Li Treatment Research Articles

Information theory characteristics improve the prediction of lithium response in bipolar disorder patients using a support vector machine classifier.

Bipolar disorder (BD) is a mood disorder with a high morbidity and death rate. Lithium (Li), a prominent mood stabilizer, is often used as a first-line treatment. However, clinical studies have shown that Li is fully effective in roughly 30% of BD patients. Our goal in this study was to use features derived from information theory to improve the prediction of the patient's response to Li as well as develop a diagnostic algorithm for the disorder. We have performed electrophysiological recordings in patient-derived dentate gyrus (DG) granule neurons (from a total of 9 subjects) for three groups: 3 control individuals, 3 BD patients who respond to Li treatment (LR), and 3 BD patients who do not respond to Li treatment (NR). The recordings were analyzed by the statistical tools of modern information theory. We used a Support Vector Machine (SVM) and Random forest (RF) classifiers with the basic electrophysiological features with additional information theory features. Information theory features provided further knowledge about the distribution of the electrophysiological entities and the interactions between the different features, which improved classification schemes. These newly added features significantly improved our ability to distinguish the BD patients from the control individuals (an improvement from 60% to 74% accuracy) and LR from NR patients (an improvement from 81% to 99% accuracy). The addition of Information theory-derived features provides further knowledge about the distribution of the parameters and their interactions, thus significantly improving the ability to discriminate and predict the LRs from the NRs and the patients from the controls.

Transcriptomics and miRNomics data integration in lymphoblastoid cells highlights the key role of immune-related functions in lithium treatment response in Bipolar disorder

BackgroundBipolar Disorder (BD) is a complex mental disease characterized by recurrent episodes of mania and depression. Lithium (Li) represents the mainstay of BD pharmacotherapy, despite the narrow therapeutic index and the high variability in treatment response. However, although several studies have been conducted, the molecular mechanisms underlying Li therapeutic effects remain unclear.MethodsIn order to identify molecular signatures and biological pathways associated with Li treatment response, we conducted transcriptome and miRNome microarray analyses on lymphoblastoid cell lines (LCLs) from 20 patients diagnosed with BD classified as Li responders (n = 11) or non-responders (n = 9).ResultsWe found 335 mRNAs and 77 microRNAs (miRNAs) significantly modulated in BD responders versus non-responders. Interestingly, pathway and network analyses on these differentially expressed molecules suggested a modulatory effect of Li on several immune-related functions. Indeed, among the functional molecular nodes, we found NF-κB and TNF. Moreover, networks related to these molecules resulted overall inhibited in BD responder patients, suggesting anti-inflammatory properties of Li.From the integrative analysis between transcriptomics and miRNomics data carried out using miRComb R package on the same samples from patients diagnosed with BD, we found 97 significantly and negatively correlated mRNA-miRNA pairs, mainly involved in inflammatory/immune response.ConclusionsOur results highlight that Li exerts modulatory effects on immune-related functions and that epigenetic mechanisms, especially miRNAs, can influence the modulation of different genes and pathways involved in Li response. Moreover, our data suggest the potentiality to integrate data coming from different high-throughput approaches as a tool to prioritize genes and pathways.

Effect of soil drought on growth and yield of maize (Zea mays L.) hybrids grown under compacted soil

AbstractIn this study, we examined responses of maize hybrids differing in susceptibility to soil compaction and drought in the case of their separate or combined action. We ran field and greenhouse experiments and determined effects on grain yield, biomass, weight of 1000 grains, shoot and roots dry matter (DM), shoot‐to‐roots ratio, harvest index, plant height, emergence index, leaf area and greening and root number and length. Individual and combined effects of both stresses were observed in the field and greenhouse. Compared with plants growing in loose soil and optimal irrigation (LI), the resistant hybrids in treatments HI, LD and HD showed a smaller reduction in GY, BY, S, R, RN and RL than the sensitive. In both groups, stress influence on HA, W‐1000, LA and SPAD was smaller and the differences were insignificant. Compared with LI treatment, the roots of LD, HI and HD increased their DM, number and length in the upper level of the soil profile and the number of roots developed at 0–30° and 30–60° in relation to the root main axis. Analysis of those traits in the hybrids resistant and sensitive to both stress factors enabled to explain a defence response. Our study demonstrated that soil compaction and soil drought, which usually occurs simultaneously, caused significant changes in components of plant yield and showed plant plasticity in response to environmental factors under natural conditions.

Combined Experimental and Simulation Studies of Lithium and Cobalt‐Modified TiO2 and Their Impacts on the Performance and Stability of Perovskite Solar Cells

AbstractPosttreatment of titanium oxide (TiO2) using lithium (Li) and cobalt (Co) precursors is widely adopted to modify the charge quenching property in perovskite solar cells (PSCs); however, the fundamental understanding of the effect of the modification layer on the material itself and, consequently, the photovoltaic performance stability is not complete. In this work, in situ X‐ray diffraction measurements show that the Li and Co ions can diffuse into TiO2 and consequently accelerate the rutile phase transformation. X‐ray photoelectron spectroscopy results reveal the appearance of a Ti3+ feature in both the Li‐ and Co‐treated samples, suggesting that the treatment ions are partially located at the subsurface/surface of the spin‐cast TiO2 layer. The Li‐treated TiO2 exhibits greatly upshifted conduction band edges, which benefits charge extraction properties and improves the average device parameters in a complete PSC. To complement the experiments, density functional theory calculations are performed. While Li treatment initially results in enhanced electronic properties, Li‐treated TiO2 tends to have more surface vacancies over time and is more susceptible to adsorption and accumulation of iodide ions compared to the Co‐treated sample, which is experimentally supported by surface photovoltage spectroscopy and time‐resolved photoluminescence results.

Improving oral bioavailability of water-insoluble idebenone with bioadhesive liposomes

The clinical application of water-insoluble idebenone (IDB) is significantly suffering from the poor aqueous solubility in the gastrointestinal (GI) fluids and limited oral bioavailability. Herein, we designed an IDB-loaded bioadhesive liposome based on poly (maleic anhydride-alt-1-octadecene) (PMO) (termed as IBL) to improve the intestinal absorption and oral bioavailability. IBL was nanometer-sized particles with a Z-average diameter of 95.12 nm and IDB exhibited as amorphous or molecular state in the IBL formulation. At 2 h of oral administration, the tissue concentration of IDB in the duodenum, jejunum, and ileum in the IBL treated group was notably improved 2.69-, 3.21- and 3.44- fold over counterpart liposomal formulation of IDB (LI). Moreover, in the IBL treated group, the oral bioavailability of IDB was obviously enhanced 3.79-fold than that in free drug suspension and 2.33-fold when compared to counterpart LI treatment. Therefore, the bioadhesive liposome represents a feasible and elegant strategy to improve the oral absorption of water-insoluble IDB.

Depressive-like behavior accompanies neuroinflammation in an animal model of bipolar disorder symptoms induced by ouabain

IntroductionA previous study from our Laboratory showed no alteration in inflammatory parameters seven days after ouabain (OUA) administration, a Na+K+ATPase inhibitor, which was previously considered only a mania model. However, the administration of OUA in rats was recently validated as a model of bipolar disorder (BD) symptoms, demonstrating that 14 days after single intracerebroventricular (ICV) administration, OUA also induces depressive-like behavior. Therefore, it is important to investigate the long-term effect of OUA on inflammatory parameters since this mechanism seems to play a key role in BD physiopathology. MethodsAdult male Wistar rats received a single ICV administration of OUA or artificial cerebrospinal fluid (aCSF). From the fourth day after the ICV infusion, the rats received saline or Lithium (Li) for 14 days. The open-field test was performed on the 7th day after OUA. On the 14th day, locomotion was re-evaluated, and the forced swimming test (FST) was used to evaluate depressive-like behavior. Inflammatory parameters were assessed in the frontal cortex and hippocampus. ResultsOUA increased the locomotion of rats after seven days, considered a mania-like behavior. In the FST, OUA increased the time of immobility on the 14th day, considered a depressive-like behavior. Li reversed the mania-like behavior and partially reversed the depressive-like behavior. Furthermore, OUA increased the levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α, and CINC-1 in the frontal cortex and hippocampus. Li treatment reverses all these inflammatory alterations. ConclusionThis study suggests that the long-term Na+K+ATPase inhibition effects induce depressive-like behavior, which was accompanied by inflammation in the BD symptoms model.

Proteomic analysis of urinary exosomes from patients with lithium‐induced nephrogenic diabetes insipidus

Lithium (Li)‐induced Nephrogenic Diabetes Insipidus (NDI) is a large healthcare problem, which affect around 40% of patients with bipolar disorder undergoing Li treatment. NDI is characterized by the inability in the kidney to concentrate urine in response to vasopressin in the kidney collecting duct (CD). In animals, Li causes a downregulation of aquaporin‐2 and a cellular remodeling of the CD in rats resulting in a reduced fraction of principal cells relative to intercalated cells. Whether Li has similar effects in the human kidney is, however, not known. Urinary exosomes are extracellular nanovesicles derived from intracellular multivesicular bodies fused with the plasma membrane of epithelial cells lining the kidney tubular system and the urinary tract. The purpose of the first part of this study is to analyze whether the urinary rat proteome reflects the Li‐induced changes in the kidney. This is followed by proteomic analyses of urinary exosomes isolated from Li‐NDI patients.Rats were divided in three groups; controls (n=8), 2‐week Li treatment (40 mmol/kg/food, n=8) and 4‐week Li treatment (40 mmol/kg/food, n=8). Treatment with Li showed a significant increase in urine output after 2‐weeks (P<0.01) and 4‐weeks (P<0.05). Additionally, the rats developed severe polydipsia, with water intake significantly increased after 2‐weeks Li treatment (P<0.001) and 4‐weeks Li treatment (P<0.0001).Early morning urine samples from the placebo group in a previous published 12‐week placebo‐controlled pilot trial (Fotso Soh et al, 2021. A double‐blind, randomized, placebo‐controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users. Bipolar Disorders 23, 66–75) involving Li‐NDI patients (n=9) were collected. The Li‐NDI participants have been on a stable dose of Li (˃2 months) and determined to have a urinary osmolality <600 mOsm/kg at baseline. In addition, urine from random healthy controls (n=6) were collected. Urine samples from the rodent study and human study were subjected to ultracentrifugation for exosome isolation and will be further processed for mass spectrometry analysis (MS/MS).

Low-Dose Aspirin Augments the Anti-Inflammatory Effects of Low-Dose Lithium in Lipopolysaccharide-Treated Rats.

Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness.

Doping-Mediated Lattice Engineering of Monolayer ReS2 for Modulating In-Plane Anisotropy of Optical and Transport Properties.

ReS2 exhibits strong anisotropic optical and electrical responses originating from the asymmetric lattice. Here, we show that the anisotropy of monolayer (1L) ReS2 in optical scattering and electrical transport can be practically erased by lattice engineering via lithium (Li) treatment. Scanning transmission electron microscopy revealed that significant strain is induced in the lattice of Li-treated 1L-ReS2, due to high-density electron doping and the resultant formation of continuous tiling of nanodomains with randomly rotating orientations of 60°, which produced a nearly isotropic response of polarized Raman scattering and absorption of Li-treated 1L-ReS2. With Li treatment, the in-plane conductance of 1L-ReS2 increased by an order of magnitude, and its angle dependence became negligible. Our result that the asymmetric phase was converted into the isotropic phase by electron injection could significantly expand the optoelectronic applications of polymorphic two-dimensional transition metal dichalcogenides.

Outcomes in Older Adults (age ≥ 70) with Acute Myeloid Leukemia Based on Choice of Frontline Treatment for Proliferative or Non-Proliferative Phenotype

IntroductionAcute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. The optimal selection of frontline therapy remains controversial, with intensive chemotherapy (IC) often favored in AML patients who present with a proliferative phenotype (P-AML) compared to a non-proliferative phenotype (NP-AML), yet evidence to support this approach is lacking. We aimed to investigate the outcomes of older AML patients based on treatment choices including intensive chemotherapy (IC), hypomethylating agents (HMA) and low intensity therapy (LI) (excluding HMAs), stratified on the basis of a proliferative and non-proliferative phenotype.MethodsWe retrospectively analyzed clinical and laboratory parameters along with treatment outcomes in 983 elderly AML patients treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to hypomethylating agents for non-AML diagnoses were excluded. Patients were placed into one of four cohorts based on the type of frontline therapy received: Intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent); hypomethylating agents (HMA) (azacitadine (AZA) or decitabine (DEC)); low intensity therapy (LI) (defined as low-dose cytarabine or similar agent excluding HMAs); or supportive care (SC) (including hydroxyurea). P-AML was defined as presence of ≥30% bone marrow (BM) myeloblasts, whereas NP-AML was defined as 20%-29% BM myeloblasts at diagnosis. Age, type of AML, history of antecedent hematologic disease, cytogenetics, ECOG performance status, Charlson comorbidity Index, complete blood counts and myeloblast percentage at diagnosis were compared for each patient. Kaplan-Meier analysis was performed to calculate overall survival and the log-rank test was used to determine significance where a p-value of <0.05 was defined as significant.ResultsOf the 983 patients, 718 patients had data regarding BM blast percentage at diagnosis without previous exposure to HMA who were included in the analyses. Of these, 479 (66.71%) were classified as P-AML and 239 (33.29%) as NP-AML. Baseline characteristics are described in Figure 1A. Overall survival (OS) of the entire cohort was 8.0 months (mo). No significant difference was noted in OS between NP-AML and P-AML (8.9 vs. 7.7mo respectively, p=0.1741). The analysis based on treatment modality with focus on HMA and IC revealed that HMA therapy in NP-AML produced a significantly superior OS compared to IC (19.1 vs. 9.6 mo, p=0.0165), whereas no significant OS difference was found in the P-AML patients (13.3 (HMA) vs. 10.3 mo (IC), p=0.3135). In the HMA cohort, OS was better in NP-AML compared to P-AML (19.1 mo vs. 13.2 mo, p=0.0276). Survival with LI treatment was inferior to IC or HMA in both P-AML and NP-AML cohorts (Figure 1C).The HMA treated cohort was then analyzed, based upon risk stratification using NCCN cytogenetic risk categories. Sample size was too small to assess OS in the favorable-risk patients (NP-AML, n=1; P-AML, n=1). In the intermediate risk patients (IRC), OS was similar between NP-AML and P-AML (23.97 months vs. 17.5 months, p=0.1650). In the poor-risk cytogenetics (PRC) subgroup, survival was superior in the NP-AML cohort compared to P-AML (11.58 months vs. 9.37 months, p=0.0132).Finally, outcome based upon the specific HMA administered (AZA vs. DEC) was compared (Figure 1B). AZA treatment was associated with a trend favoring improved OS in NP-AML compared to DEC (19.83 months vs. 11.13 months, p=0.2644). Moreover, AZA treatment statistically improved OS in NP-AML compared to P-AML (19.83 months vs. 14.43 months, p=0.0466). Survival outcomes with AZA vs DEC based on cytogenetic risk categories are illustrated in Figure 1B.ConclusionsHMAs represent effective frontline therapy for elderly patients with P-AML or NP-AML, with particular benefit compared to IC or LI in the NP-AML subset. In patients harboring poor-risk cytogenetics, HMA therapy produced an improvement in OS in NP-AMLvs.P-AML. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Sweet:Incyte: Research Funding; Ariad: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Consultancy; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Lancet:Janssen: Consultancy; Erytech: Consultancy; BioSight: Consultancy; Bio-Path Holdings: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy.

Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders

Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation.

Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: A historical cohort study.

Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. We included adult patients with BD on LTLT (≥1year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p=0.13) at the end of follow-up duration (mean duration: 3.5±4.4years for continuers and 4.9±5.3years for discontinuers). CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Investigation of Lithium Application and Effect of Organic Matter on Soil Health

The extensive use of lithium (Li) ion-based batteries has increased the contamination of soil and water systems due to widespread dispersal of Li products in the environment. In the current study, the influence of Li application on soil fertility and leachate was observed. Three soil samples were collected and five treatments of Li (0, 50, 100, 150 and 200 mg/L) were applied. After three months of Li treatment, leachate was collected and soil samples were subjected to physical and chemical analyses. The results showed that the mean values of soil pH were increased slightly after Li application while electrical conductivity (EC) ranged from 1.2 to 5.1 µS/cm, indicating that soil was slightly saline in nature. The sodium was observed to be greater than the recommended values (0.3–0.7 mg/kg) in Li-amended soil while calcium and magnesium values decreased in soils compared to untreated soil. Mean values of phosphorus and potassium were greater before Li application and reduced considerably after Li application. Leachate analysis showed that all the parameters differed significantly except those of zinc and iron. The EC of leachate samples ranged from 2286–7188 µS/cm, which shows strong salinity. The sodium adsorption ratio (SAR) ranged from 1–11, which indicates that it falls into the marginal soil category. Lithium concentration in leachate samples ranged from 0–95 mg/L, which was significantly higher than the acceptable value for lithium (2.5 mg/L) in leachate. A soil sample (3) with an additional 10% organic matter showed that after Li application, the loss of nutrients in leachate was less as compared to the other two samples, demonstrating that organic matter improved soil conditions and suppressed the negative effects of Li on soil. Our results could raise concerns about risks in situations where food and fodder crops are associated with Li-contaminated waste disposal.

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients.

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

Four-Year Follow-Up of High versus Low Intensity Summer Treatment for Adolescents with ADHD

ABSTRACT Objective Despite an emergence of psychosocial treatments for adolescent ADHD, their long-term effects are unknown. Method We examine four-year outcomes of a randomized controlled trial (N = 218) comparing high-intensity (HI; 412 h, $4,373 per participant) versus low-intensity (LI; 24 h, $97 per participant) skills-based summer intervention delivered to adolescents with ADHD at two secondary school transitions (6th/9th grade). Quantitative and qualitative analyses evaluated group×time and group×grade×time effects on 4-year outcomes. Results Relative to LI, a single dose of HI had modest but lasting effects on teen organization skills (d =.40) and ADHD symptoms (9th grade only: d =.27 to.31) at 4-year follow-up. There was no long-term incremental effect of HI (vs. LI) for parent-teen conflict, GPA, or parent use of contingency management. Treatment appeared most effective when delivered to older adolescents (i.e., 9th versus 6th grade), suggesting the long-term impact of ADHD treatment may increase with age. Qualitative data corroborated that the primary long-term benefit of HI (vs. LI) treatment was to organization skills; many of the remaining perceived benefits were to parent and teen psychological variables (i.e., increased self-esteem, self-awareness, parental optimism). HI offered no incremental benefit to long-term educational or clinical service utilization or costs. Conclusions Modest therapeutic benefits of adolescent ADHD treatment are maintained long term. However, HI treatment did not impact outcomes that could defray the intervention’s high costs ($4,373) compared to LI treatment ($97).

Effects of lithium on cytokine neuro-inflammatory mediators, Wnt/β-catenin signaling and microglial activation in the hippocampus of chronic mild stress-exposed rats

Microglial in vivo production of pro-inflammatory cytokines is central to the pathogenesis of multiple neurological disorders including depression, with a rising role of Wnt/β-catenin signaling as potential regulator of microglia-mediated neuro-inflammation. This study aimed at investigating the hippocampal expression of the Wnt/ß-catenin pathway in chronic mild stress (CMS)-exposed rats and the effects of Lithium (Li) on the expression of this pathway as a method to identify a plausible link between exposure to chronic stress, microglial activation, and neuroinflammation. MethodsThe effect of chronic administration of Li was investigated on behavioral changes, hippocampal expression of Wnt-DVL-GSK3β-β-catenin signaling pathway, and microglial activation in CMS-exposed male Wistar rats ResultsCMS induced a depressive-like behavior associated with increased pro-inflammatory microglial activation and reduced hippocampal expression of the Wnt/β-catenin signaling pathway. Chronic Li treatment ameliorated stress induced-behavioral changes, reduced microglial activation and enhanced the hippocampal expression of Wnt/β-catenin signaling pathway. ConclusionThis work highlights that Li-induced inhibition of GSK-3β with subsequent accumulation of β-catenin could impede pro-inflammatory microglia activation which is a key pathological hallmark associated with depression. Wnt/β-catenin signaling represents a promising therapeutic target, not only for alleviation of depression, but also for a wide array of neurological disorders.

Lithium Alters Expression of RNAs in a Type-Specific Manner in Differentiated Human Neuroblastoma Neuronal Cultures, Including Specific Genes Involved in Alzheimer’s Disease

Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple CNS disorders, including Alzheimer’s disease (AD). While perturbation of RNA levels by Li was reported, its effects on the whole-transcriptome remains unexplored. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels.

Na+/K+-ATPase and lipid peroxidation in forebrain cortex and hippocampus of sleep-deprived rats treated with therapeutic lithium concentration for different periods of time

Lithium (Li) is a typical mood stabilizer and the first choice for treatment of bipolar disorder (BD). Despite an extensive clinical use of Li, its mechanisms of action remain widely different and debated. In this work, we studied the time-course of the therapeutic Li effects on ouabain-sensitive Na+/K+-ATPase in forebrain cortex and hippocampus of rats exposed to 3-day sleep deprivation (SD). We also monitored lipid peroxidation as malondialdehyde (MDA) production. In samples of plasma collected from all experimental groups of animals, Li concentrations were followed by ICP-MS.The acute (1 day), short-term (7 days) and chronic (28 days) treatment of rats with Li resulted in large decrease of Na+/K+-ATPase activity in both brain parts. At the same time, SD of control, Li-untreated rats increased Na+/K+-ATPase along with increased production of MDA. The SD-induced increase of Na+/K+-ATPase and MDA was attenuated in Li-treated rats.While SD results in a positive change of Na+/K+-ATPase, the inhibitory effect of Li treatment may be interpreted as a pharmacological mechanism causing a normalization of the stress-induced shift and return the Na+/K+-ATPase back to control level.We conclude that SD alone up-regulates Na+/K+-ATPase together with increased peroxidative damage of lipids. Chronic treatment of rats with Li before SD, protects the brain tissue against this type of damage and decreases Na+/K+-ATPase level back to control level.

Rediscovering Li Zehou: From the perspective of philosophy of language

AbstractThis article seeks to shed new light on Li Zehou's thought by examining the long‐neglected dimension of the philosophy of language in his philosophical system. In addition, an effort is made to analyze how this dimension is generated by Li's creative combination of Marxism and Chinese philosophy. Insisting on the priority of life and practice to language, Li attacks the ‘linguistic turn’ so as to lead the focus of philosophy from language back to life. Li's treatment of language consistently seeks to keep pace with the development of his thinking, incorporating an evolutionary continuum from practice to life. One of the primary approaches adopted by Li in the construction of his philosophy is to deconstruct the language‐centered ontology that resulted from the ‘linguistic turn’ in the West. Notwithstanding this, his deconstruction still performs the same task as the philosophy of language typically does, that is, addressing philosophical problems through clarifying the nature of language. What is distinctive, however, is that he goes beyond this to expose the limitations of language.

Can network analysis shed light on predictors of lithium response in bipolar I disorder?

To undertake a large-scale clinical study of predictors of lithium (Li) response in bipolar I disorder (BD-I) and apply contemporary multivariate approaches to account for inter-relationships between putative predictors. We used network analysis to estimate the number and strength of connections between potential predictors of good Li response (measured by a new scoring algorithm for the Retrospective Assessment of Response to Lithium Scale) in 900 individuals with BD-I recruited to the Consortium of Lithium Genetics. After accounting for co-associations between potential predictors, the most important factors associated with the good Li response phenotype were panic disorder, manic predominant polarity, manic first episode, age at onset between 15-32years and family history of BD. Factors most strongly linked to poor outcome were comorbid obsessive-compulsive disorder, alcohol and/or substance misuse, and/or psychosis (symptoms or syndromes). Network analysis can offer important additional insights to prospective studies of predictors of Li treatment outcomes. It appears to especially help in further clarifying the role of family history of BD (i.e. its direct and indirect associations) and highlighting the positive and negative associations of different subtypes of anxiety disorders with Li response, particularly the little-known negative association between Li response and obsessive-compulsive disorder.