Effect of lithium on chemotherapy-induced neutropenia in Egyptian breast cancer patients; a prospective clinical study.

PURPOSE: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients. METHODS: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles. RESULTS: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups. CONCLUSION: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.

Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Lithium for Fracture Treatment (LiFT): a double-blind randomised control trial protocol.

INTRODUCTION: Fracture healing can fail in up to 10% of cases despite appropriate treatment. While lithium has been the standard treatment for bipolar disorder, it may also have a significant impact to increase bone healing in patients with long bone fractures. To translate this knowledge into clinical practice, a randomised clinical trial (RCT) is proposed. METHODS AND ANALYSIS: A multicentre double blind, placebo-controlled RCT is proposed to evaluate the efficacy of lithium to increase the rate and predictability of long bone fracture healing in healthy adults compared to lactose placebo treatment. 160 healthy individuals from 18 to 55 years of age presenting with shaft fractures of the femur, tibia/fibula, humerus or clavicle will be eligible. Fractures will be randomised to placebo (lactose) or treatment (300 mg lithium carbonate) group within 2 weeks of the injury. The primary outcome measure will be radiographic union defined as visible callus bridging on three of the four cortices at the fracture site using a validated radiographic union score. Secondary outcome measures will include functional assessment and pain scoring. ETHICS AND DISSEMINATION: Participant confidentiality will be maintained with publication of results. Research Ethics Board Approval: Sunnybrook Research Institute (REB # 356-2016). Health Canada Approval (HC6-24-C201560). Results of the main trial and secondary endpoints will be submitted for publication in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: NCT02999022.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

Ultrastructural Changes in Hepatocellular Carcinoma-29 Cells after Treatment with Lithium Carbonate.

We studied the effect of lithium carbonate on hepatocellular carcinoma-29 cells in CBA male mice after injection in a dose of 20 mM along the tumor periphery. Transmission electron microscopy revealed a decrease in the volume density of the granular endoplasmic reticulum in the cell cytoplasm and an increase in the total numerical and volume density of autophagosomes and autolysosomes and zones of destruction of intracellular organelles. The ability of lithium carbonate to activate intracellular degradation processes in tumor cells and to stimulate cell death can be used to develop new combined strategies in the chemotherapy for hepatocellular carcinoma.

Finding the best effective way of treatment for rapid I-131 turnover Graves' disease patients: A randomized clinical trial.

BACKGROUND: Rapid I-131 turnover Graves' disease patients have low cure rate. We aimed to compare cure percentage at 12 months among 3 treatment doses of I-131 with or without lithium carbonate (LiCO3) in rapid turnover Graves' disease patients. METHODS: Sixty Graves' disease patients referred for radioactive iodine treatment were randomised into three arms of treatment: Group A, 3.7 MBq I-131/g thyroid plus 600 mg/day LiCO3, Group B, 5.55 MBq I-131/g plus 600 mg/day LiCO3, and Group C, 7.4 MBq I-131/g without LiCO3. Data were collected at baseline, 3, 6, 9, and 12 months. The primary endpoint were cure rates (percentage of euthyroid or hypothyroid) at 12 months. Pairwise comparisons were made across 3 groups using an equality of proportions test. The secondary endpoint, the odds of cure over the total follow-up for group B and C versus group A, was analyzed using generalized estimating equation (GEE). Side effects of I-131 and LiCO3 treatment were evaluated at 1 to 2 weeks after treatment. RESULTS: The cure rate at 12 months was 45% (9/20) for group A, 60% (12/20) for group B and 80% (16/20) for group C. The mean difference in proportion cured at 12 months between group C and group A was 35 (7.0 to 66.8)%; P-value = .02. There was a statistically significant difference between cure rates over all follow-up of group C and A after adjustment for sex (adjusted OR = 3.09; 95%CI = 1.32-7.20; P-value = .009), but no significant difference was found between group B and A or C and B in the primary and/or secondary efficacy endpoints. Side effects from the treatment were found in 12% (7/60); 2 in group A, 4 in group B, and 1 in group C. Four of these were likely due to LiCO3 side effects. CONCLUSIONS: Treatment of rapid turnover Graves' disease patients with high dose I-131 (7.4 MBq/g) provides significantly higher cure rates at 12 months, and 3 times odds of cure than 3.7 MBq/g I-131 plus LiCO3 with lesser side effects. We thus recommend 7.4 MBq I-131/g for treatment in these patients.

Lactancia materna y tratamiento con litio: Caso clínico / Lithium while breastfeeding: Case report

El tratamiento con litio forma parte de la terapia habitual en las personas que sufren el trastorno bipolar. Habitualmente, aquellas madres que desean dar el pecho a sus hijos son sometidas a la disyuntiva entre modificar el tratamiento o bien administrar lactancia artificial. La administración de litio durante la lactancia materna se ha asociado con diversos efectos adversos en el lactante, tales como alteraciones tiroideas, hipotermia o hipotonía, entre otros. Son pocas las publicaciones en las que no se observan dichas anomalías en los lactantes. A continuación, se presenta el caso de un lactante amamantado por su madre en tratamiento con litio que no presentó alteraciones renales ni tiroideas.

Lithium therapy is currently a cornerstone of treatment for mothers who suffer bipolar disorders. Those who wish to breastfeed their children are often told they have to decide whether modifying the treatment for their disorder or even avoiding lactation. Lithium administration during breastfeeding has been described to produce certain side effects such as thyroid disorders, hypothermia and hypotonia. To our knowledge, there are few publications where infants have no laboratory abnormalities. Here we present the case of an infant without renal or thyroid alteration while he was breastfed.

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.

Perfil de utilización del carbonato de litio en pacientes con trastorno afectivo bipolar en 25 ciudades de Colombia / Profile of lithium carbonate use in patients with bipolar disorder in Colombia

Resumen Introducción. El litio es el medicamento de elección para el tratamiento del trastorno afectivo bipolar. Objetivo. Determinar el perfil de uso y las reacciones secundarias del litio en pacientes con trastorno afectivo bipolar en Colombia. Materiales y métodos. Se hizo un estudio observacional de cohorte retrospectiva entre el 1° de enero y el 31 de diciembre de 2013, en pacientes con diagnóstico de trastorno afectivo bipolar tratados con carbonato de litio en 25 ciudades colombianas. Se evaluaron las variables sociodemográficas, las dosis del litio, la medicación simultánea con otros fármacos, las interacciones medicamentosas y las reacciones adversas. Se hizo un análisis multivariado utilizando el programa SPSS 22.0®. Resultados. La edad promedio de los 331 pacientes fue de 44,5 ± 13,9 años, 59,2 % de ellos eran mujeres, la dosis promedio de litio fue de 898 ± 294 mg/día, y 22 % recibía dosis inferiores a las recomendadas; los participantes habían recibido el medicamento durante 38,0 ± 39,5 meses en promedio (rango: 12-159 meses), y solo a 13,5 % de ellos se les había hecho el análisis de litio en sangre. El 71,3 % recibía otros medicamentos como tratamiento coadyuvante para el trastorno afectivo bipolar, especialmente clozapina (16,6 %) y ácido valproico (16,6 %). Las principales enfermedades concomitantes fueron el hipotiroidismo (18,1 %) y la hipertensión arterial (12,7 %). Se encontraron 390 interacciones medicamentosas potencialmente tóxicas y se reportaron reacciones secundarias en 1,2 % de los casos. Se encontró una asociación estadísticamente significativa con un menor riesgo de recibir tratamiento combinado en pacientes tratados en las ciudades de Bogotá (odds ratio, OR=0,4; p=0,025), Cartagena (OR=0,3; p=0,015) e Ibagué (OR=0,3; p=0,025). Conclusiones. El litio se administraba en las dosis e intervalos recomendados, pero un porcentaje significativo recibía dosis inferiores a las recomendadas y no fue posible contrastar el efecto con los niveles de litio en suero. Se debe mejorar el reporte de reacciones adversas y la medición de los niveles de litio en suero en los pacientes con trastorno afectivo bipolar en Colombia.

Abstract Introduction: Lithium is the drug of choice for the treatment of bipolar affective disorder. Objective: To define lithium therapeutic profile and adverse reactions to its use in patients with bipolar affective disorder in Colombia. Materials and methods: We conducted an observational retrospective cohort study between January 1 and December 31, 2013, which included patients with a diagnosis of bipolar disorder treated with lithium carbonate in 25 Colombian cities; we evaluated socio-demographic variables, lithium dose, co-medication, drug interactions and adverse reactions. A multivariate analysis was done using SPSS 22.0. Results: The 331 patients had an average age of 44.5 ± 13.9 years; 59.2% were women. The mean dose of lithium was 898 ± 294 mg/day; 22% received doses lower than recommended, and patients had received lithium for 38.0 ± 39.5 months (range: 12-159 months). Lithium levels in blood had been measured only in 13.5% of patients; 71.3% of them had received adjuvant therapy for bipolar disorder with other drugs, especially clozapine (16.6%) and valproic acid (16.6%). The main comorbidities were hypothyroidism (18.1%) and hypertension (12.7%); 390 potentially toxic drug interactions were found, and adverse reactions were reported in 1.2% of patients. A statistically significant association was found between a lower risk of combination therapy and receiving treatment in the cities of Bogotá (OR=0.4, p=0.025), Cartagena (OR=0.3, p=0.015) and Ibagué (OR=0.3, p=0.025). Conclusion: Lithium was generally used at recommended doses and intervals, but a significant percentage of patients received lower doses than those recommended, and it was not possible to compare with lithium levels in blood. Adverse reactions and blood lithium levels reporting should be improved in patients with bipolar disorder in Colombia.

Desenvolvimento, caracterização e desempenho biológico de um novo biomaterial de liberação controlada à base de carbonato de lítio aplicado ao reparo ósseo / Development, characterization and biological performance of a new biomaterial of controlled release based on lithium carbonate applied to bone repair

Neste trabalho desenhou-se bases de desenvolvimento, caracterização e avaliação dos aspectos biológicos relacionados ao Sistema BoneLithium, idealizado a partir da associação de partículas de carbonato de lítio dispersas em matriz gel de carbopol®, com capacidade de atuar como um sistema liberador de fármacos. Metodologicamente este estudo se dividiu em quatro partes: Na primeira delas, o objetivo central foi o desenvolvimento e a caracterização do biomaterial através da manipulação farmacológica. Na segunda etapa, avaliou-se a reação tecidual em subcutâneo de ratos, na terceira a influência das partículas de lítio liberadas pelo Sistema BoneLithium no reparo ósseo através de modelos experimentais utilizando coelhos, e por ultimo, a capacidade de cicatrização de defeitos ósseos criados cirurgicamente em calvária de ratos, tratados com o biomaterial e diferentes opções de enxertos ósseos com o objetivo de comparar a eficiência do Sistema BoneLithium aos protocolos pré-existentes. Experimentalmente, avaliou-se a reação tecidual onde se utilizou 15 ratos machos divididos aleatatoriamente em 5 grupos onde implantouse no subcutâneo tubos de butterfly contendo o biomaterial por períodos de preservação recomendados pela norma ADA 10993 para teste de reação tecidual. Os resultados demonstram que o Sistema BoneLithium apresenta reação tecidual normal. Para a avaliação do comportamento biológico do Sistema BoneLithium foram utilizados coelhos brancos adultos da raça New Zealand nos quais defeitos ósseos bilaterais de 1 cm de diâmetro foram confeccionados cirurgicamente na calvária e foram Tratados com o Sistema Bone Lithium do (lado Direito) e somente o Gel de Carbopol (lado esquerdo)/Coágulo sanguíneo (controle). A Histomorfometria demonstrou comportamento favorável ao reparo ósseo e adicionalmente através de Microtomografia Computadorizada (CT SKYSCAN), foi possível constatar diferenças significativas considerando p> 0.05 (ANOVA, Tukey) para o processo de reparo ósseo. A avaliação da performance do Sistema BoneLithium utilizando ratos Wistar nos quais foram criados defeitos críticos no centro da calvária e tratados com diferentes modalidades de enxertos ósseos (controle, autógeno, osso de banco (Unioss®, Marília Brasil), Bio-Oss® e associações com o Sistema BoneLithium. A histomorfometria mostrou diferenças significativas considerando p> 0.05 (ANOVA, Tukey) para avaliação de tecido conjuntivo pré-osteogênico e tecido ósseo neoformado, e quando avaliado qualitativamente por tomografia computadorizada de feixe cônico (I cat Cone Beam FOV 0.05 Xoran Tecnology, LLC, EUA e E-vol, CDT, Brasil), observaram-se áreas de neoformação óssea compatíveis com hiperdensidade óssea em toda a extensão do defeito quando apuradas em analises de paridade em escala Hounsfield. Dessa forma, conclui-se que no contexto deste estudo é possível concluir que Sistema BoneLithium representa uma alternativa com potencial viabilidade clínica e necessita seguimento de aplicação em novas metodologias.(AU)

In this work, bases for the development, characterization and evaluation of the biological aspects related to the BoneLithium System were designed, based on the association of lithium carbonate particles dispersed in carbopol® gel matrix, capable of acting as a drug-releasing system. Methodologically this study was divided in four parts: In the first one, the central objective was the development and characterization of the biomaterial through the pharmacological manipulation. In the second step, the tissue reaction was evaluated in subcutaneous of rats, in the third the influence of the lithium particles released by BoneLithium System in the bone repair through experimental models using rabbits, and finally, the capacity of healing of bone defects created surgically in Calvaria of rats, treated with the biomaterial and different options of bone grafts with the objective to compare the efficiency of the BoneLithium System to the preexisting protocols. Experimentally, the tissue reaction was evaluated in which 15 male rats were randomly divided into 5 groups, where butterfly tubes containing the biomaterial were implanted in the subcutaneous tubes for preservation periods recommended by the ADA 10993 standard for biocompatibility test. The results demonstrate that the BoneLithium System is tissue reaction positive. To evaluate the biological behavior of the BoneLithium System, adult New Zealand white rabbits were used in which bilateral bone defects of 1 cm in diameter were surgically made on calvaria and treated with the Bone Lithium System (right side) and only Gel Of Carbopol (left side) / blood clot (control). Histomorphometry showed a favorable behavior to bone repair and, in addition, through Computerized Microtomography (CT SKYSCAN), it was possible to verify significant differences considering p> 0.05 (ANOVA, Tukey) for the bone repair process. The evaluation of the performance of the BoneLithium System using Wistar rats in which critical defects were created at the calvarial center and treated with different bone graft modalities (control, autogenous, bone bank (Unioss®, Marília Brazil), Bio-Oss® and associations (ANOVA, Tukey) for evaluation of pre osteogenic connective tissue and neoformed bone tissue, and when assessed qualitatively by cone beam computed tomography (I cat - Cone Beam - FOV 0.05 - Xoran Tecnology, LLC, USA and E-vol, CDT, Brazil), areas of bone neoformation compatible with bone hyperdensity throughout the extent of the defect were ascertained in Hounsfield scale parity analyzes, It is concluded that in the context of this study it is possible to conclude that the BoneLithium System represents an alternative with potential clinical feasibility And requires follow-up of application in new methodologies.(AU)

Phase I-II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury.

Umbilical cord blood-derived mononuclear cell (UCB-MNC) transplants improve recovery in animal spinal cord injury (SCI) models. We transplanted UCB-MNCs into 28 patients with chronic complete SCI in Hong Kong (HK) and Kunming (KM). Stemcyte Inc. donated UCB-MNCs isolated from human leukocyte antigen (HLA ≥4:6)-matched UCB units. In HK, four patients received four 4-µl injections (1.6 million cells) into dorsal entry zones above and below the injury site, and another four received 8-µl injections (3.2 million cells). The eight patients were an average of 13 years after C5-T10 SCI. Magnetic resonance diffusion tensor imaging of five patients showed white matter gaps at the injury site before treatment. Two patients had fiber bundles growing across the injury site by 12 months, and the rest had narrower white matter gaps. Motor, walking index of SCI (WISCI), and spinal cord independence measure (SCIM) scores did not change. In KM, five groups of four patients received four 4-µl (1.6 million cells), 8-µl (3.2 million cells), 16-µl injections (6.4 million cells), 6.4 million cells plus 30 mg/kg methylprednisolone (MP), or 6.4 million cells plus MP and a 6-week course of oral lithium carbonate (750 mg/day). KM patients averaged 7 years after C3-T11 SCI and received 3-6 months of intensive locomotor training. Before surgery, only two patients walked 10 m with assistance and did not need assistance for bladder or bowel management before surgery. The rest could not walk or do their bladder and bowel management without assistance. At about a year (41-87 weeks), WISCI and SCIM scores improved: 15/20 patients walked 10 m ( p = 0.001) and 12/20 did not need assistance for bladder management ( p = 0.001) or bowel management ( p = 0.002). Five patients converted from complete to incomplete (two sensory, three motor; p = 0.038) SCI. We conclude that UCB-MNC transplants and locomotor training improved WISCI and SCIM scores. We propose further clinical trials.

The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles.

BACKGROUND: Bipolar Disorder is characterized by episodes running the full mood spectrum, from mania to depression. Between mood episodes, residual symptoms remain, as sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities. The present review intends to reflect about the most recent and relevant information concerning the biunivocal relation between bipolar disorder and circadian cycles. METHODS: It was conducted a literature search on PubMed database using the search terms "bipolar", "circadian", "melatonin", "cortisol", "body temperature", "Clock gene", "Bmal1 gene", "Per gene", "Cry gene", "GSK3ß", "chronotype", "light therapy", "dark therapy", "sleep deprivation", "lithum" and "agomelatine". Search results were manually reviewed, and pertinent studies were selected for inclusion as appropriate. RESULTS: Several studies support the relationship between bipolar disorder and circadian cycles, discussing alterations in melatonin, body temperature and cortisol rhythms; disruption of sleep/wake cycle; variations of clock genes; and chronotype. Some therapeutics for bipolar disorder directed to the circadian cycles disturbances are also discussed, including lithium carbonate, agomelatine, light therapy, dark therapy, sleep deprivation and interpersonal and social rhythm therapy. LIMITATIONS: This review provides a summary of an extensive research for the relevant literature on this theme, not a patient-wise meta-analysis. CONCLUSIONS: In the future, it is essential to achieve a better understanding of the relation between bipolar disorder and the circadian system. It is required to establish new treatment protocols, combining psychotherapy, therapies targeting the circadian rhythms and the latest drugs, in order to reduce the risk of relapse and improve affective behaviour.

Test-retest reliability, feasibility and clinical correlates of the Eurofit test battery in people with bipolar disorder.

The physical health of people with bipolar disorder is poorer in comparison to the general population, with an increased prevalence of cardiovascular and metabolic diseases. Due to the established beneficial effects, there is growing interest in the promotion of physical activity and in particular the accurate measurement of physical fitness in this population. Currently, no existing measures of physical fitness used in the general population have been tested for validity and reliability among people with bipolar disorder. Therefore, we examined the reproducibility, feasibility and correlates of the Eurofit test battery in people with bipolar disorder. From 24 men (43.0±13.0 years) and 22 women (43.9±10.2 years) with bipolar disorder two trials of the Eurofit test, administered within three days, were analyzed. All Eurofit items showed good reproducibility with intraclass correlation coefficients ranging from 0.71 for the whole body balance test to 0.98 for the handgrip force test. Significant correlations with Eurofit test items were found with age, illness duration, body mass index, smoking behavior, mean daily lithium dosage, and depressive and lifetime hypomanic symptoms. The current study demonstrates that the Eurofit test can be recommended for evaluating the physical fitness of inpatients with bipolar disorder.

Increased plasma levels of soluble TNF receptors 1 and 2 in bipolar depression and impact of lithium treatment.

OBJECTIVE: TNF system (TNF and its soluble receptors sTNFR1 and 2) has been investigated as a potential molecular target in bipolar disorder. The aim of the study was to compare plasma levels of these receptors in unmedicated bipolar depressed patients compared with healthy controls, and to evaluate the effects of a 6-week lithium treatment on sTNFR1 and sTNFR2 levels. METHODS: The study enrolled 29 patients with unmedicated bipolar disorder in a major depressive episode and 27 matched controls. Patients had blood collected at baseline and after 6 weeks of lithium treatment. The concentration of sTNFRs was measured by ELISA. RESULTS: sTNFR1 and sTNFR2 levels were significantly increased in bipolar depression in comparison with healthy subjects. Lithium treatment did not significantly change sTNFR1 and sTNFR2 levels from baseline to endpoint. There was no correlation between improvement in depressive symptoms and the change in sTNFR1 or sTNFR1 levels. CONCLUSION: These results reinforce the involvement of an activated immune response system in the pathophysiology of bipolar disorder, with no impact of lithium treatment on the related biomarkers.

Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.

RATIONALE: Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. OBJECTIVES: This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. METHODS: Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. RESULTS: Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of "loss of appetite," "stomach aches," and "nightmares/strange dreams." No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. CONCLUSIONS: Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.

The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.