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Background: Optimising maintenance drug treatment selection for people with bipolar disorder is challenging. There is some evidence that clinical and demographic features may predict response to lithium. However, attempts to personalise treatment choice have been limited., Method: We aimed to determine if machine learning methods applied to electronic health records could predict differential response to lithium or olanzapine. From electronic United Kingdom primary care records, we extracted a cohort of individuals prescribed either lithium (19,106 individuals) or olanzapine (12,412) monotherapy. Machine learning models were used to predict successful monotherapy maintenance treatment, using 113 clinical and demographic variables, 8,017 (41.96%) lithium responders and 3,831 (30.87%) olanzapine responders., Results: We found a quantitative structural difference in that lithium maintenance responders were weakly predictable in our holdout sample, consisting of the 5% of patients with the most recent exposure. Age at first diagnosis, age at first treatment and the time between these were the most important variables in all models., Discussion: Even if we failed to predict successful monotherapy olanzapine treatment, and so to definitively separate lithium vs . olanzapine responders, the characterization of the two groups may be used for classification by proxy. This can, in turn, be useful for establishing maintenance therapy. The further exploration of machine learning methods on EHR data for drug treatment selection could in the future play a role for clinical decision support. Signals in the data encourage further experiments with larger datasets to definitively separate lithium vs . olanzapine responders., Competing Interests: Joseph F. Hayes has received consultancy fees from juli Health and Wellcome Trust. No other authors declare competing interests., (© 2024 Hayes et al.)

Lamotrigine belongs to the group of antiepileptic drugs and mood stabilizers, and its action is based on the selective blocking of voltage-deficient sodium channels. The effect of this mechanism is the stabilization of the presynaptic part of the neuronal membrane and subsequent inhibition of the secretion of the neurotransmitters glutamate and aspartate into the postsynaptic part of the neuron. Lamotrigine has been approved by the Food and Drug Administration for the maintenance treatment of adults with bipolar disorder since 1994. In the field of psychiatry, this medicine is also used off-label in the treatment of acute bipolar depression. Studies show promising effects of the use of lamotrigine in bipolar disorder type II with rapid phase change. Bipolar disorder is a common psychiatric problem that most often affects young adults. Lamotrigine is most effective in bipolar disorder in preventing depressive episodes, which dominate the clinical picture of this disease. The latest research focuses on extending its action, to include manic episodes. Lamotrigine, through an unexplained mechanism, can affect the immune system, causing Stevens-Johnson syndrome, hemophagocytic lymphohistiocytosis, and drug reaction with eosinophilia and systemic symptoms syndrome. These are rare, life-threatening adverse effects that require urgent intervention in the form of drug discontinuation and immunosuppressive treatment. Strict contraindications to the use of lamotrigine include sensitivity reactions accompanied by systemic symptoms. Phenotype testing enables screening of patients predisposed to serious hypersensitivity reactions. The aim of the article is to review the indications, contraindications, and adverse effects of lamotrigine in the treatment of bipolar disorder and depression.

Introduction: Early diagnosis and treatment concerning bipolar disorder (BD) are related to a better functioning over the long-term period. Although pharmacotherapy is indicated for approximately all youths with BD, nearly one-third of patients do not receive adequate medications for their condition., Areas Covered: The authors discuss the available scientific evidence from the current literature about the management of BD in both children and adolescents, giving particular focus to the efficacy and tolerability of the available pharmacological agents. Studies were identified searching MEDLINE and retrieved from reference listings of relevant articles and through consultation with experts in the field., Expert Opinion: Many D2-blockers, approved by the Food and Drug Administration (FDA) based on their antimanic properties in youths, are related to both short- and long-term side effects. Lurasidone was found to be effective for the treatment of acute juvenile bipolar depression, while lithium for the treatment and recurrence prevention of manic/mixed episodes. The most common anticonvulsants were found to be most useful as adjunctive antimanic agents in non-responders to first-line monotherapies. No data was found to support the use of antidepressants in juvenile BD.

Background: Lifestyle factors are being increasingly studied in bipolar disorder (BD) due to their possible effects on both course of disease and physical health. The aim of this study was to jointly describe and explore the interrelations between diet patterns, exercise, pharmacological treatment with course of disease and metabolic profile in BD., Methods: The sample consisted of 66 euthymic or mild depressive individuals with BD. Clinical and metabolic outcomes were assessed, as well as pharmacological treatment or lifestyle habits (diet and exercise). Correlations were explored for different interrelations and a factor analysis of dietary patterns was performed., Results: Adherence to the Mediterranean diet was low, seen in 37.9% of the patients and was positively associated with perceived quality of life. The amount of exercise was negatively associated with cholesterol levels, with 32.8% of participants rated as low active by International Physical Activity Questionnaire. There was a high prevalence of obesity (40.6%) and metabolic syndrome (29.7%). Users of lithium showed the best metabolic profile. Interestingly, three dietary patterns were identified: "vegetarian," "omnivore" and "Western." The key finding was the overall positive impact of the "vegetarian" pattern in BD, which was associated with reduced depression scores, better psychosocial functioning, and perceived quality of life, decreased body mass index, cholesterol, LDL and diastolic blood pressure. Nuts consumption was associated with a better metabolic profile., Conclusions: A vegetarian diet pattern was associated with both, better clinical and metabolic parameters, in patients with BD. Future studies should prioritize prospective and randomized designs to determine causal relationships, and potentially inform clinical recommendations., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes., Methods: In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study., Results: The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01)., Conclusions: This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Carbonyl stress, a metabolic state characterized by elevated production of reactive carbonyl compounds (RCCs), is closely related to oxidative stress and has been implicated in various diseases. This study aims to investigate carbonyl stress parameters in drug-free bipolar disorder (BD) patients compared to healthy controls, explore their relationship with clinical features, and assess the effect of treatment on these parameters., Methods: Patients with a primary diagnosis of a manic episode of BD and healthy controls were recruited. Exclusion criteria included intellectual disability, presence of neurological diseases, chronic medical conditions such as diabetes mellitus and metabolic syndrome, and clinical signs of inflammation. Levels of serum carbonyl stress parameters were determined using high-performance liquid chromatography., Results: Levels of glyoxal (GO) and methylglyoxal (MGO) did not differ between pre- and post-treatment patients, but malondialdehyde (MDA) levels decreased significantly post-treatment. Pre-treatment MGO and MDA levels were higher in patients compared to controls, and these differences persisted post-treatment. After adjusting for BMI and waist circumference, only MDA levels remained significantly higher in patients compared to controls., Limitations: The study's limitations include the exclusion of female patients, which precluded any assessment of potential gender differences, and the lack of analysis of the effect of specific mood stabilizers or antipsychotic drugs., Conclusions: This study is the first to focus on carbonyl stress markers in BD, specifically GO, MGO, and MDA. MDA levels remained significantly higher in patients, suggesting a potential role in BD pathophysiology. MGO levels were influenced by metabolic parameters, indicating a potential link to neurotoxicity in BD. Further research with larger cohorts is needed to better understand the role of RCCs in BD and their potential as therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response., Methods: Post hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3-12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed., Results: Patients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20 %-31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement., Limitations: Post hoc analysis; relatively short study durations; flexible-dosing (mania studies)., Conclusions: Early symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder., Competing Interests: Declaration of competing interest Dr. Tohen was an employee of Lilly (1997 to 2008) and has received honoraria from or consulted for Abbott, AbbVie, AstraZeneca, Alkermes, Atai, Biohaven Pharmaceuticals, Squibb, Rapport Neurosciences, Lilly, Johnson & Johnson, Otsuka, Merck, Sunovion, Intra-Cellular Therapies, NeuroRX, Roche, Elan, Lundbeck, Teva, Minerva, Neurocrine Biosciences, NoemaPharma, Pfizer; his spouse was a full time employee at Lilly (1998–2013). J. Yu and H.-B. Nguyen are employees of AbbVie and may hold stock. K. Kramer is a former employee of AbbVie and may hold AbbVie stock., (Copyright © 2024 AbbVie Inc. Published by Elsevier B.V. All rights reserved.)

In clinical practice, mental health professionals face diagnostic and therapeutic challenges daily. The diagnostic identification of mixed states allows the management of diagnostic and therapeutic trajectories appropriately. In our study, we evaluated 484 patients at a psychiatric rehabilitation center. The initial pre-admission diagnosis of the mixed state of 3.71% (at baseline) increased to 32.23%. The observation period was three years. The therapeutic efficacy of the pharmacological association of Antidepressants (Ads) or Second Generation Antipsychotics (SGAs) with a mood stabilizer (sodium valproate, lithium, lamotrigine, gabapentin, and pregabalin) was evaluated. An improvement in psychopathological symptoms was observed in different groups analyzed. The most significant differences were observed with the association SGAs + mood stabilizer [olanzapine + valproate sodium (p=0.005); risperidone + pregabalin (p=0.072)] and SSRIs + mood stabilizer [escitalopram + valproate sodium (p=0.005), vortioxetine + mood stabilizers (valproate or gabapentin). However, these are preliminary data and are under evaluation.

Objectives: The authors have demonstrated that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy., Methods: One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses., Results: No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate., Conclusions: The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy., Competing Interests: Conflicts of Interest and Sources of Funding: K. Mihara has received honoraria from GlaxoSmithKline and Otsuka. A. Nakamura has received honoraria from Dainippon Sumitomo Pharma, Otsuka, and Pfizer. T. Kondo has received honoraria from Eli Lilly, GlaxoSmithKline, and Otsuka. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lithium is considered to be the most effective mood stabilizer for bipolar disorder. Evolving evidence suggested lithium can also regulate bone metabolism which may reduce the risk of fractures. While there are concerns about fractures for antipsychotics and mood stabilizing antiepileptics, very little is known about the overall risk of fractures associated with specific treatments. This study aimed to compare the risk of fractures in patients with bipolar disorder prescribed lithium, antipsychotics or mood stabilizing antiepileptics (valproate, lamotrigine, carbamazepine). Among 40,697 patients with bipolar disorder from 1993 to 2019 identified from a primary care electronic health record database in the UK, 13,385 were new users of mood stabilizing agents (lithium:2339; non-lithium: 11,046). Lithium was associated with a lower risk of fractures compared with non-lithium treatments (HR 0.66, 95 % CI 0.44-0.98). The results were similar when comparing lithium with prolactin raising and sparing antipsychotics, and individual antiepileptics. Lithium use may lower fracture risk, a benefit that is particularly relevant for patients with serious mental illness who are more prone to falls due to their behaviors. Our findings could help inform better treatment decisions for bipolar disorder, and lithium's potential to prevent fractures should be considered for patients at high risk of fractures., Competing Interests: Declaration of competing interest Esther W. Chan has received grants from Research Grants Council (RGC, Hong Kong), Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Novartis, Amgen, AstraZeneca, Takeda, the RGA Reinsurance Company, Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region, the National Health and Medical Research Council Australia; consulting fees from AstraZeneca, Pfizer and Novartis; and honorarium from the Hospital Authority Hong Kong, outside the submitted work. Joseph F. Hayes has received consultancy fees from Wellcome Trust and juli Health. Kenneth K.C. Man received the CW Maplethorpe Fellowship, grants from the National Institute for Health Research (United Kingdom), the European Union Horizon 2020 Framework, Innovation and Technology Commission of the Hong Kong Special Administration Region Government, and Hong Kong Research Grant Council and personal fees from IQVIA Holdings, Inc., unrelated to this work. Ian C.K.Wong received research grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer and Bristol-Myers Squibb and Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, The European Union's Seventh Framework Programme for research, technological development, Research Grants Council Hong Kong and Health and Medical Research Fund Hong Kong; consulting fee from IQVIA and WHO; payment for expert testimony for Appeal Court in Hong Kong; serves on advisory committees for Member of Pharmacy and Poisons Board; Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization; Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; is the non-executive director of Jacobson Medical in Hong Kong; is the Founder and Director of Therakind Limited (UK), Advance Data Analytics for Medical Science (ADAMS) Limited (HK), Asia Medicine Regulatory Affairs (AMERA) Services Limited and OCUS Innovation Limited (HK, Ireland and UK). Ching-Lung Cheung received research grants and the honorarium from Amgen, research grant support from HMRF, and the honorarium from Abbott. Wallis C.Y. Lau reports grant from Diabetes UK, AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. Vanessa W.S. Ng, Miriam T.Y. Leung, and David P.J. Osborn declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD., Methods: PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected., Results: Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1β, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients., Conclusion: Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD., Competing Interests: Declaration of competing interest None of the submitted material has been published or is under consideration elsewhere. All the authors have approved the manuscript and declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response., Competing Interests: Declaration of competing interest AGP has received CME-related honoraria, or consulting fees unrelated to the present work from Angelini, Janssen-Cilag, Casen Recordati, Rovi, LCN and Lundbeck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. The rest of authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To provide up-to-date clinical guidance on the efficacy of lamotrigine in bipolar disorder (BD)., Methods: Eligible studies were identified during a systematic literature search according to PRISMA-guidelines. We included randomized controlled trials (RCTs) and cohort studies that quantitatively assessed lamotrigine's efficacy in BD. We divided the included studies into three groups: 1. acute treatment of depression, 2. acute treatment of mania and hypomania, and 3. maintenance treatment. Analyses were stratified by control group (placebo vs active comparator) and treatment strategy (monotherapy vs add-on treatment)., Results: We included 20 RCTs (n = 1166 lamotrigine users) and 20 cohort studies (n = 11,141 lamotrigine users). Twenty-four of these studies were included in meta-analyses. During depressive episodes, greater decreases in depressive symptomatology were associated with initiation of lamotrigine as add-on treatment than with placebo (SMD -0.30 [95% CI = -0.51, -0.10], df = 3, p = 0.004). Decreases in depressive symptomatology did not differ significantly between lamotrigine and the active comparator (SMD -0.28 [95% CI = -1.06, 0.50], df = 3, p = 0.488). As a maintenance treatment, lamotrigine was associated with a significantly lower relapse/recurrence rate than placebo (risk ratio (RR) 0.84 [95% CI = 0.71, 0.99], df = 2, p = 0.037). Relapse/recurrence rates did not differ significantly between lamotrigine and lithium (RR 1.06 [95% CI = 0.89, 1.25], df = 2, p = 0.513). A qualitative assessment of high-quality register-based studies found that lamotrigine was associated with lower hospital admission rates than other commonly used treatment regimes., Conclusions: There is substantial evidence for the efficacy of lamotrigine in BD, specifically as add-on treatment during acute depressive episodes and as maintenance treatment for preventing relapse and recurrence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi + Gen)., Methods: We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg., Results: The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi + Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium., Limitations: Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi + Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies., Conclusions: The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We assessed the association of prescription data with clinical manifestations and polygenic risk scores (PRS) in patients with bipolar I disorder., Methods: We enrolled 1471 individuals with BID and divided them into several groups according to treatment options and clinical manifestations. BD-PRS of each patient was calculated using the Psychiatric Genomics Consortium data. Data on single nucleotide polymorphisms, clinical manifestations, and prescriptions were extracted from BiGS., Results: Chronicity, suicidality, substance misuse, mixed symptoms, and deterioration of life functioning were significantly more severe in the group that was not prescribed any mood stabilizers (MS). Chronicity, psychotic symptoms, suicidality, and deterioration of life functioning were significantly severe in the group that received two or more antipsychotics (APs). BD-PRS between the group with AP(s) only and that with other treatment options significantly differed. BD-PRS of the group with AP(s) only was significantly lower than that with other treatment options. Our linear regression results showed that high severity of particular clinical aspects, lower BD-PRS, and prescriptions with fewer MSs or more APs were independently associated with poor life functioning., Limitations: This study had a cross-sectional design, without differentiating the bipolar phase, which could influence our results., Conclusions: Poor life functioning in patients with BID was associated with a high severity of particular clinical aspects, BD-PRS, and prescriptions including fewer MSs or more APs. BD-PRS was significantly higher in the group receiving only AP(s) than that in the groups receiving other drugs., Competing Interests: Declaration of competing interest The authors have no conflicts of interest, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Background: It has been suggested that a 30-50 % lithium dose reduction or lithium discontinuation 24-48 h before delivery could minimize neonatal complications. We investigated the maternal lithemia changes around delivery after a brief discontinuation, the placental transfer of lithium at delivery, and the association between neonatal lithemia at delivery and acute neonatal outcomes., Methods: A retrospective observational cohort study was conducted in a teaching hospital (November/2006-December/2018). Data was extracted from the medical records. We included psychopathologically stable women, with a singleton pregnancy, treated with lithium in late pregnancy, with at least one maternal and neonatal lithemia at delivery. Lithium was discontinued 12 h before a scheduled caesarean section or induction, or at admission day to hospital birth; and restarted 6-12 h post., Results: Sixty-six mother-infant pairs were included, and 226 maternal and 66 neonatal lithemias were obtained. We found slight maternal lithemia fluctuations close to 0.20 mEq/L, and early postpartum relapse of 6 %. The mean (SD) umbilical cord/mother intrapartum lithemia ratio was 1.10 (0.17). Fifty-six percent of neonates presented transient acute complications. Neonatal hypotonia was the most frequent outcome (N = 15). Mean lithemia were 0.178 mEq/L higher in those with hypotonia than in those without (p = 0.028)., Limitations: It is a retrospective cohort of a moderate sample size of healthy uncomplicated pregnancies and results cannot be generalized to all pregnant treated with lithium., Conclusions: Lithium transfers completely across the placenta. A brief predelivery lithium discontinuation was associated with slight maternal lithemia fluctuations. Neonates exposed intrautero to lithium present frequent but transient acute effects., Competing Interests: Declaration of competing interest EV has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Biogen, Biohaven, Bristol-Myers Squibb, Celon, Compass, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Viatris, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the EU Horizon 2020 and the Stanley Medical Research Institute. Other authors declare no financial interests or potential conflicts of interest regarding the authorship and publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β =  - 0.022, 95% CI - 0.081 to 0.037, p = 0.47), the total duration of use (β =  - 0.005, 95% CI - 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β =  - 0.018, 95% CI - 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use., (© 2024. The Author(s).)

Background: Bipolar Disorder (BD) is associated with alterations of circadian rhythms of activity (CRA). Experimental research suggests that lithium (Li) modifies CRA, but this has been rarely explored in BD using actigraphy., Methods: The sample comprised 88 euthymic BD-I cases with 3 weeks of actigraphy. We used a Principal Component Analysis (PCA) to generate CRA dimensions. We then used linear regression analyses to compare these dimensions between groups of individuals defined according to prescribed mood stabilizers: Li monotherapy ("Li" group, n = 28), anticonvulsant or atypical antipsychotic monotherapy ("AC or AAP" group, n = 27) or combined treatments ("Li+AC or Li+AAP" group, n = 33). Analyses were adjusted for potential confounders (gender, age, body mass index, depressive symptoms, co-prescribed benzodiazepines and antidepressants, smoking status and past alcohol use disorder)., Results: The PCA identified two dimensions: "robust CRA" (high amplitude and interdaily stability, with low intradaily variability) and "late chronotype". Univariate analyses showed higher scores for "robust CRA" in the "Li" versus the "AC or AAP" (p = 0.021) or "Li+AC or Li+AAP" groups (p = 0.047). These findings remained significant after adjustments (respectively p = 0.010 and p = 0.019). Post-hoc analyses suggested lower variability, higher stability and higher amplitude of CRA in the "Li" group. Medication groups were similar for the "late chronotype" dimension (p = 0.92)., Conclusions: This actigraphy study is the first to show more favorable CRA in BD-I individuals receiving a Li monotherapy when compared with those receiving other classes or combinations of mood stabilizers. Replications in larger samples are required. Prospective studies are also warranted to elucidate whether the introduction of Li or other mood stabilizers might influence CRA in BD-I., Competing Interests: Declaration of competing interest B.E. has received honoraria for consulting from Sanofi. F.B. is an advisor on mental health to the French government. All other authors have no conflict of interest regarding this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study examines the association between the coefficient of variation (%CV) of lithium levels and episode risk and frequency in bipolar patients maintaining serum lithium levels within the therapeutic range., Methods: We retrospectively reviewed patients with bipolar disorder under care from 2018 to 2022. Inclusion criteria were at least 2 years of follow-up, a minimum of three annual lithium level measurements within the therapeutic range. Patients were categorized based on seizure status. We calculated mean lithium levels, standard deviation (SD), and %CV., Results: The study included 75 patients (patients with-without episodes, 39-36). Demographic data revealed no significant differences. While mean lithium levels showed no significant disparity between groups, SD and %CV were notably higher in patients with episodes ( P < .05). ROC analysis demonstrated AUC values of 0.722 (95% CI: 0.607-0.836 P = .001) for %CV and 0.709 (95% CI: 0.593-0.826; P = .002) for SD. The optimal %CV cutoff was 17.39, with 67% sensitivity and 69% specificity. A weak correlation was found between %CV and the number of episodes ( P = .001, r = 0.376). The post-hoc power analysis for this study was 0.78., Conclusions: Despite acceptable lithium levels, patients with recent episodes exhibited significant lithium level fluctuations. Integrating %CV with real-time lithium measurements during bipolar disorder follow-up may enhance clinical monitoring and seizure prediction., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Psychotic bipolar depression (PBD) is a prevalent yet understudied psychiatric illness, and there are no specific guidelines or Food and Drug Administration-approved medications for its treatment. Recent studies suggest that some antipsychotics and mood stabilizers may be effective in managing bipolar depression; however, their effectiveness for PBD remains unclear. Given the urgent need for more focused research for managing PBD, we conducted a literature review to summarize the existing literature on PBD., Methods: We conducted an electronic literature search from the 1960s to 2023, utilizing PubMed, MEDLINE, EMBASE, and Google, and selected studies based on their relevance to PBD., Findings: PBD is a complex disorder, with 50%-75% of patients with bipolar disorder exhibiting psychotic features. This likelihood increases among those with a history of psychotic mania. Treatment guidelines often recommend a combination of mood stabilizers, antipsychotics, or electroconvulsive therapy, but they do not specify a first-line treatment. PBD symptoms can be masked by mixed high mood and energy feelings, potentially delaying diagnosis and treatment while increasing suicide risk. Limited research has evaluated outcomes of various treatments for PBD, and despite the lack of evidence for superior efficacy, in clinical practice, antipsychotics are frequently prescribed. Notably, combining an antipsychotic with selective noradrenaline reuptake inhibitors or tricyclic antidepressants may be effective, but including a mood stabilizer is necessary., Conclusion: PBD poses a significant challenge in mental health due to its severity and the lack of consensus on optimal treatment approaches. There is a critical need for more dedicated clinical trials and research to answer key questions about the effective treatment of acute PBD, ideal follow-up care, traits of responders to different therapies, and decision models for subsequent treatments., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias., Competing Interests: Declaration of competing interest Lars Vedel Kessing has the last three years been a consultant for Lundbeck and Teva. Christian Torp-Pedersen report grants for studies from Bayer and Novo Nordisk not related to current study. Michael Berk: Grant/Research Support: MRFF, NHMRC, Congressionally Directed Medical Research Programs (CDMRP) USA, AEDRTC Australian Eating Disorders Research and Translation Centre, Patient-Centered Outcomes Research Institute (PCORI), Baszucki Brain Research Fund, Danmarks Frie Forskningsfond. Psykiatrisk Center Kobenhavn, Stanley Medical Research Institute, Victorian Government Department of Jobs, Precincts and Regions, Wellcome Trust, Victorian Medical Research Acceleration Fund, Controversias Psiquiatria Barcelona, CRE, Victorian COVID-19 Research Fund, Consultancies: Lundbeck, Sandoz, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, RANZCP, Abbott India, ASCP, International Society of Bipolar Disorder, Precision Psychiatry, Penn State College of Medicine, Shanghai Mental Health Centre. (Last 3 years) – all unrelated to this work. Mark Bech Knudsen and Helene Charlotte Wiese Rytgaard report no financial disclosure and competing interests., (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

Aims: To compare sodium valproate dispensing in women of childbearing age diagnosed with borderline personality disorder in 2014 and 2019 to discover if prescribing practices in Aotearoa New Zealand have changed in response to international recommendations., Methods: National dispensing data from the Pharmaceutical Collection were linked with diagnostic data from PRIMHD (the national mental health and addiction database) to identify people diagnosed with borderline personality disorder in Aotearoa New Zealand who were dispensed psychotropic medication. Dispensing of sodium valproate for women of childbearing age was compared between 2014 and 2019. Rates of dispensing were compared between ethnicities., Results: In 2014, 10% of women of childbearing age diagnosed with borderline personality disorder were dispensed sodium valproate. This reduced to 6% of women in 2019 (p<0.001). In 2014, there was substantial ethnic disparity with 18.1% of Māori women and 15.8% of Pacific women dispensed sodium valproate compared with 7.4% of New Zealand Europeans. This disparity reduced in 2019, with 6.4% of Māori women and 12.5% of Pacific women dispensed sodium valproate compared with 5.6% of New Zealand Europeans., Conclusions: These findings suggest that international recommendations and guidelines have been effective in changing clinical practice and reducing ethnic inequities. Given the significant risk to offspring exposed to sodium valproate, we echo warnings against off-label prescribing of sodium valproate in borderline personality disorder., Competing Interests: None to declare., (© PMA.)

Introduction: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM., Methods: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS)., Results: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant., Conclusion: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring., (© 2024 John Wiley & Sons Australia, Ltd.)

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., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Abstract: This is a case description of a patient with bipolar disorder undergoing lithium therapy who received plasmapheresis for neuromyelitis optica spectrum disorder. Plasmapheresis resulted in lower and subtherapeutic serum lithium levels. Using therapeutic drug monitoring, a dose escalation of 80% was necessary to maintain therapeutic serum lithium levels. This underscores the importance of individualized therapy through therapeutic drug monitoring., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders., Methods: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium ( n = 1028), valproate ( n = 3580), olanzapine ( n = 797), quetiapine ( n = 1975) or risperidone ( n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy., Results: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk., Conclusion: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer., Competing Interests: E.V. has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, AbbVie, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Idorsia, Janssen, Lundbeck, Medincell, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris outside the submitted work. G.F. has received CME-related honoraria or consulting fees from Angelini, Janssen-Cilag, and Lundbeck, Abbot. A.B. has received grants and served as a consultant for miCure Therapeutics. The other authors do not have an actual or perceived conflict of interest with the contents of this article., (U.S. Government work not protected by U.S. copyright.)

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., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/purpose: Lithium is an effective psychoactive drug. It has a narrow therapeutic margin, with subtherapeutic levels or intoxication commonly occurring. Therapeutic drug monitoring (TDM) of lithium has several barriers. This scoping review aims to describe and analyze existing and emerging technologies for lithium TDM and to describe the lithium quantification parameters (precision, accuracy, detection limit) attributed to each technology., Method: PubMed, Scopus, Web of Science, and Google Scholar were searched. Studies that described lithium quantification and complied with PRISMA-ScR guidelines were included. Articles selection was conducted by 2 researchers. Good precision was defined if its relative standard deviation <3%; acceptable, from 3% to 5%; and low, >5%. Accuracy was considered good if the error <5%; acceptable, 5%1 to 0%; and low if it was >10%., Results: Of the 2008 articles found, 22 met the inclusion criteria. Of these, 14 studies concerned laboratory devices, in which precision was found to be low in one third of cases, and half had good precision. Accuracy of one third was good, another third was low, and the remaining third did not report accuracy. The other 8 studies concerned portable devices, in which precision was low in more than 60% of the cases and good in 25% of the studies. Accuracy was low in 50% of the cases, and good in just over a third. Limits of detection included the therapeutic range of lithium in all studies., Conclusions: Among emerging technologies for lithium TDM, precision and accuracy remain a challenge, particularly for portable devices., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically., Methods: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk., Results: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies., Limitations: Substantial heterogeneity among the studies precluded performing a meta-analysis., Conclusion: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention., Competing Interests: Declaration of competing interest ME's spouse is an employee of Sanofi. MAF has received grant support from Assurex Health and Mayo Foundation, received CME travel and honoraria from Carnot Laboratories and American Physician Institute, and has Financial Interest / Stock ownership / Royalties from Chymia LLC. All other authors report no financial relationships with commercial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose/background: The current study aimed to examine the differences in sleep quality, illness severity, and functioning in remitted bipolar disorder patients who are using mood stabilizers and antipsychotics either as monotherapy or as combination/additional therapy., Methods/procedures: A total of 113 remitted outpatients with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) bipolar disorder were recruited. The patients were classified on the basis of their current treatment regimen: 44 patients were receiving a single mood stabilizer, 21 patients were receiving a single antipsychotic, and 48 patients were receiving a combination therapy of a single mood stabilizer and a single antipsychotic. The Pittsburgh Sleep Quality Index (PSQI), Global Assessment of Functioning (GAF), and Insomnia Severity Index (ISI) were applied., Findings/results: The GAF score was significantly lower in the combination group compared with the other 2 groups. Scores on the PSQI and ISI did not differ between the 3 groups. More than half (66.4%) of all patients had poor sleep quality. Total score on the PSQI was significantly correlated with age, body mass index, and GAF. Insomnia Severity Index was significantly correlated with the duration of illness, total number of episodes, and GAF. Multiple linear regression analysis indicated that GAF ( β = -0.114) and ISI ( β = 0.661) were significantly associated with the PSQI total score., Implications/conclusions: Our findings suggest that implementing interventions to enhance functioning is crucial for improving sleep quality in remitted bipolar patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of competing interest Dr Salazar de Pablo has received honoraria from: Janssen-Cilag, Lundbeck, Menarini and Angelini. Prof Young has received compensation for lectures or advisory boards from the following companies: AstraZeneca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis, and Neurocentrx.

Background: Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega-analyses of prospective trials of individual participant-level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy., Methods: Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega-analysis). Hierarchical log-linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores., Results: Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = -2.33, t = -6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = -0.414, t = -6.32, p < 0.001), and a significant improvement in CGI/C across time (b = -0.47, t = -7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62)., Conclusion: Findings from this IPD mega-analysis of bipolar II depression trials suggest a divergence from current evidence-based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega-analysis suggests that antidepressant monotherapy may provide superior short-term effectiveness without clinically meaningful increase in treatment-emergent hypomanic symptoms compared to lithium monotherapy., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This year, we observe sixty's anniversary of the article by a British psychiatrist, Geoffrey Hartigan, demonstrating, for the first time, the possibility of preventing of the recurrence of mood disorders by using lithium salts. Herein, a history of prevention of recurrences of mood disorders both worldwide and in Poland will be presented concerning both lithium and other mood-stabilizing drugs. The merit for verifying the prophylactic lithium effect in the 1960-1970s should be given to Danish researchers, Mogens Schou and Poul Baastrup. In Poland, the first paper on prophylactic lithium appeared already in 1971. In the 1970s, French researchers showed prophylactic activity of valproic acid amide, and Japanese researchers - carbamazepine. In the 1980th, studies on valproic acid amide were performed in the 2nd Psychiatric Clinic of the Institute of Psychiatry and Neurology led by Prof. Pużyński. Since the mid-1990s, 2nd generation of mood-stabilizing drugs has been introduced, including some atypical antipsychotics (clozapine, olanzapine, quetiapine, aripiprazole, risperidone) and anticonvulsant drug, lamotrigine, showing prophylactic activity in bipolar mood disorder. The studies on lithium resulted in the identification of factors connected with its prophylactic efficacy as well as the antisuicidal, antiviral, and neuroprotective effects of this drug. From a sixty-year perspective following Hartigan's article, it seems that his pioneering concept on the possibility of pharmacological influence on the course of mood disorders was fully confirmed. Current Polish recommendations on pharmacological prophylaxis of mood disorders were presented in the books "Standardy leczenia niektórych zaburzeń psychicznych" and "Psychofarmakologia kliniczna", both published in 2022.

Current evidence for pharmacological treatment of mania during hospitalisation is insufficient as there are no larger well-designed randomised trials of comparative medical treatments of mania during inpatient stays. Moreover, there is considerable variation in pharmacological medication in clinical practice during hospitalisation for mania. Based on a hospital data overview, a systematic search of the literature and a three-day consensus meeting, this narrative review proposed an algorithm for optimised pharmacological treatment of mania during hospitalisation and its subsequent scientific evaluation., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Lithium carbonate has a narrow therapeutic range capable of producing various adverse effects; despite this fact, it is used as first-line therapy in patients with bipolar disorder (BD) thanks to its high effectiveness. Among its adverse events are several conditions at the endocrine level, such as hypothyroidism, hyperthyroidism, hypercalcemia, hyperparathyroidism, and nephrogenic diabetes insipidus. The adherence to current guidelines for monitoring those events is low. The objective of this review is to provide insight into the pathophysiological mechanisms of the endocrine effects of lithium and give recommendations based on the current literature for the monitoring and treatment of these conditions.

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., (© 2023. The Author(s).)

Background: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons., Methods: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling., Results: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not., Conclusions: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Bipolar disorder (BD) is a highly prevalent condition whose response to pharmacological treatment is associated with a number of factors including psychiatric comorbidity. Borderline personality disorder (BPD) shares clinical symptoms and biological vulnerability with BD and the two conditions are frequently comorbid, thus representing a clinical challenge. The purpose of the present review is to summarize the data related to treatment response in bipolar patients with comorbid BPD. According to systematic review process, a literature search was performed on the PubMed, Embase, PsycInfo, Isi Web of Knowledge, Medscape, and Cochrane Library databases. Peer-reviewed articles until December 2022 were eligible for inclusion. Comorbidity with BPD seems to be associated with a more difficult clinical stabilization in bipolar patients, often requiring poly-therapy or a longer duration of hospitalization. However, three studies, assessing the effectiveness of mood stabilizers in bipolar patients, did not demonstrate a prominent influence of BPD comorbidity in achieving clinical response. The most frequently administered pharmacological treatments in the selected studies include mood stabilizers and atypical antipsychotics. The presence of comorbid BPD in bipolar patients may hamper treatment effectiveness. Future studies, comparing different treatments and with larger samples, are needed to confirm the results critically summarized in the present review., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)