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PubMed1982

Lithium toxicology: effect of isotopic composition on lethality and behavior.

Naturally occurring lithium consists largely of the stable lithium-7 isotope but it contains 7.6% of a second stable isotope, lithium-6. Biological effects of these two isotopes were not identical. When administered in isotopically pure form, the chloride of lithium-6 was more toxic after acute intake than the chloride of pure lithium-7:its LD in Swiss-Webster mice was 13.2 mEq/kg as opposed to 15.9 mEq/kg for the salt of the heavier isotope and 14.9 mEq/kg for that of the natural mixture of the two isotopes. A single injection of one or the other pure isotope in a constant dose, 14.5 mEq/kg led to a 90% mortality in mice given lithium-6 but only 10% in mice given lithium-7. Side effects such as hypoactivity, ataxia, intense perspiration and diarrhea appeared within 10 min after administration of toxic doses of lithium-6 but more gradually after lithium-7. The differences between the isotopes in toxicity and rate of appearance of effects on spontaneous motor activity were significant at the p less than 1% level.

Animals↗
PubMed1995

Effect of lithium in immunodeficiency: improved blood cell formation in mice with decreased hematopoiesis as the result of LP-BM5 MuLV infection.

Lithium salts have been demonstrated to induce the production of hematopoietic cells following administration in vivo and to minimize the reduction of these cells following treatment with either radiation, chemotherapeutic or antiviral drugs. We have previously demonstrated that lithium, when administered in vivo to immunodeficient mice infected with LP-BM5 MuLV (MAIDS) significantly reduced the development of lymphadenopathy, splenomegaly, and the lymphoma associated with late-stage immunodeficiency disease in this model, and increased the survival of these animals compared to virus-infected controls not receiving lithium. We report here the results of in vivo studies in the MAIDS model that determined the effect of lithium on peripheral blood indices and the number of myeloid (CFU-GM), erythroid (BFU-E) and megakaryocyte (CFU-Meg) hematopoietic progenitors from bone marrow and spleen harvested from immunodeficient mice receiving lithium carbonate (1 mM) placed in their drinking water compared to virus-infected controls not receiving lithium. Time-points evaluated were at weeks 1, 5, 9, 13, 17, and 21 postviral infection. Virus-control mice not receiving lithium demonstrated all the signs that are characteristic of MAIDS, i.e., splenomegaly, lymphadenopathy, hypergammaglobulinemia, reduced hematopoiesis, and death. Infected mice receiving lithium demonstrated diminished presence of splenomegaly, lymphadenopathy, hypergammaglobulinemia, no suppression of hematopoiesis nor mortality. Enhanced hematopoiesis was demonstrated by neutrophilia, lymphocytosis, thrombocytosis, and erythrocytosis that was evident by increased myeloid, erythroid, and megakaryocyte progenitor cells cultured from bone marrow and spleen. These studies further demonstrate that lithium influences the disease process in the MAIDS model and restricts the development of hematopoietic suppression that develops in this retroviral animal model of immunodeficiency.

Animals↗
PubMed1996

Combined treatment with lithium and nimodipine in a bipolar I manic syndrome.

1. The benefit of a combined treatment with the calcium antagonist nimodipine and lithium in a bipolar I disorder (currently manic, DSM IV 296.44, ICD 10 F 31.1) was explored and documented in a longitudinal single case study. 2. Nimodipine (270 mg/d) was added to lithium (900 mg/d), substituting for previously administered neuroleptics, in an up to then unsatisfactorily treated manic patient. 3. A clear-cut improvement in the patient's condition was achieved within a fortnight, and lasted over the continuation period of this drug regimen. This combined treatment was discontinued after eight weeks and lithium alone was then administered. Within three months another manic episode appeared. 4. Side-effects and changes of lithium blood levels were not observed during the combined treatment with nimodipine and lithium. 5. Further research on the benefits of adding a calcium antagonist, instead of neuroleptics, to lithium therapy for bipolar manic disorder patients who do not respond sufficiently to lithium is recommended. In addition, the benefits of a long term prophylaxis of nimodipine alone or in combination with lithium should be evaluated in those bipolar patients who still show a high relapse frequency on lithium alone.

Adult↗
PubMed1992

Adding lithium to antidepressant therapy: factors related to therapeutic potentiation.

Lithium augmentation of antidepressant drugs was studied in 51 patients with endogenous refractory depression. The remission after 28 days of lithium was obtained in 28 patients (55%). Better effect of lithium was shown in bipolar than unipolar patients, with subjects with lower pre-lithium severity of depression and in those with rapid improvement (within 7 days) on lithium addition. Factors such as age, gender, number of prior antidepressant (or ECT) treatments, type of preceding antidepressant, mean plasma lithium concentration and the results of DST did not show any association with the outcome of lithium augmentation. The 'priming' effect of lithium may contribute to the mechanism of lithium potentiation in a proportion of depressed patients.

Adult↗
PubMed2006

Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder.

BACKGROUND: Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. METHODS: The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3beta. RESULTS: The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. CONCLUSIONS: Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.

Adult↗
PubMed2004

Lithium treatment enhances estradiol-induced proliferation and hyperplasia formation in the uterus of mice.

OBJECTIVES: It is suggested that the Wnt/beta-catenin pathway plays a role in the regulation of estrogen action in the uterus. However, this suggestion has not been proved. Lithium can mimic increased activity of the Wnt/beta-catenin pathway by blocking the activity of glycogen synthase kinase-3beta. There are no data on the effects of lithium on estrogen-dependent processes in the uterus. This work was therefore aimed to examine the action of lithium on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments. STUDY DESIGN: Ovariectomized mice received estradiol dipropionate (2 microg per 100g; s.c.) once a week or vehicle and drank tap water with 0.05% lithium chloride or plain tap water for 2 or 30 days. RESULTS: In animals treated with estradiol and lithium for a month, the incidence of atypical endometrial hyperplasia was significantly higher. In animals treated with estradiol and lithium for 2 days or for a month, uterine mass, the number of mitotic cells and BrdU-labelled cells in luminal epithelium, glandular epithelium, stromal and myometrial cells was markedly greater, whereas the levels of estrogen receptors-alpha, beta-catenin and glycogen synthase kinase-3beta were markedly lower in all uterine compartments, than in those in mice received estradiol with no lithium to drink. CONCLUSIONS: Lithium treatment results in an increase in estradiol-induced proliferative and morphogenetic changes in the uterus. This action of lithium is associated with decreased expression of estrogen receptors-alpha, beta-catenin and glycogen synthase kinase-3beta in the uterus.

Administration, Oral↗
PubMed2006

Lithium increases bcl-2 expression in chick cochlear nucleus and protects against deafferentation-induced cell death.

Approximately 20-30% of neurons in the avian cochlear nucleus (nucleus magnocellularis) die following deafferentation (i.e. deafness produced by cochlea removal) and the remaining neurons show a decrease in soma size. Cell death is generally accepted to be a highly regulated process involving various pro-survival and pro-death molecules. One treatment that has been shown to modify the expression of these molecules is chronic administration of lithium. The present experiments examined whether lithium treatment can protect neurons from deafferentation-induced cell death. Post-hatch chicks were treated with LiCl or saline for 17 consecutive days, beginning on the day of hatching. On the 17th day, a unilateral cochlea ablation was performed. Five days following surgery, the nucleus magnocellularis neurons were counted stereologically on opposite sides of the same brains. Lithium reduced deafferentation-induced cell death by more than 50% (9.8% cell death as compared with 22.4% in saline-treated subjects). Lithium did not affect cell number on the intact side of the brain. Lithium also did not prevent the deafferentation-induced decrease in soma size, suggesting a dissociation between the mechanisms involved in the afferent control of soma size and those involved in the afferent control of cell viability. A possible mechanism for lithium's neuroprotective influence was examined in a second set of subjects. Previous studies suggest that the pro-survival molecule, bcl-2, may play a role in regulating cell death following deafferentation. Tissues from lithium- and saline-treated subjects were examined using immunocytochemistry. Chronic administration of lithium dramatically increased the expression of bcl-2 protein in nucleus magnocellularis neurons. These data suggest that lithium may impart its neuroprotective effect by altering the expression of molecules that regulate cell death.

Afferent Pathways↗
PubMed2006

Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.

Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H(2)O(2)-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H(2)O(2)-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastoma SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs.

Animals↗
PubMed2005

Differential role of dopamine in drug- and lithium-conditioned saccharin avoidance.

Rats learn to avoid palatable saccharin solutions that predict the systemic administration of reinforcing drugs as well as malaise-inducing lithium chloride (conditioned saccharin avoidance, CSA). In the present study the involvement of dopamine (DA) transmission in the acquisition of morphine, nicotine and lithium-conditioned CSA was investigated in a two-bottle choice paradigm. Nicotine tartrate (0.2 and 0.4 mg/kg s.c.) administered 15 min after saccharin presentation induced CSA, with a maximum effect at 0.4 mg/kg. The DA D1 receptor antagonist, SCH 39166 (0.1 mg/kg s.c.) and the DA D2 receptor antagonist raclopride (0.3 mg/kg s.c.), administered immediately after saccharin, prevented CSA induced by the lower but not by the higher dose of nicotine. However, combined administration of the two antagonists prevented CSA induced by the higher dose of nicotine. SCH 39166 prevented CSA induced by all morphine doses while raclopride prevented only CSA induced by the lowest dose of morphine (1.75 mg/kg). CSA induced by different doses of lithium given by the same schedule of drug-CSA (i.e. two pairings, 15 min after saccharin) was not affected by SCH 39166. However SCH 39166 impaired the acquisition of lithium-CSA when lithium was given 60 min after saccharin. In contrast, raclopride failed to affect lithium-CSA independently from the delay between saccharin and lithium. These results suggest that DA can play different roles in drug- and in lithium-CSA and are consistent with a different mechanism of drug- as compared to lithium-CSA.

Analysis of Variance↗
PubMed2006

Lithium and dementia: a preliminary study.

Recent studies have shown that lithium may block the accumulation of amyloid-beta (Abeta) peptides and to inhibit the hyperphosphorylation of tau via the inhibition of GSK-3alpha in the brain of mice. The purpose of the present study is to examine whether lithium could potentially be effective for the prevention of Alzheimer's disease. We investigated the clinical records of 1,423 outpatients at a university psychiatric outpatient clinic and classified patients according to the following criteria: (a) absence of a diagnosis of dementia, (b) age 60 years or older, and (c) lithium had been prescribed and/or was currently prescribed. We compared these patients with randomly selected age and gender matched control group who had never been prescribed lithium. Despite no significant difference in MMSE scores between the lithium group, which consisted of patients receiving lithium treatment, and the control group, those who had previously received lithium and/or were currently prescribed lithium had significantly better MMSE scores than the control patients. The findings provide partial evidence to support the contention that lithium could offer hope as a preventive treatment for Alzheimer's disease. Further prospective studies with a large number of patients are warranted to investigate this potentially important effect.

Aged↗
PubMed1999

Differential expression of thyroid hormone receptor isoforms by thyroid hormone and lithium in rat GH3 and B103 cells.

BACKGROUND: The interaction between lithium, a mood stabilizer, and the thyroid axis has been extensively studied; however, the regulation of thyroid hormone receptors by lithium is yet to be investigated. METHODS: To test whether lithium affects thyroid hormones at the receptor level, we examined the effects of lithium in combination with triiodothyronine (T3) on gene expression of thyroid hormone receptor isoforms in GH3 and B103 cells. RESULTS: The pattern of expression as well as the magnitude of regulation of the different thyroid hormone receptor isoforms appeared to be cell line specific. Whereas T3 regulated all four isoforms in GH3 cells at both time points, T3 did not alter thyroid hormone receptor TR alpha 1 and TR alpha 2 mRNA in B103 cells. Addition of lithium to thyroid hormone-deficient GH3 cells decreased TR alpha 1, alpha 2, and beta 2 expression without affecting TR beta 1 expression at 2 but not 5 days. Addition of lithium to T3-treated GH3 cells did not further modulate gene expression of TR alpha 1, alpha 2, beta 1, or beta 2 when compared to cells treated with T3 alone. The effects of lithium in B103 cells appeared to be isoform specific as well as time dependent, since TR alpha 1 expression was selectively decreased in B103 cells, when treated with T3 in the presence of lithium. CONCLUSIONS: The present study provides direct evidence that T3 and/or lithium regulate TR gene expression in vitro in a both time-dependent and cell line-specific manner.

Adenoma↗
PubMed1999

Lithium at 50: have the neuroprotective effects of this unique cation been overlooked?

Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted.

Animals↗
PubMed1998

Lithium homeostasis in Xenopus oocytes: implications for the study of signal transduction.

The Xenopus oocyte has been shown to be a useful model for the study of signal transduction pathways. The present study investigated whether or not the oocyte could be used to study the effects of lithium on signal transduction mechanisms by comparing the dynamics of lithium homeostasis in the oocyte and a human immortalized hippocampal cell line using Flame Atomic Emission Spectroscopy (FAES). A biphasic pattern of lithium uptake was observed in the oocyte in the presence of 5 mM extracellular lithium. The late phase of lithium uptake, which started after 30 minutes of incubation time, was sensitive to phloretin, an inhibitor of Na+/Li+ counter-transport. Differences in lithium efflux kinetics further characterized the two observed phases of accumulation and also suggested that lithium might be distributed in different pools within the oocyte, including one sequestered in organelles or associated with cytosolic proteins. An analogous sequestered pool was not, however, observed in the hippocampal cell line indicating that lithium is distributed differently in these cell types. This suggests that the Xenopus oocyte might not be a suitable model for evaluating the effects of lithium on signal transduction pathways because of the unknown contribution of the sequestered pool on predicting relevant physiological effects.

Animals↗
PubMed2000

Behavioral and neurochemical alterations after lithium-pilocarpine administration in young and adult rats: a comparative study.

Pilocarpine and lithium-pilocarpine can induce seizures and brain damage in adult rats. However, manifestation of cerebral lesions seems to be an age-related phenomenon suggesting that maturational states of neurocircuitry may be involved. We have studied behavior changes, cerebral histopathology, and muscarinic and dopaminergic receptors density in rodents subjected to lithium-pilocarpine treatment. Wistar rats, at two different ages (21 days and 2 months), were treated with pilocarpine (15 mg/kg, SC), lithium (3 mEq/kg, IP), atropine (50 mg/kg, IP) and the combination of lithium to pilocarpine. Histopathologic studies showed that younger animals were more resistant to the development of cerebral changes and there was a preferential involvement of the striatum (Wilcoxon p = 0.02) as opposed to more generalized areas in adult animals such as hippocampus and neocortex. Lithium treatment induced an upregulation of muscarinic receptors at both ages, and this effect was reversed in younger animals after pilocarpine administration. Lithium also induced an upregulation of dopaminergic receptors in the striatum at both ages (p < 0.05), and this effect was not reversed after pilocarpine administration. Our data confirm that young animals show less brain damage after lithium-pilocarpine, and main alterations in dopaminergic receptors density occur in young and older animals after treatment with lithium and lithium combined to a low dose of pilocarpine.

Age Factors↗
PubMed2003

The trace elements in response to lithium intoxication in renal failure.

The polyuric syndrome that develops as a consequence of chronic administration of lithium salts is most frequent and often causes complication in the treatment of manic depressive disease with the administration of drugs. It is known that kidneys play an essential role in systematic depositing of toxic metals. The purpose of this study was not only the determination of dose-dependent lithium concentration in serum and urine but also an estimation of sensitive biochemical indicators of nephrotoxicity detectable at an early stage after the administration of lithium carbonate to rats. Animals were given orally lithium salt to female Wistar rats at the dose of 10 and 20mg Li/kg daily during 5 weeks. In the urine diuresis protein concentration, copper, zinc, lithium and N-acetyl-beta-glucoaminidase (NAG) activity were determined. In the serum also lithium, copper and zinc were analyzed. The results of the experiments indicate that the changes in urinary concentrations of essential copper, proteins, NAG activity and diuresis were observed when the concentration of lithium was ca. 9.79+/-1.68 mmol Li/L and in serum it corresponded to 0.3+/-0.06 mmol Li/L. These values corresponded to total doses of 150 mg Li/kg body weight administered to rats. In summary the increase of copper concentration, diuresis and urinary concentrations of protein and the NAG activity may be interpreted as a general metabolic response of kidneys induced by lithium detectable as an earlier indicator of nephrotoxicity. Therefore, regular determinations of lithium concentrations in serum of patients are important tools in the prevention of intoxication.

Acetylglucosamine↗
PubMed2002

Lithium and valproic acid: parallels and contrasts in diverse signaling contexts.

The introduction of lithium salts to treat bipolar disorder (BPD) revolutionized the therapy of psychiatric illnesses, but the pathogenesis of the disease and the mechanism of lithium action remain unknown. While several direct molecular targets of lithium have been identified, it is unknown which, if any, of these targets plays a role in the therapeutic response to lithium. Exposure to lithium evokes a wide spectrum of behavioral, physiological, and developmental responses in diverse organisms, and these effects have been exploited to explore the mechanisms of lithium action. Valproic acid (VPA), a widely used anticonvulsant, is also an effective therapy for BPD, and again its mechanism of action is not known, although new in vitro targets have been identified recently. In this review, the clinical, physiological, and developmental effects of lithium and VPA are summarized and recent work on direct targets for lithium and VPA is discussed in the context of these effects. We then describe some of the physiological effects common to the two drugs, in addition to treatment of BPD, and address signaling pathways that could be regulated by both lithium and VPA.

Animals↗
PubMed2002

Long-term outcome of lithium prophylaxis in bipolar disorder with mood-incongruent psychotic features: a prospective study.

BACKGROUND: No study has assessed systematically up to now the long-term outcome of lithium prophylaxis in bipolar patients with vs. without mood-incongruent psychotic features. METHODS: All bipolar patients with mood-incongruent psychotic features who started lithium prophylaxis at a lithium clinic during 14 years were followed up prospectively for 5 years, along with a control group of non-psychotic bipolars. RESULTS: Psychotic patients were significantly less likely than controls to be still on lithium after 5 years, and to present a reduction of at least 50% of time spent in hospital during the lithium treatment period compared with a pre-treatment period of the same duration. The time to 50% risk of readmission was significantly increased among both groups during lithium treatment. 39.6% of prospective episodes in psychotic patients did not include mood-incongruent psychotic features. LIMITATIONS: This is a naturalistic study carried out at a lithium clinic. No control group of bipolar patients who did not receive lithium was available. CONCLUSIONS: Lithium exerts a significant impact on the course of bipolar disorder with mood-incongruent psychotic features, although this impact is less pronounced than in classical manic-depressive illness.

Adult↗
PubMed1999

Trace lithium in mood disorders.

BACKGROUND: Variations in trace (endogenous) lithium exchanges have been postulated to play a role in the pathophysiology of affective diseases. This prospective study aimed to check whether plasma, erythrocytes and urine trace lithium levels were altered in mood disorders. METHODS: Trace lithium was determined by atomic absorption spectrophotometry in patients without mood stabilizing drugs or somatic diseases, hospitalized for bipolar affective disorders, major depressive episodes, and other psychiatric disorders with depressive features. Patients admitted for psychotic disorders without mood alterations and healthy volunteers served as controls. RESULTS: There were no differences in trace lithium status between the groups. Erythrocytes/plasma ratios appeared higher than described on therapeutic lithium (1.6+/-0.7, N = 199). LIMITATIONS: The study had sufficient power to detect clinically significant differences in whole body lithium handling between the groups. However, it did not address alterations of lithium exchanges across neuronal membranes or the blood-brain barrier. CONCLUSIONS: Alterations of membrane exchanges hypothetically associated with mood disorders are not reflected in plasma or erythrocytes trace lithium levels. The occurrence of mood disorders seems not to be related to abnormalities in endogenous lithium.

Antimanic Agents↗