Comparative transcriptome analysis and CRISPR/Cas9 gene editing reveal that E4BP4 mediates lithium upregulation of Per2 expression.

Bipolar disorder (BPD) is a psychiatric disorder characterized by alternate episodes of mania and depression. Disruption of normal circadian clock and abnormal sleep cycles are common symptoms of BPD patients. Lithium salt is currently an effective clinical therapeutic drug for BPD. Animal and cellular studies have found that lithium salt can upregulate the expression of the clock gene Per2, but the mechanism is unknown. We aim to understand the mechanism underlying the Per2 upregulation by lithium treatment. By taking approaches of both comparative transcriptome analysis and comparative qPCR analysis between human and murine cells, Lumicycle assay, luciferase assay and RT-qPCR assay showed that lithium could significantly upregulate the expression of Per2 in both mouse and human cells, and significantly inhibit the expression of E4bp4, which encodes a transcriptional inhibitor of Per2. After knocking out the cis-element upstream on the Per2 promoter that responds to E4BP4, the upregulation effect on Per2 by lithium disappeared. When E4bp4 gene was knocked out, the upregulation effect on Per2 by lithium salt disappeared. This study has found that lithium upregulates Per2 expression by reducing the expression of transcription factor E4BP4, but the mechanism of lithium salt downregulation of E4BP4 remains to be further studied. Our study provides a new therapeutic target and approaches for treating BPD.

Lithium Intoxication after Bariatric Surgery: A Case Report.

Bariatric surgery is a therapeutic option to treat obesity in (carefully selected) patients with psychiatric disorders. About half of the patients referred for bariatric surgery have a diagnosis of (at least one) mental disorder and most of them are treated with psychotropic drugs. This procedure may modify the bioavailability of drugs and lithium is no exception. However, although absorption seems to decrease in most drugs, in the case of lithium, there is a high risk of toxicity. In this article, we describe the case of a 44-year-old female patient with lithium intoxication after bariatric surgery. We conducted a review of the published clinical cases in the scientific literature about lithium toxicity after bariatric surgery, and we propose potential preventive clinical solutions. It is essential to increase awareness of changes to the absorption of psychotropic drugs in the post-surgery period, particularly in the case of lithium. Regular postoperative clinical and laboratory monitoring of lithium serum levels is strongly recommended.

A cirurgia bariátrica é uma opção terapêutica no tratamento da obesidade em doentes, selecionados cuidadosamente, com perturbação psiquiátrica. Cerca de metade dos doentes referenciados para cirurgia bariátrica têm diagnosticada, pelo menos, uma perturbação mental, estando a maioria medicada com psicofármacos. Este procedimento pode alterar significativamente a biodisponibilidade dos fármacos e o lítio não é exceção. Contudo, apesar da absorção parecer diminuir na maioria dos fármacos, no caso do lítio existe um elevado risco de toxicidade. Neste artigo, descreve-se o caso de uma doente de 44 anos com um quadro de intoxicação por lítio pós-cirurgia bariátrica. Realizou-se uma revisão dos casos clínicos descritos na literatura de toxicidade ao lítio pós-cirurgia bariátrica e apresentam-se potenciais soluções clínicas preventivas. É essencial uma maior consciencialização das alterações na absorção dospsicofármacos pós-cirurgia, particularmente no caso do lítio. Recomenda-se fortemente uma monitorização, de forma mais regular, pós-cirúrgica clínica e laboratorial dos níveis séricos de lítio.

Dose-Dependent Effects of Lithium Treatment on the Aggravation of Antipsychotic-Induced Pisa Syndrome.

Pisa syndrome (PS) is a rare lateral truncal dystonia that is related to dopamine-acetylcholine imbalances, and most cases develop during antipsychotic treatment. Here, we report a case of PS that developed during switching to new antipsychotics and titrating lithium, and PS was aggravated when the lithium dose was increased. Truncal deviation was not relieved with switching back to prior antipsychotics or by discontinuation of all antipsychotics. Pisa syndrome resolved only after discontinuing the lithium treatment. This is the first report of dose-dependent effects of lithium treatment on the aggravation of PS, which may be related to dose-related effects on dopaminergic and cholinergic transmission.

Application of optogenetic Amyloid-ß distinguishes between metabolic and physical damages in neurodegeneration.

The brains of Alzheimer's disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-ß plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-ß plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer's disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-ß peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-ß oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-ß peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-ß oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-ß were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-ß oligomerization from Amyloid-ß expression alone. The physical damage caused by Amyloid-ß oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-ß oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

Alzheimer's disease is a progressive condition that damages the brain over time. The cause is not clear, but a toxic molecule called Amyloid-ß peptide seems to play a part. It builds up in the brains of people with Alzheimer's disease, forming hard clumps called plaques. Yet, though the plaques are a hallmark of the disease, experimental treatments designed to break them down do not seem to help. This raises the question ­ do Amyloid-ß plaques actually cause Alzheimer's disease? Answering this question is not easy. One way to study the effect of amyloid plaques is to inject clumps of Amyloid-ß peptides into model organisms. This triggers Alzheimer's-like brain damage, but it is not clear why. It remains difficult to tell the difference between the damage caused by the injected Amyloid-ß peptides and the damage caused by the solid plaques that they form. For this, researchers need a way to trigger plaque formation directly inside animal brains. This would make it possible to test the effects of plaque-targeting treatments, like the drug lithium. Optogenetics is a technique that uses light to control molecules in living animals. Hsien, Kaur et al. have now used this approach to trigger plaque formation by fusing light-sensitive proteins to Amyloid-ß peptides in worms, fruit flies and zebrafish. This meant that the peptides clumped together to form plaques whenever the animals were exposed to blue light. This revealed that, while both the Amyloid-ß peptides and the plaques caused damage, the plaques were much more toxic. They damaged cell metabolism and caused tissue loss that resembled late Alzheimer's disease in humans. To find out whether it was possible to test Alzheimer's treatments in these animals, Hsien, Kaur et al. treated them with the drug, lithium. This increased their lifespan, reversing some of the damage caused by the plaques. Alzheimer's disease affects more than 46.8 million people worldwide and is the sixth leading cause of death in the USA. But, despite over 50 years of research, there is no cure. This new plaque-formation technique allows researchers to study the effects of amyloid plaques in living animals, providing a new way to test Alzheimer's treatments. This could be of particular help in studies of experimental drugs that aim to reduce plaque formation.

Differential effects of lithium isotopes in a ketamine-induced hyperactivity model of mania.

Sub-anesthetic doses of ketamine produce an increase in rodent ambulation that is attenuated by co-administration of naturally-occurring lithium (LiN), the drug most commonly employed in the treatment of bipolar illness. As a consequence, ketamine-induced hyperactivity has been proposed as an animal model of manic behavior. The current study employed a modified version of this model to compare the potency of LiN to that of each of its two stable isotopes - lithium-6 (Li-6) and lithium-7 (Li-7). Since Li-7 constitutes 92.4% of the parent compound it was hypothesized to produce comparable behavioral effects to that of LiN. The current study was devised to determine whether Li-6 might be more, less, or equally effective at tempering hyperactivity relative to Li-7 or to LiN in an animal model of manic behavior. Male rats were maintained on a restricted but high-incentive diet containing a daily dose of 2.0 mEq/kg of lithium (LiN), Li-6 or Li-7 for 30 days. A control group consumed a diet infused with sodium chloride (NaCl) in place of lithium to control for the salty taste of the food. On day 30, baseline testing revealed no differences in the locomotor behavior among the four treatment groups. Animals then continued their Li/NaCl diets for an additional 11 days during which every subject received a single IP injection of either ketamine (25 mg/kg) or 0.9% physiological saline. On the final four days of this regimen, locomotor activity was assessed during 60 min sessions each beginning immediately after ketamine injection. While all three lithium groups produced comparable decreases in ketamine-induced hyperactivity on the first trial, by the fourth trial Li-6 animals exhibited significantly greater and more prolonged reductions in hyperactivity compared to either Li-7 and Li. These results suggest that Li-6 may be more effective at treating mania than its parent compound.

The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: Relevance for bipolar disorder.

Metabolic and psychiatric disorders present a bidirectional relationship. GLP-1 system, known for its insulinotropic effects, has also been associated with numerous regulatory effects in cognitive and emotional processing. GLP-1 receptors (GLP-1R) agonists present neuroprotective and antidepressant/anxiolytic properties. However, the effects of GLP-1R agonism in bipolar disorder (BD) mania and the related cognitive disturbances remains unknown. Here, we investigated the effects of the GLP-1R agonist liraglutide (LIRA) at monotherapy or combined with lithium (Li) against D-amphetamine (AMPH)-induced mania-like symptoms, brain oxidative and BDNF alterations in mice. Swiss mice received AMPH 2 mg/kg or saline for 14 days. Between days 8-14, they received LIRA 120 or 240 µg/kg, Li 47.5 mg/kg or the combination Li + LIRA, on both doses. After behavioral evaluation the brain areas prefrontal cortex (PFC), hippocampus and amygdala were collected. AMPH induced hyperlocomotion, risk-taking behavior and multiple cognitive deficits which resemble mania. LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments, while Li + LIRA240 rescued all behavioral changes induced by AMPH. LIRA reversed AMPH-induced hippocampal oxidative and neurotrophic changes. Li + LIRA240 augmented Li antioxidant effects and greatly reversed AMPH-induced BDNF changes in PFC and hippocampus. LIRA rescued the weight gain induced by Li in the course of mania model. Therefore, LIRA can reverse some mania-like behavioral alterations and combined with Li augmented the mood stabilizing and neuroprotective properties of Li. This study points to LIRA as a promising adjunctive tool for BD treatment and provides the first rationale for the design of clinical trials investigating its possible antimanic effect.

Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects.

BACKGROUND: Imbalances in metal concentrations have been suggested to contribute to the pathophysiology of different brain disorders, such as bipolar disorder (BD) and schizophrenia (SCZ). OBJECTIVES: The aim of this exploratory study is to evaluate the association between the concentrations of macro/trace elements in serum from BD and SCZ patients considering the effects from different treatments. METHODS: Eleven subjects with SCZ, seven with BD treated with lithium (BDL) and eight subjects with BD treated with other medications except lithium (BDN) were recruited for the study, as well as eleven healthy controls (HC). Serum concentrations of eleven macro/trace elements (Se, Zn, Fe, K, Ca, Mg, P, Al, Cu, Mn, and Ni) were determined using inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Se and Zn concentrations were significantly lower for patients with SCZ and BD in comparison to HC by one-way ANOVA test. Moreover, serum concentrations for Fe were significantly higher (p < 0.05) in BDN (548 ± 92 µg L-1) and SCZ (632 ± 279 µg L-1) in comparison to HC (421 ± 121 µg L-1). A significant negative correlation was reported between Se and Fe in BDL group (r = -0.935, p < 0.05). In addition, a significantly higher Cu/Zn ratio was determined in SCZ group against HC (ratio = 2.4, p = 0.028). CONCLUSIONS: The obtained results suggest that the imbalance in Fe concentrations is an effect of BD treatment. Lithium is supposed to have an antagonist effect for Se in BDL patients. A negative correlation reported between Fe and BMI in SCZ group could be related to antipsychotic treatment and the Cu/Zn ratio reported could be considered as a suggesting parameter to relate oxidative stress to SCZ. Future studies including larger number of patients with SCZ and BD before and after treatment are necessary to confirm the investigative results presented herein.

The Involvement of Canonical Wnt Signaling in Memory Impairment Induced by Chronic Cerebral Hypoperfusion in Mice.

Chronic cerebral hypoperfusion (CCH) has been proposed to contribute to the progression of memory loss, which is the main symptom of vascular cognitive impairment (VCI). Accumulating evidence indicates that underlying pathophysiology, such as neurodegeneration, may lead to memory loss. However, the underlying molecular basis of memory loss in CCH remains unclear. Here, we investigated the roles of canonical Wnt signaling, which modulates hippocampal function, in a CCH model. CCH was induced by unilateral common carotid artery occlusion (UCCAO). Mice were randomly divided into a sham-operated group or one of three UCCAO groups with different endpoints (1.5, 2.5, and 3.5 months) after UCCAO. Memory function and hippocampal levels of Wnt-related proteins were measured. A Wnt activator, lithium, was administered intraperitoneally to assess memory improvements. In the groups examined 2.5 and 3.5 months after UCCAO, impaired object recognition memory was accompanied by inhibition of Wnt signaling and decreased expression of synaptic/neural activity-related proteins. Recognition memory and Wnt signaling were significantly positive correlated. Moreover, activation of Wnt signaling with lithium significantly attenuated memory loss and recovered synaptic/neural marker expression after UCCAO. Our results suggest that CCH may affect synaptic plasticity via dysregulation of signaling pathways, including canonical Wnt signaling, which could be partly involved in memory loss. As Wnt activator administration alleviated the effects of CCH on memory loss, modulation of Wnt signaling may be a promising therapeutic strategy for VCI.

Frequently overlooked realistic moral bioenhancement interventions.

Many supporters of 'moral bioenhancement' (MBE), the use of biomedical interventions for moral improvement, have been criticised for having unrealistic proposals. The interventions they suggest have often been called infeasible and their implementation plans vague or unethical. I dispute these criticisms by showing that various interventions to implement MBE are practically and ethically feasible enough to warrant serious consideration. Such interventions include transcranial direct current stimulation over the medial and dorsolateral prefrontal cortex, as well as supplementation with lithium and omega-3. Considering their efficacy and feasibility, it is strange that these interventions have rarely been proposed or discussed as MBE. I review evidence that each of those interventions can reduce antisocial behaviour, reduce racial bias, increase executive function or increase prosocial traits like fairness and altruism. I then specify and defend realistic, ethically permissible ways to implement these interventions, especially for violent offenders and public servants-the former as rehabilitation and the latter to meet the high standards of their occupations. These interventions could be given to violent offenders in exchange for a reduced sentence or compulsorily in some cases. Potential intervention methods for non-prisoners include increasing the USDA-recommended dose of omega-3, encouraging food companies to supplement their products with omega-3 or trace lithium, requiring MBE for employment as a police officer or political leader, and insurance companies providing discounts for undergoing MBE. In some reasonably limited form, using these interventions may be a good first step to implement the project of MBE.

Efficacy of folic acid as an adjunct to lithium therapy on manic-like behaviors, oxidative stress and inflammatory parameters in an animal model of mania.

Evaluate the efficacy of folic acid (FA) as a therapeutic adjunct to lithium (Li) on the manic-like behaviors as well as parameters of oxidative stress and inflammation in an animal model of mania induced by m-amphetamine (m-AMPH). Wistar rats first received m-AMPH or saline (NaCl 0.9%, Sal) for 14 days. Between the 8th and 14th day, rats were treated with water, Li, FA or a combination of thereof drugs (Li + FA). Manic-like behaviors were assessed in the open-field test. Oxidative stress and inflammation parameters were assessed in the frontal cortex, striatum, and hippocampus. Administration of m-AMPH in rats significantly enhanced the exploratory and locomotor behaviors, as well as the risk-taking and stereotypic behaviors. Li + FA reversed these behavioral alterations elicited by m-AMPH. Administration of this psychostimulant also increased oxidative damage to lipids and proteins, whereas Li + FA reversed these oxidative damages. m-AMPH also induced an increase in the glutathione peroxidase (GPx) activity and a decrease in the glutathione reductase (GR) activity. Li + FA reversed the alteration in GR activity, but not in GPx activity. In addition, m-AMPH increased the IL-1ß and TNF-α levels in the rat brain; Li + FA combined therapy reversed the alterations on these inflammatory parameters. FA administration per se reduced the increased TNF-α content induced by m-AMPH. Present study provides evidence that FA is effective as an adjunct to Li standard therapy on manic-like behaviors, oxidative stress and inflammatory parameters in a model of mania induced by m-AMPH.

Hemocompatibility of biodegradable Zn-0.8 wt% (Cu, Mn, Li) alloys.

Zinc alloys have been explored as potential materials for biodegradable vascular stents due to their tolerable corrosion rates and tunable mechanical properties. However, the performances of Zn alloys were not supported with enough toxicity or biological compatibility evaluation, particularly hemocompatibility for vascular scaffolding application. In this work, the hemocompatibility of three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) was evaluated with 316 L stainless steel and pure zinc as controls. The hemolysis ratios of 316 L stainless steel, pure Zn, Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li were 0.38 ±â€¯0.08%, 1.04 ±â€¯0.21%, 0.47 ±â€¯0.21%, 0.57 ±â€¯0.14% and 0.52 ±â€¯0.22%, respectively, for direct contact method. Platelets aggregation on the 316 L stainless steel was observed, while the adhered platelets on the Zn alloys exhibited round shape with few pseudopodia spreading. The number of adhered platelets on the three zinc alloys (Zn-0.8Cu, Zn-0.8Mn and Zn-0.8Li) had no statistically difference compared with 316 L stainless steel, while significant fewer than the pure Zn group. None remarkable platelet activation, hematocyte aggregation, coagulation or complement activation was observed in any Zn alloy group. Furthermore, the Zn alloys prolonged prothrombin time and partial thromboplastin time, demonstrating a potential function of anticoagulation. The results demonstrated that Zn alloys presented in this work are indeed meeting the hemocompatible requirements of implant and showing the promise for perspective application as biodegradable stent.

GSK3ß-mediated Keap1-independent regulation of Nrf2 antioxidant response: A molecular rheostat of acute kidney injury to chronic kidney disease transition.

Transition of acute kidney injury (AKI) to chronic kidney disease (CKD) represents an important cause of kidney failure. However, how AKI is transformed into CKD remains elusive. Following folic acid injury, mice developed AKI with ensuing CKD transition, featured by variable degrees of interstitial fibrosis and tubular cell atrophy and growth arrest. This lingering injury of renal tubules was associated with sustained oxidative stress that was concomitant with an impaired Nrf2 antioxidant defense, marked by mitigated Nrf2 nuclear accumulation and blunted induction of its target antioxidant enzymes, like heme oxygenase (HO)-1. Activation of the canonical Keap1/Nrf2 signaling, nevertheless, seems intact during CKD transition because Nrf2 in injured tubules remained activated and elevated in cytoplasm. Moreover, oxidative thiol modification and activation of Keap1, the cytoplasmic repressor of Nrf2, was barely associated with CKD transition. In contrast, glycogen synthase kinase (GSK)3ß, a key modulator of the Keap1-independent Nrf2 regulation, was persistently overexpressed and hyperactive in injured tubules. Likewise, in patients who developed CKD following AKI due to diverse etiologies, like volume depletion and exposure to radiocontrast agents or aristolochic acid, sustained GSK3ß overexpression was evident in renal tubules and coincided with oxidative damages, impaired Nrf2 nuclear accumulation and mitigated induction of antioxidant gene expression. Mechanistically, the Nrf2 response against oxidative insult was sabotaged in renal tubular cells expressing a constitutively active mutant of GSK3ß, but reinforced by ectopic expression of dominant negative GSK3ß in a Keap1-independent manner. In vivo in folic acid-injured mice, targeting GSK3ß in renal tubules via conditional knockout or by weekly microdose lithium treatment reinstated Nrf2 antioxidant response in the kidney and hindered AKI to CKD transition. Ergo, our findings suggest that GSK3ß-mediated Keap1-independent regulation of Nrf2 may serve as an actionable therapeutic target for modifying the long-term sequelae of AKI.

Hypnic headache: A review of 348 cases published from 1988 to 2018.

Hypnic headache (HH) is a rare benign disorder described initially by Raskin in 1988. It is characterized by recurrent nocturnal episodes of headache that periodically awaken the sleeping patient and usually occur in the elderly. This review aimed to describe the clinical features of the HH cases published in the literature from 1988 to 2018. Based on literature search in the major medical databases (LiLacs, SciELO, Bireme, Medline, Embase, Current Contents, Scopus, EBSCO and PubMed), we have analyzed the case reports on HH that have been published from 1988 to 2018. We described 343 adults (69.0% women and 31.0% men) and 5 children (3 girls and 2 boys) diagnosed with HH. Average age for adults and children was, respectively, 58.0 ±â€¯13.1 years (ranging from 15 to 85 years) and 9 years (ranging from 7 to 11 years). The diagnosis was made 7.6 ±â€¯14.2 years (range 0.1 to 39 years) after onset of headache. Pain occurred during nocturnal sleep (94.8%), with an average duration of 90 min, bilaterally located (55.5%), having a dull character (74.4%), and moderate intensity (61.5%). In 94.5% of the patients, headache occurred for 10 or more days per month (mean of 21 days). Autonomic manifestations occurred in 7.6% of the patients, predominantly lacrimation (61.1%) and rhinorrhea (16.7%). Caffeine presented the best therapeutic response in acute treatment. In prophylaxis, lithium, caffeine and indomethacin were effective drugs in 77.8% of the patients. In 56.7% of the patients there was remission with treatment and in 72.7% of them, without recurrence. HH is a rare disease that usually occurs for the first time in older women but may begin in childhood. Lithium and caffeine are effective drugs for pain prophylaxis, but randomized clinical trials are required.

Development of a Photoswitchable Lithium-Sensitive Probe to Analyze Nonselective Cation Channel Activity in Migrating Cancer Cells.

This is the first work to use a newly designed Li+-selective photoswitchable probe Sabrina Heng Lithium (SHL) in living colon cancer cells to noninvasively monitor cation channel activity in real time by the appearance of lithium hot spots detected by confocal microscopy. Punctate Li+ hot spots are clustered in the lamellipodial leading edges of HT29 human colon cancer cells and are colocalized with aquaporin-1 (AQP1) channels. AQP1 is a dual water and cyclic-nucleotide-gated cation channel located in lamellipodia and is essential for rapid cell migration in a subset of aggressive cancers. Both the Li+ hot spots and cell migration are blocked in HT29 cells by the AQP1 ion channel antagonist AqB011. In contrast, Li+ hot spots are not evident in a poorly migrating colon cancer cell line, SW620, which lacks comparable membrane expression of AQP1. Knockdown of AQP1 by RNA interference in HT29 cells significantly impairs Li+ hot spot activity. The SHL probe loaded in living cells shows signature chemical properties of ionic selectivity and reversibility. Dynamic properties of the Li+ hot spots, turning on and off, are confirmed by time-lapse imaging. SHL is a powerful tool for evaluating cation channel function in living cells in real time, with particular promise for studies of motile cells or interlinked networks not easily analyzed by electrophysiological methods. The ability to reset SHL by photoswitching allows monitoring of dynamic signals over time. Future applications of the Li+ probe could include high-throughput optical screening for discovering new classes of channels, or finding new pharmacological modulators for nonselective cation channels.

Low dose lithium supplementation activates Wnt/ß-catenin signalling and increases bone OPG/RANKL ratio in mice.

Lithium, a well-known inhibitor of glycogen synthase kinase-3ß (GSK3ß), can improve bone formation by activating the Wnt/ß-catenin signalling pathway. However, most studies have used higher doses of lithium, which potentially have adverse effects. Herein, we report that low dose lithium supplementation (10 mg/kg/d for 6 weeks) in mice results in a serum lithium concentration of 0.02 mM significantly inhibiting GSK3ß while activating Wnt/ß-catenin in bone. In turn, we observed a significant increase in the expression of osteoprotegerin (OPG), with unaltered expression of nuclear-factor kß ligand (RANKL), ultimately leading to a significant increase in the OPG/RANKL ratio. Altogether, our findings provide initial evidence that low dose lithium supplementation can promote the signalling pathways associated with bone formation.