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PubMed1999

Lithium activates the c-Jun NH2-terminal kinases in vitro and in the CNS in vivo.

The therapeutic efficacy of lithium in the treatment of mood disorders is delayed and only observed after chronic administration, a temporal profile that suggests alterations at the genomic level. Lithium has been demonstrated to modulate AP-1 DNA binding activity as well as the expression of genes regulated by AP-1, but the mechanisms underlying these effects have not been fully elucidated. In the present study, we found that the lithium-induced increases in AP-1 DNA binding activity were accompanied by increases in p-cJun and cJun levels in SH-SY5Y cells. Lithium also increased cJun-mediated reporter gene expression in a dose-dependent manner, with significant effects observed at therapeutically relevant concentrations. Lithium's effects on cJun-mediated reporter gene expression in SH-SY5Y cells were more pronounced in the absence of myo-inositol and were blocked by protein kinase C (PKC) inhibitors and by cotransfection with a PKCalpha dominant-negative mutant. Chronic in vivo lithium administration increased AP-1 DNA binding activity in frontal cortex and hippocampus and also increased the levels of the phosphorylated, active forms of c-Jun NH2-terminal kinases (JNKs) in both brain regions. These results demonstrate that lithium activates the JNK signaling pathway in rat brain during chronic in vivo administration and in human cells of neuronal origin in vitro; in view of the role of JNKs in regulating various aspects of neuronal function and their well-documented role in regulating gene expression, these effects may play a major role in lithium's long-term therapeutic effects.

Animals↗

PubMed2001

Lithium inhibits caspase 3 activation and dephosphorylation of PKB and GSK3 induced by K+ deprivation in cerebellar granule cells.

Lithium protects cerebellar granule cells from apoptosis induced by low potassium, and also from other apoptotic stimuli. However, the precise mechanism by which this occurs is not understood. When cerebellar granule cells were switched to low potassium medium, the activation of caspase 3 was detected within 6 h, suggesting a role of caspase 3 in mediating apoptosis under conditions of low potassium. In the same conditions, lithium (5 mM) inhibited the activation of caspase 3 induced by low potassium. As lithium did not inhibit caspase 3 activity in vitro, these results suggest that this ion inhibits an upstream component that is required for caspase 3 activation. Lithium is known to inhibit a kinase termed glycogen sythase kinase 3 (GSK3), which is implicated in the survival pathway of phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB). Here we demonstrate that low potassium in the absence of lithium induces the dephosphorylation, and therefore the activation, of GSK3. However, when lithium was present, GSK3 remained phosphorylated at the same level as observed under conditions of high potassium. Low potassium induced the dephosphorylation and inactivation of PKB, whereas when lithium was present PKB was not dephosphorylated. Our results allow us to propose a new hypothesis about the action mechanism of lithium, this ion could inhibit a serine-threonine phosphatase induced by potassium deprivation.

Animals↗

PubMed1978

[Lithium balance in healthy volunteers].

Lithium sulphate in a sustained-release preparation was given to three healthy volunteers during 10 days. The following results were obtained: 1. The daily requirement needed for maintenance of an efficient lithium serum level from 0.7 to 0.8 mmol/l amounts to 30 mval. A steady state level of the serum lithium concentration was achieved after 4 to 5 days. 2. The mean value of lithium clearance amounts to 26.8 ml/min. 3. Approx. 98% of the ingested lithium could be recovered from the urine. 4. 6 days after drug withdrawal the lithium concentration in serum and urine was determined as 0. This result shows that the study of lithium balance can rely on renal excretion excluding other pathways. It is discussed that the simultaneous ingestion of psychortropic drugs and sodium chloride may influence the elimination rate of lithium.

Adult↗

PubMed2003

The Kleine-Levin syndrome - effects of treatment with lithium -.

Kleine-Levin syndrome (KLS) is a rare disorder which affects mainly adolescents. Periods of extreme somnolence alternate with megaphagia, psychomental changes and behavioural symptoms. The cause and pathogenesis of KLS remains unknown. Several treatments have been tried and recently lithium has been proposed for a prophylactic use in single cases. In view of the rarity of KLS, long-term results of lithium therapy have not been described yet. We report the clinical course of five adolescents with KLS who were treated with lithium. All patients showed significant EEG and polysomnographic changes during the episodes and had normal results in the interval. All patients had relapses while being treated with lithium. But episodes of hypersomnia under lithium therapy were shorter and monosymptomatic with lack of behavioural symptoms. Statistical modelling showed that the risk for a relapsing episode under maintenance of lithium drops per months of therapy from 100 % to 93 %, and furthermore that the maintenance of lithium shortens the mean duration of episodes to 19 %. No severe side effects were observed. In conclusion, in KLS with a high frequency of episodes and severe behavioural changes lithium may become a treatment option.

Adolescent↗

PubMed2003

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms.

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX/CRH test. Here we review new data on the efficacy and mechanism of action of lithium augmentation.

Adrenocorticotropic Hormone↗

PubMed1989

[Long-term catamnesis on the topic of uses and side effects of lithium prevention of phasic psychoses].

A lithium long-term catamnesis of 124 patients (107 manic-depressive and 17 schizoaffective psychoses) after more than 8 years of lithium prophylaxis led to the following results: 1.) Recovering: 30.3%. Improvement - particularly mitigation of the episodes of illness -: 56%. Lack of efficiency: 13%. Mean incidence of episodes of illness before lithium 0.57 per year, during lithium 0.36. Mean incidence of hospitalisation before lithium 3.4 years, during Lithium 7.1 years. Deterioration following discontinuation of lithium: 21 of 22 cases. 2.) Side effects at the beginning: 61.2%, finally 42.7% (incidence of struma 19.5% of tremor 19%, of polydipsia/polyuria 9.1%). 3.) EEG changes (general slowing-down and dysrhythmia, to a quarter focally accentuated): 59%. 4.) Normal results of haematologic and clinical-chemical investigations (28 parameter) except serum creatinine (10%), creatinine clearance (20.5%) and leucocytosis (13%). The authors discuss the reduced incidence of recovery and the quantity of side effects based on the aspect of long-term catamnesis. Further studies are necessary with regard to the selection of lithium-treated patients, to the duration of prophylaxis without efficiency and to the shift from initial efficiency to later inefficiency.

Adult↗

PubMed1987

Lithium: clinical study by brain electrical activity mapping. A case report.

One of the axes of research in our department is oriented on the study of the action of psychotropic drugs on the Central Nervous System by the means of the non invasive and direct techniques of cerebral imagery. First approach: EEG mapping In depressive states, the modification of nocturnal wakefulness states observed under lithium therapy begins to be well known. However, under lithium monotherapy, few diurnal studies have been performed. EEG mapping, based on a protocol and a strict methodology, could represent an interesting technique to approach the mechanisms of lithium action in psychopathological states concerned by this type of therapy. Second approach: Nuclear Magnetic Resonance (NMR) We studied the manic-depressive states in man before and after chronic administration of lithium salts. This research is performed in fundamental molecular studies, in vitro, and from modification of certain parameters in protonic NMR imagery that can be observed in these pathological states. We are participating in a research program and we preliminarily present: 1. the study by protonic NMR of the in vitro interaction between the lithium ion and water which is free or bound to the total cerebral tissue of rats (acute intravenous treatment by Li+ in different doses and at different times of tissular penetration). 2. the study by lithium NMR of the in vitro kinetics of the erythrocyte's lithium penetration in man, for the plasmatic concentrations (acute intravenous dose) considered as therapeutic in manic-depressive states. These measures performed by spectroscopic NMR are coupled with a classical dosage of lithium made with a flame spectrophotometer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Early physiological effects of lithium treatment: electrooculographic and adaptometric findings in patients with affective and schizoaffective psychoses.

Electrooculography allows to measure the fundocorneal potential, a standing potential of the eye, under the conditions of light and dark adaptation. The results are expressed as the so-called Arden ratio. As was demon-strated by others in healthy volunteers, the Arden ratio, on the average, de-creases under Lithium treatment. However, in individual cases it can also remain unchanged or even rise. We have performed electrooculographic and adaptometric examinations in ten patients with affective disorders (DSM-III, 296. XX) and schizoaffective psychoses (DSM-III, 295.70). The criteria for the assignment of patients to lithium treatment were derived from a study by Angst. Arden ratios were determined six times, respectively, before lithium application and after a therapeutic lithium serum level (0.6-0.8 mmol/l) had been reached (cf. 5). The values observed during lithium treatment were significantly lower than those measured before lithium application. Dark adaptation, as measured using an adaptometer according to Goldmann-Weekers, was disturbed under lithium. The potential predictor function of these findings with regard to the lithium response is being investigated by means of a prospective study.

Adaptation, Ocular↗

PubMed1982

Trends in lithium treatment and research during the last decade.

The first systematic study on lithium prophylaxis in 1967 was supplemented some years later by (I) a study involving multiple regression analysis with cycle length and interval length as dependent variables and lithium treatment as one of the predictor variables, and (II) a double-blind study of discontinuation design in which patients were allocated randomly to lithium or placebo. Both studies confirmed the conclusions of the original trial. Interest in lithium remains vivid as reflected in many publications each year and widespread clinical usage. Overuse and misuse presumably occur to some extent. In recent years lithium research has included examination of possible predictors of response to lithium and studies on the effect of long-term lithium treatment of the kidneys. Guidelines for safe and effective lithium treatment are discussed.

Bipolar Disorder↗

PubMed1980

The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy.

To investigate whether lithium ameliorates the infectious complications that accompany systemic chemotherapy, we studied 45 patients with small-cell bronchogenic carcinoma receiving combination chemotherapy and radiation therapy. Twenty received lithium carbonate, and 25 received no additional therapy. Control subjects experienced more days with neutropenia than the lithium-treated group (2.17 days per 100 patient-days vs. 0.29), more severe febrile episodes (seven patients vs. one patient), more days hospitalized with fever and neutropenia (1.92 per 100 patient-days vs. 0.18), and more infection-related deaths (five vs. none). Infection-free survival was significantly longer in the lithium-treated group than in controls (P less than 0.05). Delay in subsequent chemotherapy was longer (P less than 0.01) and the number of dose reductions greater (P less than 0.01) in the control group. For both leukocytes and neutrophils, the first cycle nadir, mean of all treatment nadirs, and the lowest nadir observed during treatment were significantly higher in the lithium group. Mean mid-cycle monocyte counts were greater in the lithium group (P less than 0.05) and correlated with concurrent serum lithium levels (rs = 0.74, P less than 0.05). We believe that lithium carbonate shows promise as a means of lowering the risk of infection among patients receiving cytotoxic therapy.

Antineoplastic Agents↗

PubMed1985

Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy.

Vasopressin-resistant diabetes insipidus is a common side effect of the treatment of affective disorders with lithium. We studied the effect of amiloride on lithium-induced polyuria in nine such patients receiving maintenance lithium therapy who had a vasopressin-resistant defect in urinary concentrating ability. After a mean (+/- S.E.) of 24 +/- 6 days of amiloride administration, the urine volume fell (from 4.7 +/- 0.6 to 3.1 +/- 0.3 liters per 24 hours; P less than 0.005), and the urine osmolality increased (from 228 +/- 35 to 331 +/- 34 mOsm per kilogram of H2O; P less than 0.001). The decrease in urine output was sustained during six months of observation in the absence of any significant change in plasma levels of lithium, potassium, or bicarbonate; urinary excretion of sodium or lithium; or creatinine clearance. Amiloride administration was also associated with a significant increase in urine osmolality (from 575 +/- 54 to 699 +/- 48 mOsm per kilogram of H2O; P less than 0.005) measured after fluid deprivation and the injection of exogenous vasopressin. We conclude that amiloride mitigates lithium-induced polyuria, at least partly, by blunting the inhibitory effect of lithium on water transport in the renal collecting tubule. Thus, amiloride may provide a specific therapy for polyuria in lithium-treated patients while obviating the need for potassium supplementation in the treatment of this kind of polyuria.

Adult↗

PubMed1996

A molecular mechanism for the effect of lithium on development.

Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesis in the early development of numerous organisms. How lithium exerts these diverse effects is unclear, but the favored hypothesis is that lithium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 beta activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases. In support of this hypothesis, lithium treatment phenocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. These observations help explain the effect of lithium on cell-fate determination and could provide insights into the pathogenesis and treatment of bipolar disorder.

Amino Acid Sequence↗

PubMed1982

Lithium's effects on the kidney.

Although lithium was known to cause changes in renal physiology, it was considered safe until reports in late 1977 suggested that it may induce chronic irreversible nephropathy. Later reports documented similar lesions in non-lithium-treated patients with affective disturbances. Thus, the data are inconclusive. Concern for the kidney during lithium therapy is now greater than it was originally, but confidence in lithium's safety is higher than it has been for the past four years. Physician appreciation of the foregoing factors, careful patient selection, and informed consent are important in lithium therapy. An understanding of lithium use in patients in a low-sodium state or on diuretic therapy and avoidance and treatment of lithium intoxication are advocated. Good prelithium workups and closer monitoring of patients on long-term lithium therapy are recommended.

Diuretics↗

PubMed2006

Effect of lithium on rat cerebrum under different dietary protein regimens.

This study was designed to investigate the effects of lithium in adult rat brain under different dietary protein regimens. Lithium as carbonate was given at a dose of 1.1 g/kg diet to female rats fed normal (18% protein), low protein (8% protein), and high protein (30% protein) diets for 30 days. Lithium treatment resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin in the cerebrum of the rat brain. Further, administration of lithium to rats fed low protein (LP) and high protein (HP) diets also showed a significant decrease in the levels of norepinephrine and dopamine but caused no significant change in the serotonin concentration. Lithium administration to normal diet, LP, and HP groups resulted in a significant increase in the activities of acetylcholinesterase and monoamine oxidase. Lithium treatment led to decrease in the activity of enzyme Na+ K+ ATPase in all groups. On the second day, the LP group showed enhanced transfer latency (TL), a dependent variable to study elevated plus-maze test, whereas HP diet went from 34% reduction to normal. On the other hand, lithium administration restored the already enhanced TL in the LP group. The study concludes that lithium treatment to protein-deficient cases may not further aggravate the effects of protein-deficient conditions, but it may afford protection.

Acetylcholinesterase↗

PubMed2005

The impact of lithium long-term medication on suicidal behavior and mortality of bipolar patients.

The article reviews the existing evidence and the concept of the anti-suicidal effect of lithium long-term treatment in bipolar patients. The core studies supporting the concept of a suicide preventive effect of lithium in bipolar patients come from the international research group IGSLI, from Sweden, Italy, and recently also from the U.S. Patients on lithium possess an eight- time lower suicide risk than those off lithium. The anti-suicidal effect is not necessarily coupled to lithium's episode suppressing efficacy. The great number of lives potentially saved by lithium adds to the remarkable benefits of lithium in economical terms. The evidence that lithium can effectively reduce suicide risk has been integrated into modern algorithms in order to select the optimal maintenance therapy for an individual patient.

Algorithms↗

PubMed1986

Inhalation toxicity of lithium combustion aerosols in rats.

Studies of the acute inhalation toxicity of lithium combustion aerosols were undertaken to aid in evaluating the health hazards associated with the proposed use of lithium metal in fusion reactors. A system was developed to generate lithium combustion aerosols by sweeping vapor from molten lithium metal into a controlled air atmosphere. Male and female F344/Lov rats, 9-12 wk of age, were exposed once for 4 h to concentrations of 2600, 2300, 1400, or 620 mg/m3 of aerosol (MMAD = 0.69 micrometer, sigma g = 1.45) that was approximately 80% lithium carbonate and 20% lithium hydroxide to determine the acute toxic effects. Fourteen-day LC50 values (with 95% confidence limits) of 1700 (1300-2000) mg/m3 for the male rats and 2000 (1700-2400) mg/m3 for the female rate were calculated. Clinical signs of anorexia, dehydration, respiratory difficulty, and perioral and perinasal encrustation were observed. Body weights were decreased the first day after exposure in relation to the exposure concentration. In animals observed for an additional 2 wk, body weights, organ weights, and clinical signs began to return to preexposure values. Histopathologic examination of the respiratory tracts from the animals revealed ulcerative or necrotic laryngitis, focal to segmental ulcerative rhinitis often accompanied by areas of squamous metaplasia, and, in some cases, a suppurative bronchopneumonia or aspiration pneumonia, probably secondary to the laryngeal lesions. The results of these studies indicate the moderate acute toxicity of lithium carbonate aerosols and will aid in the risk analysis of accidental releases of lithium combustion aerosols.

Aerosols↗

PubMed1996

Lithium induced polyuria and renal vasopressin receptor density.

BACKGROUND: Lithium, a drug frequently used for treatment of affective disorders, is known to cause a vasopressin-resistant state, leading to polyuria and polydipsia. It has been suggested that lithium interacts with the renal V2-vasopressin receptor. Detailed studies on the influence of lithium on the AVP receptor, however, have so far been difficult due to the lack of a suitable radioligand with high specific activity and high affinity. METHODS: Using 125I-[8-(p-(OH)-phenylpropionyl)]- LVP, we studied the effects of lithium on V2-vasopressin receptors in male Sprague-Dawley rats and LLC-PK1 cells. Rats, having free access to water, were orally treated with 10 mg lithium/100 mg b.w./day or placebo for 10 days. Scatchard analysis was performed using membranes prepared from homogenized renal papillae. RESULTS: Lithium caused significant polyuria and an impaired renal concentration capacity after water deprivation. Binding studies showed no effect of lithium on binding affinity KD (0.98 +/- 0.21 nmol/l vs. 0.86 +/- 0.15 nmol/l (Li) (n.s.). Receptor density, however, significantly decreased from 130 +/- 12.3 nmol/kg protein in controls (n = 8) to 101.7 +/- 13.4 nmol/kg protein (n = 8), (P < 0.05). Plasma osmotically and AVP were not significantly altered by lithium treatment. Vasopressin receptor density on LLC-PK1-cells, a pig renal cell line, was not changed by preincubation with lithium (312 +/- 22 nmol/kg vs. 329 +/- 25 nmol/kg (Li) (n = 6, n.s.). CONCLUSIONS: The decrease of AVP-receptor density in vivo might be related to vasopressin resistance, either primary, or secondary to other factors, e.g. actual water transport.

Animals↗

PubMed1999

Lithium attenuates p53 levels in human neuroblastoma SH-SY5Y cells.

Lithium has neuroprotective effects in a number of model systems which may contribute to the therapeutic effects of lithium in mood disorders. Because the tumor suppressor p53 is linked to cell death, we tested whether lithium administration to human neuroblastoma SH-SY5Y cells modulated the activation of p53. After treatment of cells with H7 (25, 50, and 75 microM), nuclear p53 levels were increased to 464, 816 and 1079% of basal levels, respectively. A 24 h pretreatment with 5 mM lithium reduced these increases by 69, 61 and 28%, respectively. Pretreatment with 2 mM lithium for 1 or 14 days reduced the 25 microM H7-induced elevations of nuclear p53 by 40 and 70%, respectively, and even a 14-day pretreatment with 1 mM lithium caused a significant 16% reduction. Since increased nuclear p53 is a critical intermediate step in many signaling processes that culminate in cell death, attenuation of p53 activation by lithium reveals a mechanism by which lithium may support neuronal survival.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗