First-line Treatment For Bipolar Disorder Research Articles

Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging

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.

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality.

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 = 57.49years; 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.

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Rapid Detection of Lithium Concentrations in Oral Fluid.

Lithium medication is considered to be the first-line treatment for bipolar disorder as a monotherapy, and for treatment-resistant depression with lithium augmentation. However, because of potential toxicity, lithium levels must be monitored frequently. Recent studies have demonstrated a significant correlation between lithium levels measured in serum and those detected in oral fluid, suggesting that oral fluid analysis may represent an easy, noninvasive means to monitor lithium levels. The aim of this study was to evaluate the analytical performance of rapid assays for lithium measurements in oral fluid. Levels of lithium in oral fluid from psychiatric patients (n = 108 in total) taking lithium medications were quantified using 2 rapid techniques: an automated clinical chemistry analyzer and a novel, commercially available colorimetric lithium assay. These results were compared with those obtained using inductively coupled plasma optical emission spectrometry (ICP-OES). The mean and median oral fluid lithium levels in this cohort were 1.43-1.61 mM and 1.32-1.52 mM, respectively, depending on the method, with the overall range, across all methods, being 0.213-4.42 mM. Linear regression analysis showed excellent agreement between the oral fluid values measured using ICP-OES and the colorimetric method (r 2 value = 0.926; P < 0.0001; slope = 1.084 ± 0.038). Similarly, excellent agreement was observed between ICP-OES and the automated method (r 2 = 0.872; P < 0.0001; slope = 1.019 ± 0.057). These results demonstrate that lithium levels in oral fluid can be rapidly and reliably quantified using colorimetric approaches. These findings may facilitate the development of point-of-care lithium monitoring systems for use in oral fluid.

Challenges of Therapeutic Drug Monitoring and Usage of Lithium in Managing Psychiatric Disorders: A Review

Lithium is referred by all key guidelines as a first-line treatment for bipolar disorder (BD) maintenance therapy. Therapeutic drug monitoring (TDM) is necessary while using lithium as lithium treatment. The concern arose when there is one article discussed about the declining of usage of lithium in certain countries such as US and Canada. However, the prescription rates of lithium in United Kingdom and Scandinavia do not show a downward trend. The aim of this study was to determine the challenges of TDM and usage of lithium in managing psychiatric disorders. A total of 32 articles have mentioned the challenges in TDM and usage of lithium. Descriptive statistics was done to identify the challenges in TDM and usage of lithium in psychiatric disorders. There is a total of 25 and 27 challenges found in TDM and usage of lithium in psychiatric disorders respectively. The most stated challenges in TDM of lithium were drug-drug and drug-disease interactions (16.07%), poor compliance (14.28%) and different therapeutic levels or dose suggested by different authors or guidelines (14.28%). The most stated challenges in usage of lithium in psychiatric disorders were potential toxicity (16.85%), side effects of lithium (16.85%), narrow therapeutic range (15.73%) and needs frequent monitoring (15.73%). However, the usage of lithium in certain countries remains still high may be due to the benefits of lithium to psychiatric patients in reducing risk of manic relapse and depressive relapse. Although there are 52 challenges found in the TDM and usage of lithium, there is no definite article or statement stating that the usage of lithium is declining. Future multi-national study is needed to study the extend challenges in TDM and usage of lithium in developed countries as compared to developing countries.

The potentially protective effect of lithium on the risk of osteoporosis: A nationwide study of 22,912 patients with bipolar disorder

IntroductionOsteoporosis, a systemic skeletal disorder associated with substantial morbidity and mortality, has been suggested to be particularly common among individuals with bipolar disorder. Lithium, a mood-stabilizer used as first-line treatment for bipolar disorder, may have bone-protecting properties.ObjectivesWe aimed to subject both of these hypotheses to further examination in a nationwide register-based study.MethodsWe compared the incidence of osteoporosis, identified via hospital discharge diagnoses and prescribed medications, between all individuals diagnosed with bipolar disorder and age- and sex-matched controls from the general population (earliest start of follow-up at the age of 40 years) using Cox regression. Subsequently, we followed the patients with bipolar disorder and identified all prescriptions for mood-stabilizing medications. Using Cox regression, we compared the incidence of osteoporosis for patients using lithium, antipsychotics or anticonvulsants, respectively, with that of patients not using these medications.ResultsWe followed 22,912 patients with bipolar disorder (median age 50.4 years, 43.4% men) and 114,560 matched controls for 1,215,698 person-years. The incidence of osteoporosis per 1,000 person-years was 8.70 (95%CI:8.28-9.14) among patients with bipolar disorder and 7.84 (95%CI:7.67-8.01) among controls, resulting in a hazard rate ratio (HRR) of 1.15 (95%CI:1.09-1.21). Lithium treatment was associated with reduced risk of osteoporosis (HRR=0.62; 95%CI:0.53-0.72) in a treatment-duration-response-like manner. Treatment with antipsychotics and anticonvulsants was not associated with reduced risk of osteoporosis.ConclusionsThis is the first longitudinal study to show that the risk of osteoporosis is elevated among patients with bipolar disorder, and that treatment with lithium is associated with reduced risk of osteoporosis.DisclosureDr. Østergaard has received the 2020 Lundbeck Foundation Young Investigator Prize. Furthermore, SDØ owns units of mutual funds with stock tickers DKIGI, DKIDKIX, MAJGRO, NBIDE, SPIC20CAPK, SPVILRKL and WEKAFKI.

Lithium placental passage at delivery: an observational study

IntroductionLithium is used as a first-line treatment for bipolar disorder during perinatal period. Dosing of lithium can be challenging as a result of pharmacokinetic changes in renal physiology. Frequent monitoring of lithium blood levels during pregnancy is recommended in order remain within the therapeutic window (0.5 to 1.2 mEq/L). Lower neonatal lithium blood level (&lt;0.64 mEq/L) at time of delivery reduces the risk of lithium side effects in the neonate.ObjectivesThe aim of the present study was to quantify the rate of lithium placental passage in real word.MethodsWe included a total of 68 mother-infant pairs for which a lithium measurement was performed intrapartum. Lithium serum concentrations were determined by means of an AVL 9180 electrolyte analyzer. The limit of quantification (LoQ) was 0.20 mEq/L and detection limit was 0.10 mEq/L. Pearson analyse was performer to assess the correlation between mother and umbilical cord lithium serum concentrations.ResultsThe mean of umbilical cord serum concentration at delivery was 0.57 mEq/L (SD=0.26, range 0,20-1,42). The mean infant-mother lithium ratio at delivery for the 68 pairs was 1.12 (SD=0.24) across a wide range of maternal concentrations (range 0.14-1,40 mEq/L). There was a strong positive correlation between maternal and umbilical cord lithium blood levels (Peearson correlation coefficient 0.948, p&lt;0.001).ConclusionsLithium demostrates complete placental passage. This finding is consistent with the results of others studies (Newport 2005; Molenaar 2021).DisclosureNo significant relationships.

Valproic acid-induced hyperammonemic encephalopathy: a clinical case

IntroductionValproic acid is a psychotropic drug used for several years, due to its properties as a mood stabilizer, being considered as first-line treatment for bipolar disorder. In addition to its teratogenic potential, which prevents its recommendation for the treatment of bipolar disorder in women of childbearing age, valproic acid is associated with some side effects, such as gastrointestinal symptoms, alopecia, weight gain, tremor or hepatotoxicity. Hyperammonemia is a side effect that is little described, but relatively frequent, and may progress to variable encephalopathy.ObjectivesThe authors describe a clinical case of a 48-year-old female patient, hospitalized due to a manic episode, who was prescribed valproic acid, in association with lorazepam and olanzapine.MethodsAfter three days on a dose of 1000mg of valproic acid, the patient began an acute condition of confusion, psychomotor retardation, temporal-spatial disorientation and ataxia. Infection, electrolyte disturbance and acute cerebral event were excluded. Noteworthy only hyperammonemia. Valproic acid was withdrawn and replaced by lithium, with the patient recovering from the confusional state two days later.ResultsHyperamonemic encephalopathy secondary to valproic acid was concluded. The mechanisms of valproic acid-linked hyperammonemia are not clear, although it appears to be independent of hepatotoxicity. The most studied hypotheses are related to glutamine reabsorption and serum levels carnitine in patients medicated with valproic acid.ConclusionsIt is essential that there is a high level of suspicion in clinicians for this secondary effect of valproic acid, in order to adequately treat the patient who presents with acute confusional conditions, not explained by other complications.DisclosureNo significant relationships.

Acute safety assessment of lithium bioacummulated in mycelial biomass of Ganoderma lucidum

Lithium is a first-line treatment for bipolar disorder, a disorder that is characterized by alternating manic and depressive episodes. However, because of its narrow therapeutic index, lithium can cause adverse effects. The association of lithium with more complex molecules, such as proteins and polysaccharides, may help control the release of lithium throughout the digestive system, thereby reducing the doses that are used by patients and consequently reducing adverse effects. The present study evaluated the acute oral toxicity of lithium bioaccumulated in mycelial biomass of Ganoderma lucidum, a research step that precedes preclinical efficacy studies. The study followed Organization for Economic Cooperation and Development guideline. Male Wistar rats (n = 6) were acutely treated by gavage with fixed doses (300 and 2000 mg/kg) of lithium bioaccumulated in mycelial biomass of G. lucidum. Changes in clinical signs, body mass, relative organ mass, biochemical parameters, blood count, leukocytes, and histopathological changes were evaluated. A group of animals that were treated with vehicle (n = 6) served as the basal group. No signs of toxicity were observed in any of the investigated parameters. Lithium bioaccumulation in mycelial biomass of G. lucidum did not induce signs of toxicity in rats that were acutely orally treated.

Lithium: Current Clinical Guidelines for Nurse Practitioners.

Bipolar disorder is a serious neuroprogressive disorder associated with structural and functional brain changes, multiple comorbidities, and heightened risk for suicide. Lithium has been a first-line treatment for bipolar disorder for more than 50 years and recent research suggests that early identification and treatment of bipolar disorder with lithium can alter the progression of the illness. The purpose of the current article is to review evidence for lithium's neurotrophic and neuroprotective actions and clinical guidelines for safe and effective use. [Journal of Psychosocial Nursing and Mental Health Services, 60(1), 6-9.].

Lithium treatment and human hippocampal neurogenesis

Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes, which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.

Dose-dependent transcriptional effects of lithium and adverse effect burden in a psychiatric cohort

Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the “Udvalg for Kliniske Undersøgelser” (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.

Clinical predictors of non‐response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p<0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

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

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

P0284RENAL FUNCTION AFTER DISCONTINUATION OF CHRONIC LITHIUM TREATMENT: FINDINGS FROM THE LISIE RETROSPECTIVE COHORT STUDY

Abstract Background and Aims Current guidelines consider lithium a first-line treatment for bipolar disorder to prevent relapse and suicide. Lithium, however, has renal adverse effects that can accumulate over decades of treatment. Studies have found a positive association between duration of lithium use and incidence of chronic kidney disease and prevalence of end stage renal disease. When the kidney function declines the treating clinician is presented with a choice of either continuing lithium, despite the risk of renal failure, or discontinuing lithium, despite an increased risk of relapse of the underlying affective disorder. One recent study showed that concerns about reduced renal function may account for 9% of reasons for lithium discontinuation. Yet it remains unknown, whether after lithium discontinuation, decline of renal function will continue unchanged, become less steep, or whether renal function can even improve. The aim of our study was to investigate the effect of lithium discontinuation on renal function. Method A retrospective mirror-image study, examining the decline of renal function five years before and after lithium discontinuation. Our study was part of LiSIE, a retrospective cohort study of patients with bipolar disorder, schizoaffective disorder and depression in the Swedish county of Norrbotten 1997 - 2017. We included all patients who had discontinued lithium between 1997 and 2013. We excluded patients who (a) had renal diseases possibly affecting renal function acutely (e.g. glomerulonephritis) or (b) used lithium less than 90% of the 5 years of the pre-mirror period. The patients provided informed verbal consent. In accordance with the ethical approval, deceased patients were also included. Patients were followed for 5 years after lithium discontinuation, until they initiated renal replacement therapy, restarted lithium treatment or died. To evaluate renal function, we calculated eGFR by the CKD-EPI -formula from all creatinine measurements taken during out- or in-patient care in the county of Norrbotten. We censored values for episodes of acute kidney injury or values not reflective of the underlying kidney function, such as in terminal cancer and cachexia. All data was manually validated in the medical records. A mixed effects model was fitted including eGFR as dependent variable. Age, hypertension and diabetes mellitus were included as fixed effects. Results Of 1340 patients with lithium treatment 579 patients had discontinued lithium. 172 patients (55.2% women, 44.8% men) with 5335 creatinine samples were eligible for inclusion. Mean age at discontinuation was 61.5 (min. 24.5 max. 91.3). Mean duration of lithium treatment was 15.8 (min. 4.5, max. 42.5) years. 19.2% of patients had diabetes and 48.9% had hypertension diagnosed before or during the study period. There was a statistically significant change in annual decline of renal function (p&amp;lt;0.001), from -1.96 ml/min/year before (95% CI -2.22 to -1.70) and -0.22 ml/min/year (95% CI -0.50 to 0.07) after discontinuation. Diagnosed hypertension added -1.27 ml/min/year in decline of eGFR (p&amp;lt;0.001). Diabetes mellitus did not affect the decline. Conclusion Mean annual decline of renal function is significantly steeper during lithium treatment than after discontinuation. However, decline still occurs. In patients with hypertension, the decline of renal function is accelerated irrespective of lithium discontinuation. The implications for renal function in individual patients considering lithium discontinuation remain unclear. The decision of whether to discontinue lithium depends on a careful trade-off of potential psychiatric risks against potential renal benefits.

Predicted Cellular and Molecular Actions of Lithium in the Treatment of Bipolar Disorder: An In Silico Study.

Lithium remains the first-line treatment for bipolar disorder (BD), but patients respond to it variably. While a myriad of studies have attributed many genes and signaling pathways to lithium responsiveness, a comprehensive study with an integrated conclusion is still lacking. We aim to present an integrated mechanism for the therapeutic actions of lithium in BD. First, a list of lithium responsiveness-associated genes (LRAGs) was collected by searching in the literature. Thereafter, gene set enrichment analysis together with gene-gene interaction network analysis was performed, in order to find the cellular and molecular events related to the LRAGs. Gene set enrichment analyses showed that the chromosomal regions 3p26, 4p21, 5q34 and 7p13 could be novel associated loci for lithium responsiveness in BD. Also, expression pattern analysis of the LRAGs showed their enrichment in adulthood stages and different cell lineages of brain, blood and immune system. Most of the LRAGs exhibited enriched expression in central parts of human brain, suggesting major contribution of these parts in lithium responsiveness. Beside the prediction of several biological processes and signaling pathways related to lithium responsiveness, an interaction network between these processes was constructed that was found to be regulated by a set of microRNAs. Proteins of the network were mainly classified as transcription factors and kinases, which also highlighted the crucial role of glycogen synthase kinase 3β (GSK3β) in lithium responsiveness. The predicted cellular and molecular events in this study could be considered as mechanisms and also determinants of lithium responsiveness in BD.

Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla

BackgroundLithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used 7Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years. MethodsThree-dimensional 7Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T1 and T2 relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel- and parcellation-based group analyses were conducted for the first time for 7Li magnetic resonance imaging. ResultsUsing unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li]B ≈ 0.40 × [Li]P, R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort. ConclusionsThis observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD.

Lithium Use and Non-use for Pregnant and Postpartum Women with Bipolar Disorder.

Despite being recognized as a first-line treatment for bipolar disorder, there is still inconsistent use of lithium in perinatal populations. This article will review data regarding lithium use during the peripartum and provide management recommendations for general psychiatric clinicians. In contrast to prior data, recent studies indicate that lithium use in pregnancy is associated with either no increased malformations risk or a small increase in risk for cardiac malformations including Ebstein's anomaly. Limited data also show no significant effect on obstetric or neurodevelopmental outcomes. Data regarding infant lithium exposure via breastmilk remains limited. Lithium is currently under-prescribed and is an important treatment for women with bipolar disorder in pregnancy and the postpartum. Clinicians must weigh the risk of lithium treatment versus the risk of withholding or changing lithium treatment when managing bipolar disorder in this population.

Exploring lithium\u2019s transcriptional mechanisms of action in bipolar disorder: a multi-step study

Lithium has been the first-line treatment for bipolar disorder (BD) for more than six decades. Although the molecular effects of lithium have been studied extensively and gene expression changes are generally believed to be involved, the specific mechanisms of action that mediate mood regulation are still not known. In this study, a multi-step approach was used to explore the transcriptional changes that may underlie lithium’s therapeutic efficacy. First, we identified genes that are associated both with lithium exposure and with BD, and second, we performed differential expression analysis of these genes in brain tissue samples from BD patients (n = 42) and healthy controls (n = 42). To identify genes that are regulated by lithium exposure, we used high-sensitivity RNA-sequencing of corpus callosum (CC) tissue samples from lithium-treated (n = 8) and non-treated (n = 9) rats. We found that lithium exposure significantly affected 1108 genes (FDR < 0.05), 702 up-regulated and 406 down-regulated. These genes were mostly enriched for molecular functions related to signal transduction, including well-established lithium-related pathways such as mTOR and Wnt signaling. To identify genes with differential expression in BD, we performed expression quantitative trait loci (eQTL) analysis on BD-associated genetic variants from the most recent genome-wide association study (GWAS) using three different gene expression databases. We found 307 unique eQTL genes regulated by BD-associated variants, of which 12 were also significantly modulated by lithium treatment in rats. Two of these showed differential expression in the CC of BD cases: RPS23 was significantly down-regulated (p = 0.0036, fc = 0.80), while GRIN2A showed suggestive evidence of down-regulation in BD (p = 0.056, fc = 0.65). Crucially, GRIN2A was also significantly up-regulated by lithium in the rat brains (p = 2.2e-5, fc = 1.6), which suggests that modulation of GRIN2A expression may be a part of the therapeutic effect of the drug. These results indicate that the recent upsurge in research on this central component of the glutamatergic system, as a target of novel therapeutic agents for affective disorders, is warranted and should be intensified.

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review.

Background:Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications.Objectives:To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data.Methods:Clinical trials in pediatric samples with at least one standardized measure of efficacy/effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients.Results:Different and non-alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe.Conclusions:Lithium seems an effective and well-tolerated medication in pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications.