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PubMed1990

Lithium toxicity: when is hemodialysis necessary?

A case of severe lithium intoxication is presented in which the function of the lithium pump was monitored, and was found to improve as the signs of lithium toxicity abated. The status of the lithium pump may provide an index of the severity of lithium intoxication. Since the lithium pump regulates the extrusion of lithium from the intracellular to the extracellular space, it is argued that the activity of the lithium pump is an index of the severity of lithium intoxication and crucial to the process of detoxification.

Adult↗
PubMed1992

Urinary excretion of albumin and retinol-binding protein in lithium-treated patients: a longitudinal study.

The urinary excretion of albumin and retinol-binding protein was determined by means of sensitive immunochemical methods in a 2-year longitudinal study of 22 lithium-treated patients. During lithium treatment, there were no significant changes in the median albumin:creatinine ratios or retinol-binding protein:creatinine ratios. However, the median albumin:creatinine ratios were significantly higher in lithium-treated patients than in 22 normal subjects, which indicates that glomerular permeability is increased; no correlation with serum lithium level or duration of lithium treatment could be shown. In patients treated with slow-release tablets, the urinary excretion of albumin was significantly higher after 2 years than in patients given lithium carbonate. The median retinol-binding protein:creatinine ratios did not differ significantly between lithium-treated patients and normal subjects, suggesting that lithium does not affect the catabolism of low-molecular-weight proteins in the proximal tubules. In conclusion, the study supports the hypothesis that lithium treatment produces a small but significant and nonprogressive elevation of the urinary excretion of albumin.

Adult↗
PubMedDate not supplied

Lithium isotope geochemistry and origin of Canadian shield brines.

Hypersaline calcium/chloride shield brines are ubiquitous in Canada and areas of northern Europe. The major questions relating to these fluids are the origin of the solutes and the concentration mechanism that led to their extreme salinity. Many chemical and isotopic tracers are used to solve these questions. For example, lithium isotope systematics have been used recently to support a marine origin for the Yellowknife shield brine (Northwest Territories). While having important chemical similarities to the Yellowknife brine, shield brines from the Sudbury/Elliot Lake (Ontario) and Thompson/Snow Lake (Manitoba) regions, which are the focus of this study, exhibit contrasting lithium behavior. Brine from the Sudbury Victor mine has lithium concentrations that closely follow the sea water lithium-bromine concentration trajectory, as well as delta6Li values of approximately -28/1000. This indicates that the lithium in this brine is predominantly marine in origin with a relatively minor component of crustal lithium leached from the host rocks. In contrast, the Thompson/Snow Lake brine has anomalously low lithium concentrations, indicating that it has largely been removed from solution by alteration minerals. Furthermore, brine and nonbrine mine waters at the Thompson mine have large delta6Li variations of approximately 30/1000, which primarily reflects mixing between deep brine with delta6Li of -35 +/- 2/1000 and near surface mine water that has derived higher delta6Li values through interactions with their host rocks. The contrary behavior of lithium in these two brines shows that, in systems where it has behaved conservatively, lithium isotopes can distinguish brines derived from marine sources.

Calcium↗
PubMed2006

Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis.

Lithium confers cell protection against stress and toxic stimuli. Although lithium inhibits a number of enzymes, the antiapoptotic mechanisms of lithium remain unresolved. Here, we report a novel role of lithium on the blockage of ceramide- and etoposide-induced apoptosis via inhibition of protein phosphatase 2A (PP2A) activity. Overexpression of PP2A resulted in caspase-2 activation, mitochondrial damage, and cell apoptosis that were inhibited by okadaic acid (OA) and lithium. Lithium and OA abrogated ceramide- and etoposide-induced Bcl-2 dephosphorylation at serine 70. Furthermore, ceramide- and etoposide-induced PP2A activation involved methylation of PP2A C subunit, which lithium suppressed. Lithium caused dissociation of PP2A B subunit from the PP2A core enzyme, whereas ceramide caused recruitment of the B subunit. Taken together, lithium exhibited an antiapoptotic effect by inhibiting Bcl-2 dephosphorylation and caspase-2 activation, which involved, at least in part, a mechanism of down-regulating PP2A methylation and PP2A activity.

Animals↗
PubMed2001

Molecular targets of lithium action.

Lithium is highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis, and other processes. However, the mechanism of lithium action is still unclear. A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation. Thus, the challenge is to determine which target, if any, is responsible for a given response to lithium in cells. Comparison of lithium effects with genetic disruption of putative target molecules has helped to validate these targets, and the use of alternative inhibitors of a given target can also lend strong support for or against a proposed mechanism of lithium action. In this review, lithium sensitive enzymes are discussed, and a number of criteria are proposed to evaluate which of these enzymes are involved in the response to lithium in a given setting.

Animals↗
PubMed1997

More marked stimulation by lithium than insulin of the glycogenic pathway in rat skeletal muscle.

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.

Androstadienes↗
PubMed1995

Potentiation of angiotensin II-stimulated vascular contraction by lithium.

Previous studies have suggested that lithium prolongs or enhances vascular contractions stimulated by alpha-adrenergic agents. The present study was performed to determine whether a similar phenomenon occurs with angiotensin II (ANG II)-stimulated contractions and whether this phenomenon results from interactions with the phosphoinositide signaling system. Contractions of rat aortic rings with 100 nM ANG II were 38% greater in the presence of 20 mM LiCl than in its absence (0.47 +/- 0.07 vs. 0.34 +/- 0.05 g tension/mg dry tissue wt, P < 0.01). The effects of lithium on inositol phosphate responses, diacylglycerol responses, and intracellular calcium concentration on single or repeated stimulations with ANG II were then examined in vascular smooth muscle cells cultured from rat aorta. Cells exposed twice to 100 nM ANG II contained 50% lower inositol trisphosphate levels (InsP3) and 10% lower diacylglycerol levels than cells exposed to ANG II only once. LiCl or lithium acetate abolished these desensitizations in a concentration-dependent manner. Similarly, InsP3 and diacylglycerol responses to a single exposure of ANG II were heightened by lithium (by 75 and 25%, respectively), and the duration of the responses was prolonged by lithium (5- and 2-fold, respectively). In contrast, ANG II-stimulated calcium transients were not enhanced or prolonged by lithium, nor was desensitization of ANG II-stimulated cytosolic calcium mobilization upon serial exposures abolished by lithium. When ring contraction studies were repeated in the presence of the protein kinase C inhibitor staurosporine (150 nM), lithium no longer potentiated ANG II contractions [0.38 +/- 0.03 (control) vs. 0.35 +/- 0.06 g tension/mg dry tissue wt (lithium)].(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1976

A preventive effect of potassium against fatal lithium intoxication in rats.

The effect of potassium against lithium intoxication was studied in two groups of rats given food containing 100 mmol of sodium and 100 or 1,100 mmol of potassiam/kg dry weight. After 1 week 80 mmol of lithium chloride/kg dry weight was added to both diets. Four days later the body weight, serum lithium concentration, and urinary lithium clearance were all significantly higher in the high potassium group than in the other group. After 15 days the lithium clearance had fallen to one fifth in the lowest potassium group but was unaltered in the high potassium group. All rats in the low potassium group continued to lose weight and died of lithium intoxication within 20 days, while the rats given high potassium survived and gained weight. A high potassium content of the food was able to prevent a fatal lithium-induced loss of sodium and to maintain a normal lithium clearance. It is suggested that also a lithium-induced loss of potassium was counteracted.

Animals↗
PubMed1981

Attenuation of the lithium-induced diabetes-insipidus-like syndrome by amiloride in rats.

The effect of amiloride on lithium-induced polydipsia and polyuria and on the lithium concentration in the plasma, brain, kidney, thyroid and red blood cells was investigated in rats, chronically treated with LiCl. Amiloride reduced the drinking and urine volume of rats in an acute (6 or 12 h) and a subacute (3 days) experiment. 6 h after the administration of amiloride, a reduction was observed in the lithium content of the renal medulla but not in the other organs studied. At 12 h, all the tissues showed a slight increase in lithium levels. After 3 days of combined treatment, a marked elevation in plasma and tissue lithium levels accompanied a reduction in water intake. In all the experiments, the attenuation of the lithium-induced diabetes-insipidus-like syndrome by amiloride was accompanied by a reduction of the ratio between the lithium concentration in the renal medulla and its levels in the blood and an elevation in the plasma potassium level. It is concluded that acute amiloride administration to lithium-treated patients suffering from polydipsia and polyuria might relieve these patients but prolonged amiloride supplementation would result in elevated lithium levels and might be hazardous.

Amiloride↗
PubMed1981

Glomerular filtration rate and calcium metabolism in long-term lithium treatment.

Does long-term lithium treatment induce an irreversible renal damage, and does polyuria or changes in the calcium metabolism indicate this? To elucidate these questions GFR, diuresis, S-Ca, S-Mg, S-PTH and bone mineral content (photonabsorptiometry) were determined in 29 consecutive patients on long-term lithium therapy for 2.5--12 years and in 4 patients, who had been admitted to the Renal Clinic with lithium-induced polyuria. Only 1 of the patients had had a known lithium intoxication (S-Li > 2 mmol/l). None had a history of renal disease or significant analgesic consumption. In the consecutive series the GFR was not significantly reduced and no correlations were found between this parameter and the duration of lithium therapy, average S-Li, highest S-Li noted, diuresis or any of the calcium parameters. The morning diuresis was significantly increased in comparison with a control group with normal kidney function. 2 of the 4 polyuric patients had a decreased GFR, but in 1 case it was normalized on desmopressin supplementation. Renal biopsy in the patient with one S-Li of 2.35 and a low GFR in the consecutive series, and in 3 of the polyuric patients, revealed focal interstitial fibrosis and nephron atrophy. The mean S-Ca, S-Mg, S-PTH and bone mineral content were increased, but no significant intercorrelations between these parameters were found. Neither were any intercorrelations found between the calcium parameters and time on lithium therapy, average S-Li, highest S-Li noted or morning diuresis. In conclusion a relatively well-managed lithium therapy for up to 12.5 years does not seem to influence the GFR, even if renal biopsy in 4 of our patients revealed interstitial nephritis and data in the literature indicate a progressive interstitial nephritis. The present study did not support the proposition that polyuria is an alarming sign of pronounced renal lesion. Calcium metabolism is influenced by lithium therapy but from the clinical point of view no negative effects could be found. S-Ca should probably be checked regularly in patients on long-term lithium therapy.

Adult↗
PubMed1992

Comparison between acetate and bicarbonate dialysis for the treatment of lithium intoxication.

Lithium is used to treat manic-depressive disorders, but toxic side effects commonly occur. The preferred treatment of severe lithium intoxication is hemodialysis. No data, however, exist comparing the effectiveness of acetate to bicarbonate dialysis for the removal of lithium. We present a case of lithium intoxication treated with both. During acetate dialysis, lithium removal occurred exclusively from the extracellular fluid space, while during bicarbonate dialysis, lithium removal occurred equally from both the extracellular and intracellular fluid spaces. We hypothesize that acetate but not bicarbonate activates the sodium-hydrogen antiporter on cell membranes, and that lithium, substituting for sodium, is driven into cells. This may explain the rebound in lithium levels commonly noted after conventional dialysis. We recommend bicarbonate hemodialysis as the therapy of choice for severe lithium intoxication.

Acetates↗
PubMed2003

Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death.

BACKGROUND AND PURPOSE: In vitro and in vivo studies have demonstrated neuroprotective actions of lithium. The present study investigated the effect of a low dose of lithium on infarct volume and neurological outcome as well as on apoptotic and inflammatory processes in rats exposed to focal ischemia. METHODS: Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes followed by reperfusion. Lithium (1 mmol/kg) was given subcutaneously daily for 14 days before the onset of MCAO and 2 days thereafter. Blood parameters and cerebral blood flow were assessed before, during, and after MCAO. Rats were examined for neurological deficits 24 and 48 hours after MCAO. Two days after MCAO, the brains were removed for immunohistochemical evaluation of caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), activated microglia, and the expression of AP-1 proteins (c-Fos and c-Jun). Infarct volume was assessed by cresyl violet staining. RESULTS: Pretreatment with lithium did not alter cerebral blood flow or blood parameters. Neurological deficits were significantly decreased in rats treated with lithium at 24 and 48 hours after ischemia. Infarct volume was reduced in rats treated with lithium at 48 hours after ischemia. Lithium significantly decreased the ischemia-induced caspase-3 immunoreactivity and TUNEL staining as well as the AP-1 protein expression in the penumbra of the ischemic cortex. No changes in activated microglia were observed. CONCLUSIONS: The present study demonstrates that chronic treatment with lithium at a low dose exhibits neuroprotection in transient focal cerebral ischemia. Antiapoptotic mechanisms are involved in the lithium-induced neuroprotective effects.

Animals↗
PubMed1974

On the mechanism of lithium-induced diabetes insipidus in man and the rat.

The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results in part from interference with the mediation of vasopressin at a step distal to the formation of 3',5' cyclic AMP.

Animals↗
PubMed1992

Lithium, benzodiazepines, and sexual function in bipolar patients.

OBJECTIVE: Lithium and benzodiazepines are widely used in the treatment of bipolar patients. Yet studies of the effect of these drugs on sexual function are scarce. This study surveyed sexual function in bipolar patients treated with lithium, either alone or in combination with other drugs. METHOD: Sexual function was assessed by self-rating scale in 104 outpatients (45 men and 59 women) with a DSM-III diagnosis of bipolar disorder who were attending an affective disorders clinic. All patients were under treatment with lithium, either alone (35%) or in combination with benzodiazepines (49%), tricyclic antidepressants (17%), neuroleptics (17%), tryptophan (10%), or carbamazepine (1%). The patients were in a stable and euthyroid state at the time of the assessment. Serum lithium and plasma prolactin concentrations were measured at the same time. RESULTS: Multiple regression analysis revealed an association between concomitant benzodiazepine administration and sexual dysfunction scores. Difficulties in sexual functioning were significantly more common in patients treated with a combination of lithium and benzodiazepines (49%) than in those treated with either lithium alone (14%) or lithium in combination with other drugs (17%). No relationship was found between serum lithium or plasma prolactin levels and sexual dysfunction scores. CONCLUSIONS: Lithium, when given alone, did not appear to have a major effect on sexual function, whereas its combination with benzodiazepines was associated with sexual dysfunction in about half of the patients. More attention should be given to drug-induced sexual dysfunction, since its presence can have important consequences for clinical management and compliance.

Adult↗
PubMed1996

Lithium use and discontinuation in a health maintenance organization.

OBJECTIVE: For decades, lithium has been prescribed to treat bipolar disorder. Its efficacy has been documented by clinical trials and by data from specialized clinics. An issue of considerable interest is the use of lithium in managed care systems. This project examined the use of lithium and its continuity of use by enrollees of a health maintenance organization (HMO). METHOD: In a 6-year longitudinal cohort study, 1,594 lithium users aged 15 years and older who were enrolled in an HMO were followed from 1986-1991. Data were obtained from automated databases and from medical record review of a random 5% subsample of the group (N = 74). RESULTS: Bipolar disorder was the most frequent morbidity treated. Eighty-four percent (N = 62 or 74) received services from a psychiatrist. Annual prevalence of lithium use increased over the 6-year period from 1.4 to 2.3 persons per thousand HMO members. Duration of use varied widely with some long-term but many short-term users. Discontinuation of treatment was associated with evaluated rates of psychiatric hospitalization and use of psychiatric emergency services. Lithium users were much more likely to receive a variety of other psychotropic drugs than nonusers of the same sex and age. CONCLUSIONS: Lithium use in this population was more often sporadic than continuous. Discontinuation of lithium was associated with psychiatric hospitalization. If lithium is to be a cost-effective treatment for bipolar disorder, managed care systems will need to improve adherence to drug treatment regimens.

Adolescent↗
PubMed2005

New thyroxine treatment in older adults beginning lithium therapy: implications for clinical practice.

OBJECTIVE: The authors sought to determine the incidence of lithium-induced hypothyroidism in a population-based cohort of older adults beginning lithium therapy and thereby to inform clinical guidelines on the frequency of monitoring necessary in this group. METHODS: The authors conducted a population-based observational cohort study using four administrative databases that contained information on over 1.3 million older adults in Ontario who receive universal healthcare coverage in terms of physician services, drugs, and hospitalizations. Over an 18-month period, they studied adults age>or=65 who were newly prescribed lithium or valproate, monitoring subjects for initiation of T4 therapy (as a proxy for hypothyroidism) while they continued their lithium use. RESULTS: The authors identified 1,705 new users of lithium and 2,406 new users of valproate with similar baseline characteristics. Lithium users were significantly more likely to be treated with T4 than were valproate users. The rate of T4 treatment per 100 person-years was 5.65 in the lithium group and 2.70 in the valproate group. CONCLUSION: T4 treatment was initiated in almost 6% of lithium-treated patients, suggesting the possibility that hypothyroidism developed twice as frequently among these patients as would be expected among a mixed-age population. Increased vigilance and continued monitoring of thyroid functioning for at least 2 years is necessary in older adults beginning lithium therapy.

Aged↗
PubMed2000

Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression.

OBJECTIVE: Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression. The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder. METHOD: Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a randomized, parallel-group, double-blind, placebo-controlled trial of lithium augmentation during continuation treatment. After a 2-4-week stabilization period following remission, patients were randomly assigned to receive either lithium or placebo for a 4-month period. Antidepressant medication was continued throughout the study. RESULTS: Relapses (including one suicide) occurred in seven (47%) of the 15 patients who received placebo in addition to antidepressants. None (0%) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study. Five of the seven relapsing patients in the placebo group developed a depressive episode, and the other two experienced a manic episode. CONCLUSIONS: Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse. Patients who respond to lithium augmentation should be maintained on lithium augmentation for a minimum of 6 months or even longer.

Adolescent↗
PubMed2005

Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials.

OBJECTIVE: Observational studies suggest that long-term lithium treatment has a strong antisuicidal effect in mood disorders, but it is uncertain whether this association is a genuine therapeutic effect or is due to confounding factors in nonrandomized studies. The authors conducted a systematic review and meta-analysis of randomized trials to investigate the effect of lithium, compared to placebo and other active treatments, on the risk of suicide, deliberate self-harm, and all-cause mortality in patients with mood disorder. METHOD: The data source was the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE (1966-June 2002), EMBASE (1980-June 2002), CINAHL (1982-March 2001), PsycLIT (1974-June 2002), PSYNDEX (1977-October 1999), and LILACS (1982-March 2001). The Cochrane Central Register of Controlled Trials (CENTRAL) was searched with the term "lithium" for new records entered into the database from 1999 to 2003. Studies selected included randomized, controlled trials comparing lithium with placebo or all other compounds used in long-term treatment for mood disorders (unipolar depression, bipolar disorder, schizoaffective disorder, dysthymia, and rapid cycling, diagnosed according to DSM or ICD criteria). Of 727 references identified in the search, 52 articles were marked as possibly relevant on the basis of the abstract, and 32 randomized, controlled trials were eligible for inclusion in the review. Two independent reviewers extracted the data, and disagreements were resolved by consensus with a third reviewer. Methodological quality was assessed according to the criteria of the Cochrane Collaboration. When the outcomes of interest were not reported, an attempt was made to obtain the required data from the original authors. RESULTS: In 32 trials, 1,389 patients were randomly assigned to receive lithium and 2,069 to receive other compounds. Patients who received lithium were less likely to die by suicide (data from seven trials; two versus 11 suicides; odds ratio=0.26; 95% confidence interval [CI]=0.09-0.77). The composite measure of suicide plus deliberate self-harm was also lower in patients who received lithium (odds ratio=0.21; 95% CI=0.08-0.50). There were fewer deaths overall in patients who received lithium (data from 11 trials; nine versus 22 deaths; odds ratio=0.42, 95% CI=0.21-0.87). CONCLUSIONS: Lithium is effective in the prevention of suicide, deliberate self-harm, and death from all causes in patients with mood disorders.

Cause of Death↗