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Journal of Clinical Pharmacology Nov 2022The pharmacokinetics of lithium, the gold standard for the treatment of bipolar disorder, are well described in nonpregnant patients. Because lithium is commonly...
The pharmacokinetics of lithium, the gold standard for the treatment of bipolar disorder, are well described in nonpregnant patients. Because lithium is commonly prescribed to women of childbearing age, more data are essential to characterize lithium pharmacokinetics during the perinatal period. Lithium is primarily eliminated by the kidney. As a result, shifts in lithium elimination clearance parallel pregnancy-related changes in glomerular filtration rate. Lithium's narrow therapeutic window increases the risk for therapeutic failure and toxicity when lithium elimination clearance is altered. To characterize the pharmacokinetics of lithium in pregnancy and postpartum, 3 women treated with lithium for bipolar disorder completed serial blood sampling protocols during each trimester of pregnancy and at least once postpartum. The trajectory of lithium elimination clearance, creatinine clearance, and serum lithium concentrations were determined. Manic, depressive, and anxiety symptoms were also assessed at each study visit. Compared to the nonpregnant state, lithium elimination clearance increased an average of 63.5% by the third trimester. Lithium elimination clearance was inversely related to changes in serum lithium concentration. Mood symptoms worsened with declines in serum lithium concentration. Lithium elimination clearance returned to baseline at 4 to 9 weeks postpartum. To maintain lithium effectiveness during pregnancy and prevent toxicity postpartum, lithium therapeutic drug monitoring and dose adjustments are warranted.
Topics: Bipolar Disorder; Creatinine; Drug Monitoring; Female; Humans; Lithium; Postpartum Period; Pregnancy
PubMed: 35620848
DOI: 10.1002/jcph.2089 -
Cell Transplantation 2009Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological... (Review)
Review
Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.
Topics: Animals; Antipsychotic Agents; Bipolar Disorder; Brain; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lithium
PubMed: 19523343
DOI: 10.3727/096368909X471251 -
Pharmacology & Therapeutics Nov 2010Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness.... (Review)
Review
Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium's therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium's main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington's, Alzheimer's, and Parkinson's diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium's neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.
Topics: Animals; Apoptosis; Bipolar Disorder; Central Nervous System Diseases; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Lithium; Neurodegenerative Diseases; Signal Transduction
PubMed: 20705090
DOI: 10.1016/j.pharmthera.2010.07.006 -
Frontiers in Public Health 2022Although suicide is considered a major preventable cause of mortality worldwide, we do not have effective strategies to prevent it. Lithium has been consistently... (Review)
Review
Although suicide is considered a major preventable cause of mortality worldwide, we do not have effective strategies to prevent it. Lithium has been consistently associated with lowering risk of suicide. This effect could occur at very low concentrations, such as trace doses of lithium in tap water. Several ecological studies and recent meta-analysis have suggested an inverse association between lithium in water and suicide in the general population, with a lack of knowledge of clinically significant side effects. This paper is aimed as a proposal to discuss the addition of lithium to drinking water to decrease the suicide rate. For this, we review the evidence available, use previous experiences, such as water fluoridation to prevent dental caries, and discuss the complexity involved in such a public policy. Considering the limited data available and the controversies contained in this proposal, we suggest that a consensus on lithium concentration in water is needed, where the suicide rates start to reduce, as happened with water fluoridation. This measure will require to develop community-controlled trials with strict monitoring of any side effects, where democratic procedures would constitute one of the most appropriate ways to validate its implementation according to the reality of each community.
Topics: Dental Caries; Drinking Water; Humans; Lithium; Public Policy; Suicide Prevention
PubMed: 35252091
DOI: 10.3389/fpubh.2022.805774 -
CNS Neuroscience & Therapeutics Jun 2022Vasogenic cerebral edema resulting from blood-brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation...
BACKGROUND
Vasogenic cerebral edema resulting from blood-brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β-catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β-catenin signaling.
METHODS
We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV-induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β-catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124.
RESULTS
Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm vs. 19.97 ± 3.20 mm in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β-catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin-5 and ZO-1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124-mediated endothelial Wnt/β-catenin signaling.
CONCLUSION
Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.
Topics: Animals; Blood-Brain Barrier; Brain Edema; Cerebral Hemorrhage; Hematoma; Lithium; Mice; Mice, Knockout; Wnt Signaling Pathway; beta Catenin
PubMed: 35343071
DOI: 10.1111/cns.13832 -
International Journal of Medical... 2024Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard... (Review)
Review
Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium's efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium's neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.
Topics: Humans; Lithium; Neuroprotective Agents; Ischemic Stroke; Glycogen Synthase Kinase 3; Apoptosis
PubMed: 38169754
DOI: 10.7150/ijms.88195 -
International Journal of Biological... Oct 2022Cellulose, an abundant natural polymer, has promising potential to be used for energy storage systems because of its excellent mechanical, structural, and physical... (Review)
Review
Cellulose, an abundant natural polymer, has promising potential to be used for energy storage systems because of its excellent mechanical, structural, and physical characteristics. This review discusses the structural features of cellulose and describes its potential application as an electrode, separator, and binder, in various types of high-performing batteries. Various surface and structural characteristics of cellulose (e.g., fiber size, surface functional groups, the hierarchy of pores, and porosity levels) that contribute to its electrochemical performance are discussed. Cellulose structure/property/processing/function relationships are further focused and elucidated in terms of the latest developments in the emerging field of sustainable materials in Li-Ion, Na-Ion, and LiS batteries.
Topics: Cellulose; Electric Power Supplies; Electrodes; Lithium; Sodium
PubMed: 35963345
DOI: 10.1016/j.ijbiomac.2022.08.026 -
European Journal of Pharmaceutical... Feb 2019Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium...
Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium has been used as a measure to determine proximal tubule reabsorption based on the assumption that lithium and sodium transport go in parallel in the proximal tubule. However, the exact mechanism by which lithium is reabsorbed remains elusive. The majority of proximal tubule sodium reabsorption is directly or indirectly mediated by the sodium-hydrogen exchanger 3 (NHE3). In addition, sodium-phosphate cotransporters have been implicated in renal lithium reabsorption. In order to better understand the role of sodium-phosphate cotransporters involved in lithium (re)absorption, we studied lithium pharmacokinetics in: i) tubule-specific NHE3 knockout mice (NHE3), and ii) mice challenged with low or high phosphate diets. Intravenous or oral administration of lithium did not result in differences in lithium bioavailability, half-life, maximum plasma concentrations, area under the curve, lithium clearance, or urinary lithium/creatinine ratios between control and NHE3 mice. After one week of dietary phosphate challenges, lithium bioavailability was ~30% lower on low versus high dietary phosphate, possibly the consequence of a smaller area under the curve after oral administration. This was associated with higher apparent lithium clearance after oral administration and lower urinary lithium/creatinine ratios on low versus high dietary phosphate. Collectively, renal NHE3 does not play a role in lithium pharmacokinetics; however, dietary phosphate could have an indirect effect on lithium bioavailability and lithium disposition.
Topics: Administration, Oral; Animal Feed; Animals; Diet; Injections, Intravenous; Lithium; Mice; Mice, Knockout; Phosphates; Phosphorus, Dietary; Sodium-Hydrogen Exchanger 3
PubMed: 30419292
DOI: 10.1016/j.ejps.2018.11.008 -
Molecular Psychiatry Jul 2023Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell...
Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.
Topics: Humans; Lithium; Bipolar Disorder; Induced Pluripotent Stem Cells; Lithium Compounds; Neurons
PubMed: 36653674
DOI: 10.1038/s41380-023-01944-0 -
Aging Jan 2023Lithium is a nutritional trace element that is also used pharmacologically for the management of bipolar and related psychiatric disorders. Recent studies have shown...
Lithium is a nutritional trace element that is also used pharmacologically for the management of bipolar and related psychiatric disorders. Recent studies have shown that lithium supplementation can extend health and lifespan in different animal models. Moreover, nutritional lithium uptake from drinking water was repeatedly found to be positively correlated with human longevity. By analyzing a large observational aging cohort (UK Biobank, = 501,461 individuals) along with prescription data derived from the National Health Services (NHS), we here find therapeutic supplementation of lithium linked to decreased mortality ( = 0.0017) of individuals diagnosed with affective disorders. Subsequent multivariate survival analyses reveal lithium to be the strongest factor in regards to increased survival effects (hazard ratio = 0.274 [0.119-0.634 CI 95%, = 0.0023]), corresponding to 3.641 times lower (95% CI 1.577-8.407) chances of dying at a given age for lithium users compared to users of other anti-psychotic drugs. While these results may further support the use of lithium as a geroprotective supplement, it should be noted that doses applied within the UK Biobank/NHS setting require close supervision by qualified medical professionals.
Topics: Animals; Humans; Lithium; Longevity; Biological Specimen Banks; Lithium Compounds; United Kingdom
PubMed: 36640269
DOI: 10.18632/aging.204476