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Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of MARK2 loss. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), we show that MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2 +/− mice showed abnormal cortical formation and partition and ASD-like behavior. Through the use of RNA sequencing (RNA-seq) and lithium treatment, we link MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identify lithium as a potential drug for treating MARK2 -associated ASD. [Display omitted] MARK2 plays essential roles in the central nervous system. Here, we demonstrate the association between MARK2 variants, downregulated WNT/β-catenin signaling, and autism spectrum disorder (ASD) through the study of individuals with ASD and Mark2 +/− mice. [ABSTRACT FROM AUTHOR]

GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit a shift from a diurnal anxiety state to a nocturnal normal or anxiolytic-like state. Overexpression of NEK4 also affects the circadian fluctuations in dendritic spine morphology and synaptic structure. Furthermore, we show that treatment with lithium ameliorates the effects of NEK4 overexpression in male mice. We then perform phosphoproteomic analyses to demonstrate that the diurnal and nocturnal phosphoproteomic profiles of male control and NEK4 overexpressing mice are different. These results suggest that male mice with different NEK4 expression levels may recapitulate some of the core features observed in patients with bipolar disorder, indicating that interruption of the homeostatic dynamics of synapses may underlie the emotional swings in bipolar disorder. The expression levels of NEK4 have been associated with bipolar disorder in GWAS. Here, the authors examine the physiological effects of overexpressing NEK4 in the hippocampus of mice, showing that it leads to aberrations in circadian traits. [ABSTRACT FROM AUTHOR]

Background: Lithium is the gold-standard treatment for Bipolar Disorder (BD) in both adults and adolescents, effectively managing mood episodes and reducing suicide risk. While its efficacy in neurotypical youth is well established, its use in adolescents with Autism Spectrum Disorder (ASD) and comorbid BD remains under-researched. Here, we present the protocol for a study aiming to evaluate the efficacy and tolerability of Extended-Release Lithium Salts in treating adolescents with BD and comorbid ASD compared to neurotypical BD patients. Methods: This longitudinal prospective naturalistic comparative study will enroll lithium-naïve adolescents aged 12–18 with BD, with or without comorbid ASD, from the Department of Child and Adolescent Psychiatry and Psychopharmacology. Participants will be followed for six months while receiving Extended-Release Lithium Salts treatment. Primary outcomes will include mood instability, suicidality, emotional dysregulation, and aggression, assessed through a range of clinical rating scales and diagnostic tools at baseline, three months, and six months. Secondary outcomes will focus on the safety and tolerability of Extended-Release Lithium Salts, with measures including side effect ratings, physical exams, and laboratory tests. Results: We hypothesize that Extended-Release Lithium Salts will demonstrate non-inferiority in treating BD symptoms in adolescents with comorbid ASD compared to those without ASD. Conclusions: This study is poised to fill a significant gap in the literature by providing critical data on the use of lithium for adolescents with BD and ASD. Findings will inform clinical practice and future research, potentially guiding more personalized treatment approaches for this complex and vulnerable population. [ABSTRACT FROM AUTHOR]

Copyright of Food Research & Development is the property of Food Research & Development Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

It is studied how the treatment of a metal lithium surface with a 1 M LiN(CF3SO2)2 solution in the 1,3-dioxolane/1,2-dimethoxyethane (2 : 1) mixture affects the resistance of the interphases formed by lithium with the polymer and nanocomposite electrolytes based on the 1-ethyl-3-methylimidazolium tetrafluoroborate ionic liquid. The liquid-phase therapy is shown to reduce the resistance at the Li/electrolyte interphase by a factor of 2.5 at room temperature and extend the working temperature range to –30°C. The introduction of TiO2 nanoparticles into the polymer electrolyte, along with the liquid-phase therapy of both the cathode and the Li-anode, provides a high and stable discharge capacity of the Li//LiFePO4 battery for 100 charge–discharge cycles. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to review and summarise the existing human literature on the association between lithium and hyperparathyroidism. Methods: A systematic literature search was carried out according to PRISMA guidelines (last search 27 February 2024), using MEDLINE, Web of Science, Embase and the Cochrane Library. A meta-analysis was performed to determine the prevalence of lithium-associated hypercalcemia (LAHca) in lithium-treated patients. Results: The pooled prevalence of LAHca based on total calcium and ionised calcium was comparable, at 3.17% and 4.23%, respectively. Calcium, and PTH if the patient is hypercalcaemic, is insufficiently measured in lithium-treated patients in clinical practice. Lithium use is associated with higher calcium and PTH levels, as well as a higher incidence of hyperparathyroidism. There is a high prevalence of multiglandular disease in lithium-associated hyperparathyroidism (LAH), with a pooled prevalence of 51.28%. Parathyroid surgery and cinacalcet are effective treatments for LAH. Regarding lithium discontinuation, there is anecdotal but conflicting evidence suggesting that it can result in the resolution of LAH in selected cases. Conclusions: Lithium treatment increases the risk of hyperparathyroidism, a treatable complication with a pooled prevalence of around 4%, compared to 0.5% in the healthy population. [ABSTRACT FROM AUTHOR]

Lithium, a natural element, has been employed as a mental stabilizer in psychiatric treatments; however, some reports indicate it has an anticancer effect, prompting the consideration of repurposing lithium for cancer treatment. The potential anticancer use of lithium may depend on its form (salt type) and the type of cancer cells targeted. Little is known about the effects of Li2CO3 or LiCl on cancer cells, so we focused on exploring their effects on proliferation, apoptosis, migration, and cell cycle as part of the hallmarks of cancer. Firstly, we established the IC50 values on HeLa, SiHa, and HaCaT cells with LiCl and Li2CO3 and determined by crystal violet that cell proliferation was time-dependent in the three cell lines (IC50 values for LiCl were 23.43 mM for SiHa, 23.14 mM for HeLa, and 15.10 mM for HaCaT cells, while the IC50 values for Li2CO3 were 20.57 mM for SiHa, 11.52 mM for HeLa, and 10.52 mM for HaCaT cells.) Our findings indicate that Li2CO3 and LiCl induce DNA fragmentation and caspase-independent apoptosis, as shown by TUNEL, Western Blot, and Annexin V/IP assay by flow cytometry. Also, cell cycle analysis showed that LiCl and Li2CO3 arrested the cervical cancer cells at the G1 phase. Moreover, lithium salts displayed an anti-migratory effect on the three cell lines observed by the wound-healing assay. All these findings imply the viable anticancer effect of lithium salts by targeting several of the hallmarks of cancer. [ABSTRACT FROM AUTHOR]

Introduction: Lithium is a key medication for treating various neuropsychiatric disorders, with a narrow therapeutic index and significant drug interactions. Monitoring lithium blood levels is crucial. This study aims to investigate the relationship between lithium blood levels and demographic characteristics such as age and gender, as well as possible drug interactions, in patients with a history of lithium use who applied to various services and outpatient clinics. Materials & Methods: The files of 438 patients who were admitted to various services and outpatient clinics of Kırklareli Training and Research Hospital between January 1 and December 31, 2023, were retrospectively reviewed. Patients' blood lithium levels, gender, age, service/outpatient clinic they admitted to, other medications used, urea, creatinine, and eGFR values were recorded. Results: When the demographic characteristics of 438 patientswere examined, 62% were female (270), 38%weremale (168), and the average agewas 46.3 ± 14.8 years, showing a normal distribution. It was found that 192 patients (71 males, 121 females) had therapeutic lithium blood levels, while 244 patients (97 males, 147 females) had levels below 0.6 mmol/L. Two female patients had blood levels above the therapeutic range (1.23 and 1.43 mmol/L). Among the clinics and services, the four most frequented were the psychiatry clinic (314 patients), internalmedicine clinic (36 patients), emergency service (27 patients), and medical oncology clinic (17 patients). Of the 314 patients admitted to the psychiatry clinic, 168 had therapeutic drug levels; only 7 of the 36 admitted to internal medicine had therapeutic levels; 12 of the 27 patients in the emergency service had therapeutic levels; and all 17 patients in medical oncology had levels below therapeutic limits. Discussion: The data emphasize the importance of regular blood level monitoring to ensure lithium treatment's efficacy and patient safety. It is noteworthy that most patients in the psychiatry clinic had therapeutic drug levels, while those in other clinics had lower levels. Conclusion: In conclusion, this study highlights the importance of regular blood level monitoring to ensure the efficacy and safety of lithium treatment. [ABSTRACT FROM AUTHOR]

Introduction: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests hemodialysis in severe lithium poisoning if specific criteria are met. One criterion is if the expected time to obtain a lithium concentration <1.0 mEq/L with optimal management is >36 h. There are a lack of data regarding which patient characteristics are associated with the rate at which patients achieve a lithium concentration <1.0 mEq/L. Methods: We conducted a retrospective chart review analyzing hospital electronic medical records. Inclusion criteria consisted of a lithium concentration >1.2 mEq/L during hospitalization. We excluded patients who received extracorporeal treatment before 36 h elapsed from time of initial lithium concentration >1.2 mEq/L. The primary analysis consisted of a Cox regression and a secondary analysis evaluated the nomogram method described by Buckley and colleagues for predicting prolonged supratherapeutic lithium concentration. Results: One hundred and one patients were included in the study. The median time to reach a lithium concentration <1.0 mEq/L was 42.5 h (IQR: 33.8–51.1). Older patients, patients taking a thiazide, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, patients with a higher initial lithium concentration, and patients with higher sodium concentrations achieved a lithium concentration <1 mEq/L at a slower rate. For the nomogram analysis, sensitivity (61.5%) and specificity (54.5%) were moderate, the positive predictive value (16.7%) was poor, and the negative predictive value (90.6%) was excellent. Discussion: The results from our primary analysis suggest that identifying higher serum sodium concentration and use of certain antihypertensives that decrease glomerular filtration rate as predictors of an increased time to reach a therapeutic lithium concentration may help identify patients who meet the Extracorporeal Treatments in Poisoning criteria for hemodialysis. The nomogram method performed similarly to prior validation studies. Conclusions: In this retrospective chart review of patients with supratherapeutic lithium concentrations, we identified several risk factors for prolonged supratherapeutic lithium concentrations. [ABSTRACT FROM AUTHOR]

Lithium is commonly used in the treatment of bipolar disorders (BD) and consumer electronics. It has been reported that lithium exposure is associated with mitochondrial dysfunction and oxidative stress in isolated cardiac mitochondria. Mitochondrial protection has a key role in myocardial tissue homeostasis, cardiomyocyte survival and inhibition of cardiotoxicity. Hesperidin as a flavanone and cardioprotective agent has shown high potential in antioxidant activity and restoration of mitochondrial dysfunction in different models. Therefore, we aimed to evaluate the ameliorative effects of hesperidin against lithium-induced mitochondrial toxicity in rat cardiac mitochondria. Isolated mitochondria were classified into six groups; control, lithium carbonate (125 µM), three groups of lithium + hesperidin-treated received lithium (125 µM) and hesperidin with various concentrations (10, 50, and 100 µM) and hesperidin (100 µM). Succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial glutathione (GSH) and lipid peroxidation (LPO) were measured. The mitochondria received lithium showed a significant reduction of SDH activity, MMP collapse, mitochondrial swelling, induction of ROS formation and lipid peroxidation. However, we observed that the administration of hesperidin (50 and 100 µM) resulted in the increase of SDH activity, improved MMP collapse, mitochondrial swelling, and reduced ROS formation and lipid peroxidation. Also, there were no obvious changes in cardiac mitochondria received of hesperidin. These findings suggest that hesperidin could reduce lithium-induced mitochondrial dysfunction through antioxidant activities in cardiac mitochondria, may be beneficial for prevention and treatment of lithium toxicities, either as a drug to treat BD or as an environmental pollutant. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical results of single-tooth ceramic crowns in the posterior region produced from three different monolithic materials.Materials and Methods: A total of 36 posterior single-tooth crowns were fabricated from lithium silicate glass-ceramic (LSGC; n = 12), lithium disilicate glass-ceramic (LDGC; n = 12), and polymer-infiltrated ceramic network (PICN; n = 12) in 27 patients. Restorations were evaluated for prosthetic and periodontal criteria at baseline and after 6 and 12 months. Prosthetic evaluation was performed according to the Modified United States Public Health Service criteria, and probing depth (PD), clinical attachment level (CAL), gingival bleeding time index (GBTI), and gingival (GI) and periodontal indices (PI) were evaluated in the periodontal assessment. Friedman and Kruskal-Wallis tests were used for statistical analyses (P = .05).Results: All restorations were evaluated according to survival and success rates. No dropouts occurred. The survival rate of all three materials was 100% after 1 year. However, in the PICN group, a statistically significant difference was found between baseline (0) and 12 months for color match (from Alpha to Bravo) and surface texture (from Alpha to Charlie) (P < .001).Conclusion: Although long-term clinical follow-up periods are needed, all three ceramics showed clinically acceptable survival and success rates over 1 year. The ceramics evaluated in the present study could be preferred for single-tooth full-crown restorations in the posterior region. [ABSTRACT FROM AUTHOR]

Background/Objectives: Lithium taken during pregnancy was linked in the past with increased risk for foetal/newborn malformations, but clinicians believe that it is worse for newborn children not to treat the mothers' underlying psychiatric illness. We set to review the available evidence of adverse foetal outcomes in women who received lithium treatment for some time during their pregnancy. Methods: We searched four databases and a register to seek papers reporting neonatal outcomes of women who took lithium during their pregnancy by using the appropriate terms. We adopted the PRISMA statement and used Delphi rounds among all the authors to assess eligibility and the Cochrane Risk-of-Bias tool to evaluate the RoB of the included studies. Results: We found 28 eligible studies, 10 of which met the criteria for inclusion in the meta-analysis. The studies regarded 1402 newborn babies and 2595 women exposed to lithium. Overall, the systematic review found slightly increased adverse pregnancy outcomes for women taking lithium for both the first trimester only and any time during pregnancy, while the meta-analysis found increased odds for cardiac or other malformations, preterm birth, and a large size for gestational age with lithium at any time during pregnancy. Conclusions: Women with BD planning a pregnancy should consider discontinuing lithium when euthymic; lithium use during the first trimester and at any time during pregnancy increases the odds for some adverse pregnancy outcomes. Once the pregnancy has started, there is no reason for discontinuing lithium; close foetal monitoring and regular blood lithium levels may obviate some disadvantages of lithium administration during pregnancy. [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]

Key content: The perinatal period confers an elevated risk of both relapses and new onset of mental illness. Suboptimal treatment can have a profound impact on maternal mortality and morbidity, neonatal outcomes and longer term child development.Most psychotropic medication can be used safely in pregnancy, with some notable exceptions.While decisions on the use of psychotropic medications in pregnancy are often complex and should be multidisciplinary, it is imperative that obstetricians and gynaecologists familiarise themselves with current literature to provide evidence‐based counselling and care.Existing guidelines on the use of psychotropic medication are largely aimed at psychiatrists, and to date there has been a lack of concise, digestible information with a focus on core knowledge for obstetricians and gynaecologists.We summarise existing evidence on the use of antidepressants, antipsychotics, mood stabilisers and sedatives in the perinatal period. For each drug class we describe the teratogenicity, impact on pregnancy, breastfeeding and the newborn. Learning objectives: To be familiar with common psychotropic medication used in pregnancy and the postpartum period.To understand key evidence on the safety profile of psychiatric medication in the perinatal period and apply this to individualised counselling. [ABSTRACT FROM AUTHOR]

Kleine Levin syndrome (KLS) is a rare entity. It presents with subacute onset episodic hypersomnia, cognitive decline, altered perception, and occasional hyperphagia and hypersexuality with full recovery during the interepisodic period. Five cases presented with episodic hypersomnia and met the diagnostic criteria of KLS. The majority of the cases were females (3/5) in whom KLS is even rarer. The initial presentation was in the age range of 10--25 years. Cognitive dysfunction (5/5), derealization (4/5), viral prodrome (3/5), hyperphagia (3/5), and hypersexuality (2/5) were other clinical presentations. A differential diagnosis of atypical depression is the major challenge, and thorough history taking would help in differentiation. Treatment with stimulants (modafinil) and mood stabilizers (lithium) proved effective. A high degree of suspicion should be kept for cases of episodic hypersomnolence for early diagnosis and management of KLS. [ABSTRACT FROM AUTHOR]

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]

Copyright of Acta Stomatologica Croatica is the property of Acta Stomatologica Croatica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Stenotrophomonas maltophilia is a gram-negative bacterium that can cause hospital infections and outbreaks within hospitals. This study aimed to evaluate an outbreak of Stenotrophomonas maltophilia, caused by ready-to-use commercial syringes containing liquid lithium and heparin for arterial blood gas collection in a university hospital. Methods: Upon detecting an increase in Stenotrophomonas maltophilia growth in blood cultures between 15.09.2021 and 19.11.2021, an outbreak analysis and a case-control study (52 patients for the case group, 56 patients for the control group) were performed considering risk factors for bacteremia. Samples from possible foci for bacteremia were also cultured. Growing bacteria were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The genetic linkage and clonal relationship isolates were investigated with pulsed-field gel electrophoresis (PFGE) in the reference laboratory. Results: In the case-control study, the odds ratio for the central venous catheter [3.38 (95% confidence interval [CI]: 1.444, 8.705 ; p = 0.006)], for surgery [3.387 (95% confidence interval [CI]: 1.370, 8.373 ; p = 0.008)] and for arterial blood gas collection history [18.584 (95% confidence interval [CI]:4.086, 84.197; p < 0.001)] were identified as significant risk factors. Stenotrophomonas maltophilia growth was found in ready-to-use commercial syringes used for arterial blood gas collection. Molecular analysis showed that the growths in the samples taken from commercial syringes and the growths from blood cultures were the same. It was decided that the epidemic occurred because the method for sterilization of heparinized liquid preparations were not suitable. After discontinuing the use of the kits with this lot number, the outbreak was brought under control. Conclusions: According to our results, disposable or sterile medical equipment should be included as a risk factor in outbreak analyses. The method by which injectors containing liquids, such as heparin, are sterilized should be reviewed. Our study also revealed the importance of the cooperation of the infection control team with the microbiology laboratory. [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]

Autophagy may play an important role in the occurrence and development of glucocorticoid‐induced osteonecrosis of the femoral head (GC‐ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC‐ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC‐ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC‐induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC‐ONFH was used for evaluating the therapeutic effect of oral lithium on GC‐ONFH and underlying mechanism. Findings demonstrated that GC over‐activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over‐activated autophagy of GC‐treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC‐ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over‐activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up‐regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC‐ONFH. Lithium may be a promising therapeutic agent for GC‐ONFH. However, the role of autophagy in the pathogenesis of GC‐ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC‐ONFH, and the efficacy of lithium in the treatment of GC‐ONFH and its underlying mechanisms. [ABSTRACT FROM AUTHOR]

The International Society for Bipolar Disorders (ISBD) has recognized the need to support early- and mid-career professionals in the field of bipolar disorder (BD). A survey was conducted to identify barriers to career progression, including lack of funding and limited resources. Based on the survey results, the ISBD has proposed initiatives such as an online community, publicizing opportunities, and providing workshops and resources. These initiatives aim to support and promote career progression, increase resources and training, and address issues such as equity and mentorship. The ISBD EMCC seeks to support the career development of individuals in bipolar disorder research and promote equity and inclusion. [Extracted from the article]

Intro: Valproic acid (VPA) is a commonly prescribed mood stabilizer, available in both oral (OS) and intravenous (IV) formulations. However, few studies have compared their safety and efficacy. This retrospective study aimed to investigate the safety and efficacy of and IV‐VPA in patients with Bipolar Disorder. Methods: Fifty patients with Bipolar Disorder experiencing a manic or depressive episode, with concomitant symptoms of opposite polarity, admitted to our inpatient unit and treated with IV‐VPA were included in a retrospective, single‐centre, non‐randomized, open‐label, parallel‐group comparative study. Fifty patients experiencing a manic or depressive episode, with concomitant symptoms of opposite polarity, treated with oral‐VPA and selected among those who were admitted to the inpatient unit prior to the introduction of IV‐VPA in our clinical practice, were included as the control group (matched based on age, gender and clinical scales score at baseline). The Clinical Global Impression (CGI), Young Mania Rating Scale (YMRS), Montgomery‐Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM‐A) scores were recorded at baseline, after 3 days of treatment and discharge from the inpatient unit. Patients were asked to respond on the basis of the symptoms present on the day the scale was administered. Response rate and the presence of adverse effects were also recorded. Results: Both patients treated with oral and IV‐VPA demonstrated significant improvements in all psychometric scales (p < 0.001). However, the IV group exhibited superior efficacy, with significantly lower scores on the CGI, YMRS, MADRS and HAM‐A scales on Day 3 and at discharge from the inpatient unit. The IV‐VPA treatment showed higher response rates on all psychometric scales, and no adverse effects were reported in either group. Conclusion: This retrospective study supports the use of IV‐VPA as a more efficacious treatment option for patients with Bipolar Disorder, particularly in acute settings where rapid symptom improvement is crucial. Both oral and IV‐VPA were found to be safe and well‐tolerated. [ABSTRACT FROM AUTHOR]

Lithium (Li) is a mood-stabilizing drug. Although one of the potential mechanisms underlying the neuroprotective effects of lithium is related to its antioxidative effect, its mechanisms of action are not fully understood. Herein we aimed to investigate the impact of varied dosages of long-term lithium therapy on oxidative stress parameters in the brains of healthy rats, and on anxiety-like behaviors, and whether any changes in behavior can be attributed to modifications in oxidative stress levels within the brain. Thirty-two adult Wistar albino male rats were randomly assigned to four treatment groups. While the control (C) group was fed with a standard diet, low Li (1.4 g/kg/diet), moderate Li (1.8 g/kg/diet), and high Li (2.2 g/kg/diet) groups were fed with lithium bicarbonate (Li2CO3) for 30 days. Malondialdehyde increased, while superoxide dismutase and catalase levels decreased in the brains of the high Li group animals. In addition, anxiety-like behaviors of animals increased in the high Li group considering fewer entries to and less time spent in the open arms of the elevated plus maze test. Our findings underscore the potential adverse effects of prolonged lithium treatment, especially at doses approaching the upper therapeutic range. The induction of toxicity, manifested through heightened oxidative stress, appears to be a key mechanism contributing to the observed increase in anxiety-like behaviors. Consequently, caution is warranted when considering extended lithium therapy at higher doses, emphasizing the need for further research to delineate the precise mechanisms underlying these effects and to inform safer therapeutic practices. [ABSTRACT FROM AUTHOR]

Mnemonic discrimination (MD), the ability to discriminate new stimuli from similar memories, putatively involves dentate gyrus pattern separation. Since lithium may normalize dentate gyrus functioning in lithium-responsive bipolar disorder (BD), we hypothesized that lithium treatment would be associated with better MD in lithium-responsive BD patients. BD patients (N = 69; N Responders = 16 [23 %]) performed the Continuous Visual Memory Test (CVMT), which requires discriminating between novel and previously seen images. Before testing, all patients had prophylactic lithium responsiveness assessed over ≥1 year of therapy (with the Alda Score), although only thirty-eight patients were actively prescribed lithium at time of testing (55 %; 12/16 responders, 26/53 nonresponders). We then used computational modelling to extract patient-specific MD indices. Linear models were used to test how (A) lithium treatment, (B) lithium responsiveness via the continuous Alda score, and (C) their interaction, affected MD. Superior MD performance was associated with lithium treatment exclusively in lithium-responsive patients (Lithium x AldaScore β = 0.257 [SE 0.078], p = 0.002). Consistent with prior literature, increased age was associated with worse MD (β = −0.03 [SE 0.01], p = 0.005). Secondary pilot analysis of retrospectively collected data in a cross-sectional design limits generalizability. Our study is the first to examine MD performance in BD. Lithium is associated with better MD performance only in lithium responders, potentially due to lithium's effects on dentate gyrus granule cell excitability. Our results may influence the development of behavioural probes for dentate gyrus neuronal hyperexcitability in BD. • This is the first study of mnemonic discrimination (MD) in bipolar disorder (BD). • Lithium may improve MD exclusively BD patients who are lithium responders. • MD may be a useful probe of BD-related dentate gyrus abnormalities. • Future studies with prospective within-subjects designs are needed. [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]

This case report expands the reported range of clinical presentations of CV2/CRMP5 antibody‐related syndromes with two novel findings (manic psychosis and psychogenic polydipsia). A systematic literature review highlights a potentially higher incidence of psychosis than previously reported, clinical features that should prompt antibody testing, and the potential for treatment response. [ABSTRACT FROM AUTHOR]

Background: The thyroid hormone's significant impact on the treatment of depressive and other mood disorders is well documented. Even minor hypothyroidism can modify the progression and treatment results of major depressive disorder. This research aims to explore the correlation between initial thyroid levels and the treatment outcome in bipolar mood disorder using lithium, a well-established treatment method. Methodology: The study involved 45 bipolar mood disorder patients diagnosed according to the Diagnostic and Statistical Manual 5 criteria and admitted to a tertiary care teaching institute in Northeast India. The patients received lithium treatment, with injectable lorazepam used for immediate agitation control when necessary. On the 1st day, a semi-structured questionnaire and Brief Psychiatric Rating Scale (BPRS) 24-item scale were used to evaluate symptoms, and samples were collected for a thyroid profile, including T3, T4, FT3, FT4, and thyroid-stimulating hormone (TSH). The BPRS scale was used again on the 30th day to assess treatment response. Results: The BPRS subscale showed the highest treatment response for grandiosity and the lowest for depression. Factors such as age, illness duration, substance use, and family history of mood disorder were inversely correlated with the BPRS score's decrease. Initial thyroid levels were identified as a predictor of treatment response, with baseline T4 levels showing a significant positive correlation with treatment response, while baseline TSH levels showed a negative correlation. Conclusion: Lithium proved to be an effective treatment for bipolar mood disorder, particularly for the manic subtype. Initial T4 and TSH levels were found to significantly predict treatment response, with T4 showing a positive correlation and TSH showing a negative correlation. [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]

Benzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an 'azatropic shift' in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps. [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]

Suicidal behavior is more prevalent in bipolar disorders than in other psychiatric illnesses. In the last thirty years evidence has emerged to indicate that long-term treatment of bipolar disorder patients with lithium may reduce risk of suicide and attempts, with possibly similar benefits in recurrent major depressive disorder. We review and update selected research literature on effects of lithium treatment in reducing suicidal behavior and consider proposals that higher levels of lithium in drinking water may be associated with lower suicide rates. We summarize results of a growing number of randomized, controlled studies of lithium treatment for suicide prevention including comparisons with placebos or alternative treatments, and comment on the severe challenges of such trials. The basis of a proposed protective effect of lithium against suicidal behaviors remains uncertain but may include protective effects against recurrences of depressive phases of mood disorders, especially with mixed features or agitation, and possibly through beneficial effects on impulsivity, agitation and dysphoric mood. [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]

Lithium is a psychotropic drug used primarily in the treatment of bipolar disorder. It is renally excreted and characteristically causes nephrogenic diabetes insipidus as an adverse drug reaction. Lithium also requires serum level monitoring as there is a narrow therapeutic window and untreated toxicity can result in neurological sequelae including drowsiness, coma, seizures, and ultimately death. We present the case of a 65-year old man admitted for pituitary surgery complicated by post-operative difficult fluid management and subsequent lithium toxicity. We highlight this rare situation and the need to be vigilant in the peri-operative period with any patients on lithium who undergo pituitary surgery. [ABSTRACT FROM AUTHOR]

We report a case study of a 60-year-old man with bipolar disorder on stable lithium treatment who developed severe toxicity while admitted to ICU with sepsis and multiorgan failure. Despite unchanged lithium administration, his serum levels escalated due to renal dysfunction, resulting in lithium toxicity. After regaining consciousness, he exhibited a cerebellar syndrome marked by ataxia, tremor, and scanning speech. MRI revealed cerebellar atrophy. Following discontinuation of lithium and hemodialysis, the patient's symptoms remained static. The patient was diagnosed with syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), a chronic cerebellar disorder characterized by persistent ataxia, nystagmus, and gait abnormalities extending beyond two months post-lithium exposure. The disorder has a predilection for cerebellar and basal ganglia dysfunction. MRI findings include cerebellar gliosis and atrophy and leptomeningeal enhancement. This case report highlights that SILENT is both preventable and permanent, urging heightened awareness among clinicians to facilitate early detection and intervention. Patients on lithium with compromised renal function or fever necessitate vigilant lithium level monitoring, dose adjustment, or cessation, to forestall enduring morbidity. This case emphasizes the significance of recognizing and managing SILENT, particularly in critical care settings, to mitigate long-term cerebellar impairment and optimize patient outcomes. [ABSTRACT FROM AUTHOR]

This article discusses the phenomenon of ultrarapid cycling (Ultra-RC) in bipolar disorder (BD). Ultra-RC is characterized by rapid alternations between manic, hypomanic, depressive, or mixed mood episodes, with at least four affective episodes occurring within a month or less. The article presents a case study of a 34-year-old male patient who experienced frequent mood swings and was initially diagnosed with cyclothymic disorder. The severity of his symptoms, including psychotic features, led to a reevaluation of his diagnosis and the consideration of BD. The article emphasizes the need for further research on the etiology, clinical presentation, and treatment options for Ultra-RC in BD. [Extracted from the article]

Background and aim: Lithium is considered to be the first-line treatment for bipolar disorder, and paliperidone was approved for the treatment of schizophrenia and acute bipolar manic/mixed episodes. However, both agents have been associated with thyroid dysfunction and cardiovascular adverse effects like subclinical hypothyroidism, bradycardia, and sinus arrest, even at therapeutic doses. Case presentation: Here, we reported a case of a 17-year-old Han Chinese female who developed symptomatic hypothyroidism, sinus bradycardia, and sinus arrest while being treated with lithium and paliperidone for bipolar disorder with psychotic features including auditory hallucinations. Her workup suggested that these adverse effects might be related to the combined lithium and paliperidone treatment, although other causes could not be ruled out. After discontinuing both medications, her thyroid function and heart rhythm normalized over 20 days. Conclusion: To our knowledge, hypothyroidism, sinus bradycardia, and sinus arrest associated with the combined use of lithium and paliperidone had not been reported previously. Further research is warranted to elucidate the potential risks and benefits of this combination therapy for bipolar disorder with psychotic symptoms. [ABSTRACT FROM AUTHOR]

Objective: Suicide risk in bipolar disorder (BD) is estimated to be up to 20 times higher than in the general population. While there is a large body of evidence suggesting that increased sympathetic activation is associated with disease and death, there is a paucity of research on the role of autonomic nervous system (ANS) dysfunction in patients with BD who have attempted suicide. Methods: Fifty-three participants with BD used a wearable device to assess the association between history of suicide attempt, current suicidal ideation, and ANS dysfunction, including measures of heart rate variability (HRV) and respiratory rate. Data were analyzed in a series of unadjusted and adjusted bivariate models of association controlling for relevant variables. Results: A history of suicide attempts was significantly associated with an increase in respiratory rate (p < 0.01). These results remained significant after adjusting for age, BMI, and current mood state. There was no association between current suicidal ideation and heart rate or respiratory rate. In the frequency domain, HRV parameters suggest reduced parasympathetic (i.e., vagal) activity in participants with a history of suicide attempts and in those with current suicidality, suggesting changes in sympathicovagal balance in BD. Conclusions: Our results suggest that changes in the ANS in patients with BD and a history of suicide attempt are not restricted to pure vagally mediated HRV parameters, but rather signal a general ANS dysregulation. This ANS imbalance may be contributing to illness burden and cardiovascular disease. Further research on the relationship between ANS and suicidality in BD is needed. [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]

Intravenous racemic ketamine is a promising treatment for treatment-resistant depression. However, its clinical utility compared with intranasal esketamine and the other well-studied conventional pharmacological interventions (i.e., aripiprazole and lithium) as augmentative treatments for treatment-resistant unipolar depression in adults remains unclear. Therefore, we aimed to compare the efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium under such conditions. The Cochrane Library, PubMed, CINHAL and ClinicalTrials.gov databases were systematically searched from their inception to 10 May 2023. Randomised controlled trials evaluating these drugs were included. A random-effects network meta-analysis was also performed. In the primary analysis, all four drugs were significantly more effective than placebo. In addition, intravenous racemic ketamine was significantly more effective and acceptable than intranasal esketamine and aripiprazole. Intravenous racemic ketamine was not significantly different from placebo in tolerability, whereas intranasal esketamine and aripiprazole were significantly less tolerable than placebo. Lithium did not differ significantly from intravenous racemic ketamine in efficacy, tolerability and acceptability. The sample size of patients treated with intravenous racemic ketamine was small. Intravenous racemic ketamine may be a better augmentative treatment for treatment-resistant unipolar depression than intranasal esketamine and aripiprazole. Whether intravenous racemic ketamine or lithium is superior is unclear currently. A larger head-to-head trial of intravenous racemic ketamine versus conventional augmentative treatments for treatment-resistant unipolar depression is needed. • The relative clinical usefulness of intravenous racemic ketamine was evaluated. • It may be superior to aripiprazole and intranasal esketamine. • Its superiority over lithium is not clear. [ABSTRACT FROM AUTHOR]

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

Introduction: Lithium is a medication used to treat bipolar disorder. It has a narrow therapeutic index, which frequently causes toxicity in patients. Case Report: We present an unusual case of a 66-year-old female with a history of bipolar disorder on chronic lithium, who developed a third-degree heart block, encephalopathy, and acute renal failure because of lithium toxicity. Conclusion: This case highlights a rare but life-threatening case of complete heart block in the setting of lithium toxicity. The patient was treated with hemodialysis and pacemaker placement. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) lacks objective measures for illness activity and treatment response. Electrodermal activity (EDA) is a quantitative measure of autonomic function, which is altered in manic and depressive episodes. We aimed to explore differences in EDA (1) inter-individually: between patients with BD on acute mood episodes, euthymic states and healthy controls (HC), and (2) intra-individually: longitudinally within patients during acute mood episodes of BD and after clinical remission. A longitudinal observational study. EDA was recorded using a research-grade wearable in patients with BD during acute manic and depressive episodes and at clinical remission. Euthymic BD patients and HC were recorded during a single session. We compared EDA parameters derived from the tonic (mean EDA, mEDA) and phasic components (EDA peaks per minute, pmEDA, and EDA peaks mean amplitude, pmaEDA). Inter- and intra-individual comparisons were computed respectively with ANOVA and paired t -tests. 49 patients with BD (15 manic, 9 depressed, and 25 euthymic), and 19 HC were included. Patients with bipolar depression showed significantly reduced mEDA (p = 0.003) and pmEDA (p = 0.001), which increased to levels similar to euthymia or HC after clinical remission (mEDA, p = 0.011; pmEDA, p < 0.001; pmaEDA, p < 0.001). Manic patients showed no differences compared to euthymic patients and HCs, but a significant reduction of tonic and phasic EDA parameters after clinical remission (mEDA, p = 0.035; pmEDA, p = 0.004). Limited sample size, high inter-individual variability of EDA parameters, limited comparability to previous studies and non-adjustment for medication. EDA ecological monitoring might provide several opportunities for early detection of depressive symptoms, and might aid at assessing early response to treatments in mania and bipolar depression. • EDA is reduced during bipolar depression and increases after remission. • Ecological monitoring of EDA might allow early detection of depressive symptoms. • Electrodermal activity (EDA) is reduced after remission of a manic episode. • EDA might aid to asses early response to treatment in mania and bipolar depression. [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]

Lithium has been the frontline treatment for bipolar disorder for over 60 years. However, its mode of action and distribution in the brain is still incompletely understood. The primary isotope of lithium, lithium-7 (7Li), is a magnetic resonance (MR) active, spin-3/2 nucleus. However, its low MR sensitivity and the small brain size of mice make 7Li MR imaging (MRI) difficult in preclinical research. We tested four MRI sequences (FLASH, RARE, bSSFP, and SPIRAL) on lithium-containing phantoms, and bSSFP and SPIRAL on orally lithium-treated adult C57BL/6 mice. 7Li MR spectroscopy was acquired weekly at 9.4T to monitor the lithium uptake. The in vivo T1 relaxation time of 7Li was estimated in four mice. 4-h SPIRAL 7Li MRI was acquired in ten mice at a resolution of 2 × 2 × 3 mm3. SPIRAL MRI provided the highest signal-to-noise ratio (SNR) per unit acquisition time and the best image quality. We observed a non-homogeneous distribution of lithium in the mouse brain, with the highest concentrations in the cortex, ventricles, and basal brain regions. Almost no lithium signal was detected in the olfactory bulb and the cerebellum. We showed that in vivo 7Li MRI in mice is feasible, although with limited spatial resolution and SNR. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. Methods: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). Results: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31–2.45) and suicide death (10.80, 5.88–19.84) than controls. Lithium (0.62, 0.55–0.70), divalproex (0.89, 0.83–0.95), and aripiprazole (0.81, 0.66–1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89–1.01), risperidone (0.92, 0.82–1.02), and paliperidone (1.24, 0.88–1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65–0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). Conclusion: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality. [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]