinal experiences with lithium administration greatly exceed those with other mood stabilizers. Among the adverse side effects of lithium, renal, gastrointestinal, neurological, thyroid, metabolic, cognitive, dermatological, cardiologic, and sexual are listed. Probably, the most important negative effect of lithium, occurring mostly after 10–20 years of its administration, is interstitial nephropathy. Beneficial side-effects of long-term lithium therapy also occur such as anti-suicidal, antiviral, and anti-dementia ones. Pharmacokinetic and pharmacodynamic interactions of lithium, mostly those with other drugs, may have an impact on the success of long-term lithium treatment. This paper makes the narrative updated review of lithium-induced side-effects and interactions that may influence its prophylactic effect in bipolar disorder. Their description, mechanisms, and management strategies are provided. The papers appearing in recent years focused mainly on the long-term lithium treatment are reviewed in detail, including recent research performed at Department of Psychiatry, Poznan University of Medical Sciences, Poland. Their own observations on ultra-long lithium treatment of patients with bipolar disorder are also presented. The review can help psychiatrists to perform a successful lithium prophylaxis in bipolar patients. [ABSTRACT FROM AUTHOR]

Background: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. Methods: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. Results: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. Conclusions: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment. [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]

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]

Background: The efficacy and safety of adjunctive therapy are unclear in bipolar depression. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of second-generation antipsychotic, lamotrigine, lithium, or valproate therapy used in adjunction with lamotrigine, lithium, or valproate monotherapy in bipolar depression. A literature search of major electronic databases was conducted in February 2021, and all articles published until then were eligible. Two researchers independently screened relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria. Results: Five studies met the inclusion criteria. The meta-analysis revealed significant differences in the following outcomes: (i) remission rates from depressive episodes (risk ratio [RR]: 1.23, 95% confidence interval [CI] 1.01–1.50, p = 0.04), (ii) improvement in depressive symptoms (standardized mean difference [SMD]: 0.21, 95% CI 0.09–0.34, p = 0.001), (iii) improvement in quality of life (SMD: 0.22, 95% CI 0.06–0.37, p = 0.005), and (iv) rate of adverse events during the study period (RR: 1.12, 95% CI 1.03–1.22, p = 0.008). There was no significant difference between adjunctive therapy and monotherapy in the emergence of suicide-related behaviors, dropout rate during the study period, or rate of manic switching. Conclusions: Our results suggest that adjunctive second-generation antipsychotics, lamotrigine, lithium, or valproate increase both the benefits and risks in patients with bipolar depression, although there is no significant difference in severe adverse events. Adjunctive therapy should be provided through shared decision-making while considering the patients' condition in clinical settings. [ABSTRACT FROM AUTHOR]

Purpose: Despite lithium being a gold standard treatment for bipolar disorder, the percentage of patients with bipolar disorder who are prescribed lithium medication has declined in many parts of the world over the past two decades. The use of lithium is limited by its narrow therapeutic window and adverse side effects, which necessitates frequent serum lithium monitoring; hence, there is a critical need for improved ways to monitor lithium levels in psychiatric patients. We have recently shown that saliva lithium levels are highly correlated with those in blood, thereby presenting an alternative to venipuncture. Saliva sampling could open the door for at-home collections – potential that has been exemplified throughout the COVID-19 pandemic – thereby allowing samples to be collected remotely and delivered to a specific site for testing. In addition, prototype point-of-care devices have been developed by others for serum lithium monitoring, suggesting potential for a saliva lithium monitoring device. Our objective was to query the perspectives of American psychiatrists on lithium treatment practices and obstacles, the potential for at-home saliva collection and point-of-care devices, for lithium monitoring, as an alternative to pathology-based blood testing. Methods: Data was collected through an online, anonymous survey, distributed to American psychiatric societies. Results: Sixty-five respondents from 21 American states completed the survey. The majority of respondents were female, over 65 years of age, and/or had practiced for 30 years or more. The most frequent obstacles encountered with regard to lithium monitoring were adverse drug effects, and the need for monitoring. Overall, respondents believed saliva lithium monitoring and point-of-care devices would be useful, however raised concerns regarding validity and time-delay. Conclusion: Point-of-care devices and saliva lithium monitoring are promising alternatives to blood testing that would be welcomed by psychiatric societies, however, require extensive development and validation before implementation into a clinical setting. [ABSTRACT FROM AUTHOR]

Childhood Disintegrative Disorder (CDD) is a rare condition characterized by regression of developmental and behavioral functioning after a period of apparently normal development, with an age of onset around 4 years. CDD is not included within the latest edition of the Diagnostic and Statistical Manual of Mental Disorders. We present a case report of an 11-year-old male who achieved normal development for up to 7 years followed by a deterioration of previously acquired linguistic, intellectual, and social skills. Following treatment with lithium carbonate combined with risperidone, the patient experienced a reduction in irritability and aggression. CDD is a rare condition; therefore, the data presented may be useful to investigate its characteristics of the onset, to improve the understanding of the aspects of differentiation from the Autism Spectrum Disorder and finally to propose the possibility of treatment [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]

The affective variability of bipolar disorder (BD) is thought to qualitatively differ from that of borderline personality disorder (BPD), with changes in affect persisting longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group, and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 y from patients with BD or BPD and nonclinical controls. In a separate experimental medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week 22 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD, whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses. [ABSTRACT FROM AUTHOR]

BACKGROUND Lithium is widely used for the treatment of bipolar disorder. Owing to its narrow therapeutic index and side-effect profile, regular monitoring is recommended by all major guidelines on lithium use. AIMS The aim of this study was to determine whether routine lithium monitoring practice at the local mental hospital in Malta reaches the standard set by the NICE guidelines in 2014. METHOD All patients on lithium maintenance treatment for bipolar disorder at the local Mental Hospital were included. Blood tests within the last one year were collected using iSOFT clinical manager (iCM). After the first audit cycle, a lithium monitoring sheet was created in accordance with the NICE guideline and after 6 months of implementation, the second audit cycle was conducted. RESULTS In the first cycle, 28 patients met the NICE criteria for increased risk of toxicity and have a recommended testing frequency for lithium levels of every 3 months. However, only 1 patient (3.7%) was observed to meet this criteria. When assessing the last lithium level only 35.7% were within 0.4-0.8 mmol/L. In the second audit cycle, 28 patients met the NICE criteria for increased risk of toxicity and have a recommended testing frequency for lithium levels of every 3 months. Almost half of the patients (12 patients, 42.8%) were to observed to meet this criteria. When assessing the last lithium level, 50.0% were within 0.4-0.8 mmol/L. CONCLUSIONS The introduction of the lithium monitoring sheet helped significantly in increasing the monitoring of lithium levels in patients which are at a higher risk of lithium toxicity. Moreover, the monitoring sheet helped the clinicians in maintaining lithium levels within the normal therapeutic range, hence prevent unwanted side effects related to lithium toxicity. [ABSTRACT FROM AUTHOR]

Objective: In a nation-wide population-based longitudinal register linkage study for the first time 1) to investigate long-term response to lithium in patients with bipolar disorder with and without comorbid epilepsy, and 2) within patients with bipolar disorder and comorbid epilepsy to compare differences in responses between lithium, valproate and lamotrigine.Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 154 patients with bipolar disorder and comorbid epilepsy and 8381 patients with bipolar disorder without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with lithium, valproate or lamotrigine without switch to or add-on of an antipsychotic drug or an antidepressant or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy.Results: Response to lithium was decreased in patients with bipolar disorder with versus without comorbid epilepsy during the ten-year follow-up period and the difference remained after standardization for comorbidity with other physical disorders than epilepsy. Within patients with bipolar disorder and comorbid epilepsy, response to lithium was decreased compared with responses to valproate and lamotrigine.Conclusions: The findings suggest that valproate and lamotrigine should be given priority in patients with comorbid bipolar disorder and epilepsy. The study highlights the need for closely clinical monitoring and psychological support for patients with bipolar disorder and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate lithium in the treatment of acute bipolar depression.Methods: We conducted a systematic literature review for: 1) cross-over or parallel-group design studies comparing lithium response in bipolar versus unipolar depressed patients, and 2) parallel group studies of bipolar depressed patients comparing lithium versus placebo or other psychotropics. Meta-analyses using response rate as the primary outcome were conducted to evaluate lithium's efficacy.Results: The literature search yielded 947 records. Ultimately, 17 studies were included, totaling 1545 patients, including 676 who received lithium. The overall summary effects reveal that there were no statistically significant differences between lithium versus antidepressants or placebo, however, lithium performed numerically worse than antidepressants (RR = 0.61; 95%CI, 0.37-1.02; p = 0.06) but better than placebo (RR = 1.18; 95%CI, 0.99-1.41; p = 0.07). The specificity of lithium for bipolar versus unipolar depression was not supported in the primary analysis of all trials, though an analysis limited to double-blinded, monotherapy, cross-over studies revealed a statistically significant result supporting lithium's efficacy for those with bipolar depression.Limitations: Limitations include study selection rules, the use of response rates rather than remission rates or continuous score outcomes, and the small number of studies included in each meta-analysis.Conclusions: These meta-analyses do not support lithium as a first-line treatment for acute bipolar depression. However, the bipolar vs. unipolar sensitivity analysis and the modest, though non-significant advantage over placebo suggest lithium may still be a viable treatment option. Larger and more rigorously-designed studies are needed to determine lithium's full range of efficacy relative to placebo and other psychotropics. [ABSTRACT FROM AUTHOR]

Background: Comorbid anxiety is pervasive and carries an immense psychosocial burden for patients with bipolar disorder. Despite this, trials reporting anxiety-related outcomes in this population are uncommon, particularly with regards to monotherapies.Methods: Patients (n = 31) with both bipolar I or II disorder in current depressive episodes were enrolled in a six-week, open-label, single-center trial assessing the efficacy of lithium monotherapy in treating symptoms depression and comorbid anxiety. Patients were mostly medication-free and lithium-naïve at baseline.Results: Significant improvements in depression (HAMD) and anxiety (HAM-A) were observed at the six-week endpoint, with remission and response rates greater than 50%. There was a positive correlation between endpoint HAM-A scores and HAM-D scores, r = 0.80, (p < 0.01). Improvements were realized at low serum lithium concentrations (0.49 ± 0.20 mEq/L).Limitations: Lack of placebo control and small sample size warrants validation in larger randomized studies.Conclusions: Taken in the context of prior evidence, lithium may have an important role in treating comorbid anxiety in bipolar disorder, both as adjunct and monotherapy. Lower doses of lithium may provide equivalent efficacy and enhance tolerability and compliance. [ABSTRACT FROM AUTHOR]

Background: Vasogenic cerebral edema resulting from blood–brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β‐catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β‐catenin signaling. Methods: We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV‐induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β‐catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124. Results: Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β‐catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin‐5 and ZO‐1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124‐mediated endothelial Wnt/β‐catenin signaling. Conclusion: Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH. [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]

Background: Dementia is the leading cause of death in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. There are no disease-modifying treatments currently available. Lithium has been proposed as a potential treatment. We assessed the association between lithium use and the incidence of dementia and its subtypes. Methods and findings: We conducted a retrospective cohort study comparing patients treated between January 1, 2005 and December 31, 2019, using data from electronic clinical records of secondary care mental health (MH) services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million). Eligible patients were those aged 50 years or over at baseline and who had at least 1 year follow-up, excluding patients with a diagnosis of mild cognitive impairment (MCI) or dementia before, or less than 1 year after, their start date. The intervention was the use of lithium. The main outcomes were dementia and its subtypes, diagnosed and classified according to the International Classification of Diseases-10th Revision (ICD-10). In this cohort, 29,618 patients (of whom 548 were exposed to lithium) were included. Their mean age was 73.9 years. A total of 40.2% were male, 33.3% were married or in a civil partnership, and 71.0% were of white ethnicity. Lithium-exposed patients were more likely to be married, cohabiting or in a civil partnership, to be a current/former smoker, to have used antipsychotics, and to have comorbid depression, mania/bipolar affective disorder (BPAD), hypertension, central vascular disease, diabetes mellitus, or hyperlipidemias. No significant difference between the 2 groups was observed for other characteristics, including age, sex, and alcohol-related disorders. In the exposed cohort, 53 (9.7%) patients were diagnosed with dementia, including 36 (6.8%) with Alzheimer disease (AD) and 13 (2.6%) with vascular dementia (VD). In the unexposed cohort, corresponding numbers were the following: dementia 3,244 (11.2%), AD 2,276 (8.1%), and VD 698 (2.6%). After controlling for sociodemographic factors, smoking status, other medications, other mental comorbidities, and physical comorbidities, lithium use was associated with a lower risk of dementia (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40 to 0.78), including AD (HR 0.55, 95% CI 0.37 to 0.82) and VD (HR 0.36, 95% CI 0.19 to 0.69). Lithium appeared protective in short-term (≤1-year exposure) and long-term lithium users (>5-year exposure); a lack of difference for intermediate durations was likely due to lack of power, but there was some evidence for additional benefit with longer exposure durations. The main limitation was the handling of BPAD, the most common reason for lithium prescription but also a risk factor for dementia. This potential confounder would most likely cause an increase in dementia in the exposed group, whereas we found the opposite, and the sensitivity analysis confirmed the primary results. However, the specific nature of the group of patients exposed to lithium means that caution is needed in extending these findings to the general population. Another limitation is that our sample size of patients using lithium was small, reflected in the wide CIs for results relating to some durations of lithium exposure, although again sensitivity analyses remained consistent with our primary findings. Conclusions: We observed an association between lithium use and a decreased risk of developing dementia. This lends further support to the idea that lithium may be a disease-modifying treatment for dementia and that this is a promising treatment to take forwards to larger randomised controlled trials (RCTs) for this indication. Shanquan Chen and colleagues investigate the association between lithium use and the incidence of dementia and its subtypes. Author summary: Why was this study done?: Dementia is the leading cause of death and disability in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. Lithium has been proposed as a potential treatment, but limited population-level research has been conducted to support the idea that lithium might delay the onset of dementia. What did the researchers do and find?: We identified 548 patients who were exposed to lithium and 29,070 patients who were not exposed to lithium between January 1, 2005 and December 31, 2019, using data from electronic clinical records of secondary care mental health (MH) services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), UK. We assessed the association between lithium use and the incidence of dementia and its subtypes, including Alzheimer disease (AD) and vascular dementia (VD). We found that lithium was associated with a lower risk of receiving a diagnosis of dementia, including a lower risk of being diagnosed with either AD or VD. The extended analysis by the duration of lithium treatment indicated that both short- (≤1-year exposure) and long-term (>5-year exposure) lithium exposure (but not medium term, 1- to 5-year lithium exposure) was associated with decreased incidence of dementia and its subtypes. Power was less for the intermediate durations. There was some evidence for additional benefit with longer exposure durations. What do these findings mean?: Our findings support the possibility that lithium treatment could decrease the risk of developing dementia and supports the need for further randomised controlled trials (RCTs) to test the efficacy of lithium as a disease-modifying drug in dementia. The main limitation is that 73% of the patients in lithium-exposed group had mania/bipolar affective disorder (BPAD), which is a significant risk factor for dementia. Our results were in the opposite direction, however, and were supported by sensitivity analyses. [ABSTRACT FROM AUTHOR]

Background: Lithium-induced nephrotoxicity has long been debated. However, it has been rarely explored in Asian populations. The aim of the present study was to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in Korean patients diagnosed with a psychiatric illness. Methods: This was a single-centered, retrospective study that included patients treated with lithium or comparator drug (valproate) in Samsung Seoul Medical Center between November 1994 and July 2020. Patients diagnosed with ICD codes F20-33 who had ≥ 6 months of exposure to lithium or valproate were included. Patients had to have ≥ 1 baseline and ≥ 2 post-baseline eGFR data with post-baseline data having an interval of at least 30 days. Chronic kidney disease (CKD) was defined as CKD stage 3 (eGFR < 60 mL/min/1.732). To be considered as CKD, the threshold had to be met at two consecutive post-baseline measurements. Those treated with both lithium and valproate, diagnosed with CKD stages 3–5, diagnosed with a renal disease, or received kidney transplantation were excluded. Results: A total of 766 patients were included (242 treated with lithium and 524 with valproate). Two (0.8%) in the lithium group and 8 (1.5%) in the valproate group developed CKD stage 3. None developed CKD stages 4–5. Median yearly eGFR change was − 1.3 mL/min/1.732 (IQR: − 6.8, 1.7) for the lithium group and − 1.1 mL/min/1.732 (IQR: − 4.5, 1.5) for the valproate group, showing no significant difference between the two groups (p = 0.389). The rate of decline was more rapid for those with CKD in both groups. eGFR values of lithium and valproate groups did not show significant differences during a follow-up duration of 15 years or more. A significant negative correlation between baseline eGFR and yearly eGFR change was identified in a linear regression analysis. Conclusions: In Korean patients, treatment with lithium did not increase the risk of developing CKD compared to treatment with valproate. Prevalence of CKD was lower than those previously reported in western populations. Low baseline eGFR showed significant correlation with changes in renal function. [ABSTRACT FROM AUTHOR]