Lithium Treatment Research Articles

Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder.

Over a half century, lithium has been used as the first-line medication to treat bipolar disorder. Emerging clinical and laboratory studies suggest that lithium may exhibit cardioprotective effects in addition to neuroprotective actions. Fractalkine (CX3CL1) is a unique chemokine associated with the pathogenesis of mood disorders and cardiovascular diseases. Herein we aimed to ascertain whether lithium treatment is associated with favorable cardiac structure and function in relation to the reduced CX3CL1 among patients with bipolar disorder. We recruited 100 euthymic patients with bipolar I disorder aged over 20 years to undergo echocardiographic study and measurement of plasma CX3CL1. Associations between lithium treatment, cardiac structure and function and peripheral CX3CL1 were analyzed according to the cardiovascular risk. The high cardiovascular risk was defined as (1) age ⩾ 45 years in men or ⩾ 55 years in women or (2) presence of concurrent cardiometabolic diseases. In the high cardiovascular risk group (n = 61), patients who received lithium as the maintenance treatment had significantly lower mean values of left ventricular internal diameters at end-diastole (Cohen's d = 0.65, p = 0.001) and end-systole (Cohen's d = 0.60, p = 0.004), higher mean values of mitral valve E/A ratio (Cohen's d = 0.51, p = 0.019) and superior performance of global longitudinal strain (Cohen's d = 0.51, p = 0.037) than those without lithium treatment. In addition, mean plasma levels of CX3CL1 in the high cardiovascular risk group were significantly lower among patients with lithium therapy compared with those without lithium treatment (p = 0.029). Multiple regression models showed that the association between lithium treatment and mitral value E/A ratio was contributed by CX3CL1. Data from this largest sample size study of the association between lithium treatment and echocardiographic measures suggest that lithium may protect cardiac structure and function in patients with bipolar disorder. Reduction of CX3CL1 may mediate the cardioprotective effects of lithium.

Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10−37) and replication groups (p = 6.36 × 10−13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence.

Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder

Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated. In this study, we profiled circular RNAs in the brain tissue of individuals with bipolar disorder. Total RNA sequencing was initially performed in samples from the anterior cingulate cortex of a cohort comprised of individuals with bipolar disorder (N = 13) and neurotypical controls (N = 13) and circular RNAs were identified and analyzed using “circtools”. Significant circular RNAs were validated by RT-qPCR and replicated in the anterior cingulate cortex in an independent cohort (24 bipolar disorder cases and 27 controls). In addition, we conducted in vitro studies using B-lymphoblastoid cells collected from bipolar cases (N = 19) and healthy controls (N = 12) to investigate how circular RNAs respond following lithium treatment. In the discovery RNA sequencing analysis, 26 circular RNAs were significantly differentially expressed between bipolar disorder cases and controls (FDR < 0.1). Of these, circCCNT2 was RT-qPCR validated showing significant upregulation in bipolar disorder (p = 0.03). This upregulation in bipolar disorder was replicated in an independent post-mortem human anterior cingulate cortex cohort and in B-lymphoblastoid cell culture. Furthermore, circCCNT2 expression was reduced in response to lithium treatment in vitro. Together, our study is the first to associate circCCNT2 to bipolar disorder and lithium treatment.

P.0734 Pisa syndrome with lithium treatment: case report and literature review

A 23-year-old male patient who was a follow-up case of neurosurgery presented to our emergency department with a history of high-grade fever and clinical features of meningitis for 1 week. The cerebrospinal fluid (CSF) was sent to our laboratory for culture. The culture demonstrated growth of 1-2 mm in diameter light yellow coloured colonies of Gram-negative bacilli on chocolate and blood agar. There was no growth on MacConkey agar. The bacterium was multidrug resistant. Based upon the growth characteristics, bio-chemical reactions, drug susceptibility pattern and identification by Vitek 2 system the isolate was identified as Elizabethkingia meningoseptica. Patient was treated with injection piperacillin-tazobactam, injection vancomycin and cotrimoxazole tablets for 21 days along with intrathecal injection of tigecycline and finally, patient improved clinically and the CSF cultures became sterile. The presence in hospital environment along with multidrug resistance makes E. meningoseptica a successful emerging nosocomial pathogen.

Low‐dose lithium treatment of behavioral complications in Alzheimer’s disease: Lit‐AD randomized clinical trial

AbstractBackgroundTo evaluate low‐dose lithium treatment of agitation in Alzheimer’s disease (AD).MethodIn a four‐site trial, patients with AD and agitation/aggression on the Neuropsychiatric Inventory (NPI) were randomized, double‐blind, to lithium carbonate 150‐600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response defined by 30% reduction in NPI combined score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved. Somatic, cognitive, metabolic, and neurological side effects were assessed.ResultFifty‐eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium did not differ from placebo in agitation/aggression change scores. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p=0.26). Moderate or marked improvement on global CGI change, which incorporated behavior, cognition, and function, was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher’s exact test p&lt;0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p’s&lt;0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI, 1.18 to 8.94, p=0.01). Oral dose and serum lithium levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on any safety outcome.ConclusionLow dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted with precision pharmacological targeting of likely lithium‐responsive behavioral symptoms that overlap with mania.

P.0253 Two-week lithium treatment modulates translocator protein expression in brain regions in the animal models of acute bipolar episodes

P.0253 Two-week lithium treatment modulates translocator protein expression in brain regions in the animal models of acute bipolar episodes

P.0877 Lithium treatment influences blood transcriptome during manic but not depressive episode in bipolar patients

P.0877 Lithium treatment influences blood transcriptome during manic but not depressive episode in bipolar patients

Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-based cohort study

BackgroundLithium is prescribed during pregnancy, but there is limited information about pregnancy and neonatal outcomes following in utero exposure. Thus, this study aimed to investigate the associations between lithium use and adverse pregnancy and neonatal outcomes.MethodsThis population-based cohort study examined associations between maternal lithium use and major adverse pregnancy and neonatal outcomes via inverse probability weighted propensity score regression models.ResultsOf 854,017 women included in this study, 434 (0.05%) used lithium during pregnancy. Among pre-specified primary outcomes, lithium use during pregnancy was associated with an increased risk of spontaneous preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64 95% CI 1.82, 3.82) and birth of a large for gestational age infant (9.0% vs 3.5%; aRR 2.64 95% CI 1.91, 3.66), but not preeclampsia nor birth of a small for gestational age infant. Among secondary outcomes, lithium use was associated with an increased risk of cardiac malformations (2.1% vs 0.8%; aRR 3.17 95% CI 1.64, 6.13). In an analysis restricted to pregnant women with a diagnosed psychiatric illness (n=9552), associations remained between lithium and spontaneous preterm birth, birth of a large for gestational age infant, and cardiovascular malformations; and a positive association with neonatal hypoglycaemia was also found. These associations were also apparent in a further analysis comparing women who continued lithium treatment during pregnancy to those who discontinued prior to pregnancy.ConclusionsLithium use during pregnancy is associated with an increased risk of spontaneous preterm birth and other adverse neonatal outcomes. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

Lithium administered to pregnant, lactating and neonatal rats: entry into developing brain

BackgroundLittle is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults.MethodsLithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15–18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0–P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry.ResultsLithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups’ blood was consistently below that in maternal blood (30–35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2.ConclusionsInformation obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

Thyrotoxicosis treatment with lithium corbanate. Cases reported

Treatment of thyrotoxicosis caused by Graves’ disease or multinodular toxic goiter, is not difficult, in most cases, since the prescription of thionamides allows to normalize the level of thyroid hormones quickly and safety. But in a number of cases this therapy might be associated with serious side effects (agranulocytosis, toxic hepatitis, cholestasis), severe allergic reactions and also individual intolerance on thionamides. In such cases lithium carbonate is used, especially in severe thyrotoxic syndrome. It is known, that lithium can accumulate in the thyroid gland at a concentration 3–4 times higher than in the plasma. Perhaps, lithium uses Na+/I- ions. It can inhibit the synthesis and secretion thyroid hormones of thyroid gland. The article presents the cases reported the use of lithium carbonate in thyrotoxicosis treatment before thyroidectomy. Administering low doses of carbonate lithium (900 mg/ per day) renders significant decrease or normalization of thyroid hormones concentration within 7–14 days, thus it let perform thyroidectomy on the patients. No side effects have been identified with such a short course of lithium carbonate treatment.

Prevalence of impaired kidney function in patients with long-term lithium treatment: A systematic review and meta-analysis.

Although lithium renal effects have been extensively investigated, prevalence rates of chronic kidney disease (CKD) in lithium-treated patients vary. Our aim was to provide prevalence estimates and related moderators. We performed a systematic review in PubMed/Embase until November 01, 2021, conducting a random effects meta-analysis of studies evaluating CKD prevalence rates in lithium-treated patients calculating overall prevalence ±95% confidence intervals (CIs). Meta-regression analyses included sex, age, body mass index, smoking, hypertension, diabetes, cardiovascular disease, lithium-treatment dose, duration, and blood levels. Subgroup analyses included sample size, diagnoses, and study design. Pooled odds ratios (OR) were estimated for studies including patients receiving nonlithium treatment. Study quality was assessed using the Newcastle-Ottawa scale. Five, nine, and six trials were rated as high, fair, and low quality, respectively. In 20studies (n=25,907 patients), we estimated an overall prevalence of 25.5% (95% CI=19.8-32.2) of impaired kidney function; despite lack of differences (p=0.18), prevalence rates were higher in elderly samples than mixed samples of elderly and nonelderly (35.6%, 95% CI=21.4-52.9, k=2, n=3,161 vs. 25.1%, 95% CI=19.1-31.3, k=18, n=22,746). Prevalence rates were associated with longer lithium treatment duration (p=0.04). Cross-sectional studies provided lower rates than retrospective studies (14.5%, 95% CI=13.5-15.5, k=6, n=4,758 vs. 29.5%, 95% CI=22.1-38.0, k=12, n=17,988, p<0.001). Compared with 722,529 patients receiving nonlithium treatment, the OR of impaired kidney function in 14,187lithium-treated patients was 2.09 (95% CI=1.24-3.51, k=8, p=0.005). One-fourth of patients receiving long-term lithium may develop impaired kidney function, although research suffers from substantial heterogeneity between studies. This risk may be twofold higher compared with nonlithium treatment and may increase for a longer lithium treatment duration.

Poorly differentiated thyroid carcinoma arising from a lithium-induced goiter in a patient with schizophrenia: a case report

BackgroundLithium use causes goiter by increasing serum thyroid-stimulating hormone levels through the inhibition of thyroid hormone release. However, there are no reports of poorly differentiated thyroid carcinoma resulting from lithium-induced goiter. Herein, we report the case of a patient with schizophrenia who developed poorly differentiated thyroid carcinoma arising from a lithium-induced goiter.Case presentationA 61-year-old woman who was taking lithium for schizophrenia, visited the thyroid-endocrine center with a 10 × 12 cm anterior neck mass. She had a slowly growing goiter approximately 30 years ago; however, when she came to the hospital for diabetes diagnosis 2 years ago, she had no accompanying symptoms and refused evaluation. Three months before her visit, her dysphagia and dyspnea worsened as the size of her goiter increased rapidly. A neck ultrasound and enhanced thyroid computed tomography (CT) examination revealed a 10.9 × 9.2 × 12.8 cm size multi-lobulated mass on the right thyroid gland, leading to a leftward deviation of the trachea. Diagnostic total thyroidectomy was performed, and microscopic findings and immunohistochemical staining results indicated poorly differentiated thyroid carcinoma (PDTC) in the right thyroid mass. Mutation analyses for BRAF and the telomerase reverse transcriptase (TERT) promoter was performed. No BRAF gene mutations were detected; however, TERT promoter C228T point mutation was present in the PDTC. The patient underwent radioactive iodine therapy two months after the surgery. At a recent follow-up 4 months postoperatively, she was taking thyroid hormone replacement and remained in a relatively good health with a serum thyroglobulin level of 0.55 ng/ml.ConclusionsThyroid examination of psychiatric patients who develop goiter due to long-term lithium treatment should be monitored regularly, and appropriate investigations and surgery should be performed in a timely manner if the goiter is growing rapidly.

Lithium carbonate alleviates colon inflammation through modulating gut microbiota and Treg cells in a GPR43-dependent manner

BackgroundRecent evidence suggests that neuropsychiatric stabilizers have a place in resolving gastrointestinal disorders. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder clinically. Here, we estimate the therapeutic function of LC against colitis and investigate the mechanism of intestinal flora and metabolism modulation. MethodsA colitis model was constructed by continuously administering 2.5% dextran sodium sulfate (DSS) solution daily for 7 days. Analysis of gut microbiota was carried out by 16S rRNA gene high-throughput sequencing. Spectrum antibiotic cocktail (ABX) and faecal microbiota transplantation (FMT) were employed to evaluate the protective effect of intestinal flora. Colonic Treg cells and related immune responses were detected by flow cytometry. ResultsLC treatment significantly alleviated colon inflammation by regulating gut microbial diversity and altering flora composition. Notably, LC treatment upregulated short-chain fatty acid (SCFA)-producing bacteria, especially Akkermansia muciniphila (A. muciniphila), and transformed metabolite SCFA profiles. LC activated anti-inflammatory Treg cell responses in colonic lamina propria (LP) in a G-protein coupled receptor 43 (GPR43)-dependent mechanism. ABX, FMT and single bacteria gavage experiments were conducted to confirm the above mechanism. ConclusionsAs an intestinal microbiome and metabolite modulator, LC alleviates colon inflammation in a GPR43-dependent manner through activating Treg cell responses. Therefore, the therapeutic strategy of the microbiome-metabolite-immune axis, as observed in the A. muciniphila-SCFA-Treg cell axis in our study, might provide a new direction for the treatment of IBD.

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder

Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. ClinicalTrials.gov Identifier: NCT01928446.

Testing for Antisuicidal Effects of Lithium Treatment

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The Impact of Lithium on Brain Function in Bipolar Disorder: An Updated Review of Functional Magnetic Resonance Imaging Studies.

Lithium remains a gold standard treatment for bipolar disorder (BD), and functional magnetic resonance imaging (fMRI) studies have contributed to clarifying its impact on neural circuitries in affected individuals. However, the specific neurobiological mechanisms through which lithium exerts its effects on brain function are not fully understood. In this review, we aimed to summarize the results of recent fMRI studies evaluating the impact of lithium on brain functional activity and connectivity in patients diagnosed with BD. We performed a literature search of available sources found in the PubMed database reported in English since 2016, when the last available review on this topic was published. Five fMRI studies in resting-state condition and six studies performed during the execution of emotional tasks met the inclusion criteria. Overall, the available evidence supports normalizing effects of lithium on brain activity and connectivity. Most of these studies reported a normalization in prefrontal regions and interconnected areas involved in emotion regulation and processing, regardless of the task employed. Importantly, lithium treatment showed distinct patterns of activity/connectivity changes compared with other treatments. Finally, lithium modulation of neural circuitries was found to be associated with clinical improvement in BD. These results are consistent with the hypothesis that selective abnormalities in neural circuitries supporting emotion processing and regulation improve during lithium treatment in BD. However, the heterogeneity of the examined studies regarding study design, sample selection, and analysis methods might limit the generalizability of the findings and lead to difficulties in comparing the results. Therefore, in future studies, larger cohorts and homogeneous experimental tasks are needed to further corroborate these findings.

Chronic lithium administration in a mouse model for Krabbe disease.

Krabbe disease (KD; or globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by deficiency of the galactosylceramidase (GALC) enzyme. No cure is currently available for KD. Clinical applied treatments are supportive only. Recently, we demonstrated that two differently acting autophagy inducers (lithium and rapamycin) can improve some KD hallmarks in‐vitro, laying the foundation for their in‐vivo pre‐clinical testing. Here, we test lithium carbonate in‐vivo, in the spontaneous mouse model for KD, the Twitcher (TWI) mouse. The drug is administered ad libitum via drinking water (600 mg/L) starting from post natal day 20. We longitudinally monitor the mouse motor performance through the grip strength, the hanging wire and the rotarod tests, and a set of biochemical parameters related to the KD pathogenesis [i.e., GALC enzymatic activity, psychosine (PSY) accumulation and astrogliosis]. Additionally, we investigate the expression of some crucial markers related to the two pathways that could be altered by lithium: the autophagy and the β‐catenin‐dependent pathways. Results demonstrate that lithium has not a significant rescue effect on the TWI phenotype, although it can slightly and transiently improves muscle strength. We also show that lithium, with this administration protocol, is unable to stimulate autophagy in the TWI mice central nervous system, whereas results suggest that it can restore the β‐catenin activation status in the TWI sciatic nerve. Overall, these data provide intriguing inputs for further evaluations of lithium treatment in TWI mice.