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PubMed1991

Lithium increases tritiated thymidine uptake by abnormal human parathyroid tissue.

Patients receiving lithium for the management of manic depressive disorders appear to be at increased risk for development of hypercalcemia. Some (but not all) clinical studies and several in vitro studies suggest that lithium alters release of parathyroid hormone. Because hypercalcemia may result from an increase in the mass of parathyroid tissue, we studied the in vitro effect of lithium on tritiated thymidine (3H-TdR) incorporation as a measure of DNA synthesis. Dispersed cells from previously cryopreserved tissue from 18 patients undergoing surgery for single-gland hyperparathyroidism (adenoma) and five patients with secondary hyperparathyroidism were incubated with graded concentrations of lithium chloride and, after a 5-day incubation, were pulsed with 3H-TdR. Adenoma cells exposed to 2.0 mmol/L lithium (therapeutic level is approximately 0.8 to 2.0 mmol/L) demonstrated increased 3H-TdR incorporation compared with cells not exposed to lithium (average increase 56%). Secondary hyperplasia cells exhibited a similar but less striking response. There was no lithium-induced 3H-TdR incorporation in four preparations with normal bovine parathyroid cells. We conclude that lithium in therapeutic doses increases 3H-TdR incorporation into adenoma cells, may serve as a mitogen for human parathyroid adenoma, and could promote or accelerate hyperparathyroidism.

Animals↗
PubMed1990

[Screening and evaluation on predictive factors in lithium carbonate maintenance treatment of manic-depressive disorders].

The prophylactic effect of lithium carbonate was studied prospectively in 95 patients with recurrent manic-depressive disorders. Maintenance lithium treatment started at the stage of recovery after previous episodes lasting for 20-24 months. Of all the 95 patients, 55 cases (57.9%) were responders, with no relapse during the follow-up period; whereas the other 40 cases (42.1%) were non-responders, having at least one relapse occurred from 4 to 12 months after the index episode. Of the parameters studied, (1) minor primary episode; (2) higher lithium RBC/plasma ratio (greater than 0.4); (3) increase of plasma calcium level during lithium treatment; (4) extraversion-cycloid personality featured by EPQ have higher predictive sensitivity and specificity (greater than 70%) and maybe used as the core predictive factors for long-term outcome in lithium treatment. The other parameters, the age of unset, frequency of episodes, euphoric and grandiose symptoms, clinical respond of first lithium anti-episode medications and lithium clearance can also be used as corresponding predictive factors in selecting cases for long-term lithium treatment.

Adolescent↗
PubMed1987

Pharmacokinetics of lithium in the elderly.

The disposition and elimination of lithium was examined in nine female geriatric patients (aged 67 to 80 years) maintained on lithium carbonate as a once daily dose (300 to 600 mg) for the treatment of recurrent depression. Following the morning lithium dose (0.21 +/- 0.06 mmol/kg/day, mean +/- standard deviation), a peak steady state serum concentration of 0.83 +/- 0.25 mmol/liter was achieved at 2.2 +/- 1.2 hours. The mean distribution half-life (alpha-t1/2) was 2.7 +/- 1.2 hours, with distribution being complete at 10.6 +/- 3.0 hours. The mean terminal elimination half-life (beta-t1/2), the mean apparent oral clearance (Cl), and the mean apparent volume of distribution (Varea) were 26.9 +/- 5.5 hours, 15.6 +/- 4.0 ml/min, and 0.64 +/- 0.16 liter/kg, respectively. Compared to a younger adult cohort (35 +/- 10 years), the lithium Cl and Varea were significantly reduced and the alpha- but not beta-t1/2 prolonged in the elderly (p less than 0.05). Based on these pharmacokinetic differences, geriatric patients may require one-third to one-half less lithium than younger adults. The 12-hour standard serum lithium concentration remained a value of minimal intersubject variability when lithium was administered once daily. However, the therapeutic concentration range based on this 12-hour standard serum lithium concentration needs to be redefined for the prophylaxis of unipolar disorders in the elderly.

Adult↗
PubMed1985

[Effectiveness of combined administration of lithium carbonate and prednisolone in neutropenias].

Use was made of 3 schedules of the combined use of lithium carbonate and prednisolone in patients with neutropenias of different genesis. Prednisolone was used in a single dose on day 10 of lithium carbonate intake (1), prednisolone was included into lithium carbonate therapy (2), and lithium carbonate was included into prednisolone therapy (3). The effect attained with the combined use of prednisolone and lithium carbonate appeared higher as compared to that with the use of each drug alone. The data obtained point to the differences between lithium carbonate and prednisolone if viewed from the standpoint of the mechanism of the neutropoiesis-stimulating action. It is recommended that lithium carbonate (0.3 g thrice a day) may be combined with prednisolone (0.4 mg/kg bw a day). The latter drug should be included into the treatment schedule since the 4th day of lithium therapy for neutropenias of different genesis including those caused by cytostatic treatment and irradiation.

Adult↗
PubMed1983

[Transport of lithium in rat renal cortex slices].

Slices of the renal cortex take up lithium from the incubation medium; this uptake does not follow a saturation kinetics and is demonstrable under aerobic and anaerobic conditions alike. The lithium uptake is associated with a variation of the sodium and potassium content in the slices. These changes are distinguishable from the electrolyte movements caused by the introduction of the slices into the incubation medium. The present findings characterize the lithium uptake into the renal tissue as a passive process. With the in vivo experiments, accumulation of lithium in the renal tissue against the serum should presuppose glomerular filtration and enrichment of lithium in the lumen of the tubuli through processes of urine concentration. In slices of the renal cortex, like in the intact animal the uptake of lithium can be influenced by inhibitors of the renal electrolyte movement. The present findings have provided evidence that lithium enters the tubular cells passively, and that slices of the renal cortex are suited for testing substances acting on the renal handling of lithium.

Animals↗
PubMed1984

Lithium administration and urinary electrolyte excretion in the rat.

The effect of lithium administration on urine eletrolyte excretion is controversial with reports of increased, unaltered and reduced excretion rates of sodium, potassium, calcium, magnesium and inorganic phosphate. Therefore rats treated with daily intraperitoneal lithium chloride for 3 weeks were studied and were found to have marked fluctuations in electrolyte excretion when compared to untreated rats. Although lithium-treated rats were always polyuric, urinary sodium, potassium and calcium excretion was significantly elevated immediately following intraperitoneal lithium but their excretion rates then returned towards normal. Magnesium excretion was initially unaltered by lithium administration (6.8 +/- 1.3 compared with 7.3 +/- 1.7 mumol/100 g/8 h) but then decreased (2.5 +/- 0.5 with 7.8 +/- 1.1 mumol of magnesium/100 g/8 h; p less than 0.01) during the final collection period. A persistent phosphaturia also occurred with lithium treatment (122 +/- 5 compared with 92 +/- 6 mumol/100 g body weight/24 h). Despite these significant changes in renal electrolyte transport with lithium administration, similar changes were also noted in rats similarly treated with equimolar doses of sodium chloride although polyuria did not occur. Thus it is postulated that lithium ions exert their effect on renal electrolyte transport in a similar manner to that of sodium.

Animals↗
PubMed1994

Lithium: a review of its pharmacokinetics, health effects, and toxicology.

Lithium (Li) is commonly used in treating bipolar disease. Therapeutic concentrations of lithium have almost no psychotropic effects in normal man. It is not a sedative, depressant, or euphoriant and this characteristic differentiates lithium from other psychotropic agents. Prospective epidemiologic studies demonstrate that lithium carbonate in therapeutic oral doses with the plasma level between 1.2 and 1.5 meq/L (225 to 676 mg of lithium) do not cause diabetes insipidus, urine output increases in men to 3 liters; GFR does not significantly increase; creatinine clearance remains stable in women but decreases in men; renal concentrating capacity is significantly reduced; calcium metabolism is altered by lowering urinary calcium excretion and increasing serum calcium concentrations, thereby increasing circulating PTH. In pregnancy Li causes an increase in high perinatal death rate and a high malformation rate. The use of lithium in early pregnancy is associated with a several fold increase in the incidence of cardiovascular anomalies in the newborn, tricuspid valve abnormalities. The woman on lithium therapy who attempts to become pregnant should notify her physician. Careful monitoring of blood lithium levels must be done every three days.

Adult↗
PubMed1996

[Is lithium a teratogen?].

Beginning with the seventies literature has brought a series of publications drawing attention to possible effects of lithium on the origin of congenital malformations. The discussion on the teratogenic effects of lithium in world literature has not come to final conclusion yet. The paper reviews some knowledge from home and foreign literature, dealing with the problems of lithium teratogenicity. A series of information has been provided on the basis of metaanalysis of data having been published until 1994 in the review systems MEDLINE, TOXLINE and Lithium Information Center database. The aim of the contribution has been to review the published data on this question. The available literature has shown that teratogenicity of lithium has not been proved univocally. Last studies rather suggest that lithium is not a strong teratogen. In view of the fact that teratogenicity of lithium cannot be safely excluded, the paper recommends that this kind of risk should be taken into account, if lithium administration is considered to be applied in pregnant women, especially during the first three months of pregnancy.

Abnormalities, Drug-Induced↗
PubMed2000

A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder.

BACKGROUND: A subgroup of children and adolescents with conduct disorder are characterized by severe and persistent aggression. Although there is no agreed on treatment for such aggression, lithium carbonate has shown promise in some studies involving children. Our study was designed to critically assess the efficacy of lithium in the treatment of aggression in children and adolescents using a measure specific for aggression. METHODS: Subjects were inpatients with conduct disorder hospitalized because of severe and chronic aggression. A parallel-groups design was used in this double-blind, placebo-controlled trial with randomization to lithium or placebo. Only those who met the aggression criterion during the 2-week placebo-baseline period were randomized to 4 weeks of treatment. Outcome measures included Clinical Global Impressions, the Global Clinical Judgements (Consensus) Scale, and the Overt Aggression Scale. RESULTS: Eighty-six inpatients enrolled in the study; 40 (33 male and 7 female; median age, 12.5 years) entered and completed the treatment phase. Lithium was statistically and clinically superior to placebo. Sixteen of 20 subjects in the lithium group were responders on the Consensus ratings vs 6 of 20 in the placebo group (P=.004). Ratings on the Overt Aggression Scale decreased significantly for the lithium group vs the placebo group (P=.04). More than half of the subjects in the lithium group experienced nausea, vomiting, and urinary frequency. CONCLUSIONS: Lithium is a safe and effective short-term treatment for aggression in inpatients with conduct disorder, although its use is associated with adverse effects.

Adolescent↗
PubMedDate not supplied

Effect of lithium on hepatic lipid peroxidation and antioxidative enzymes under different dietary protein regimens.

Lithium in the form of lithium carbonate was administered at a dose level of 1.1 g kg(-1) food to rats fed normal (18% protein), low-protein (LP; 8%) and high-protein (HP; 30%) diets for a period of 1 month. A highly significant (53%) increase in the level of lipid peroxidation (LPO) was observed in protein-deficient rats but this increase was marginal in rats fed an HP diet (18%). Lithium treatment of rats fed a normal diet caused a marked decrease (22%) in LPO. Lithium administration to rats fed an LP diet also reduced the raised levels of LPO to the extent of 16%. Furthermore, lithium treatment normalized the HP-induced increase in the levels of LPO. The activities of glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were reduced significantly in protein-deficient rats. On the other hand, an HP diet caused a decrease in SOD activity only. The activities of GPx and catalase were appreciably enhanced in lithium-treated rats. Lithium treatment to LP-fed rat markedly increased GPx activity and brought the decreased levels of SOD and catalase to within normal limits. Lithium administration to HP-fed rats did not cause any significant alteration in the activities of these antioxidative enzymes.

Animals↗
PubMed2003

Lithium augmentation increases post-dexamethasone cortisol in the dexamethasone suppression test in unipolar major depression.

Although considerable evidence exists on the efficacy of lithium as an augmenting agent in refractory depression, the underlying neurobiology of this phenomenon is unknown. In patients with major depression, changes of the hypothalamic-pituitary-adrenocortical (HPA) system have been detected by means of the dexamethasone suppression test (DST), when administered during treatment with tricyclic antidepressants. We investigated whether the DST also reveals alterations of the HPA system during lithium augmentation. We also sought to identify whether response to lithium augmentation can be predicted with the DST. Twenty-five patients with unipolar major depression, who did not respond to an adequate antidepressant monotherapy of at least 4 weeks, were measured for basal (pre-dexamethasone, 0800h) cortisol and ACTH levels and were administered the DST the day before initiation of lithium augmentation treatment. The same neuroendocrine procedures were repeated after 3 to 4 weeks. Criteria of response to lithium augmentation, defined as a reduction of the Hamilton Depression Rating Scale (HDRS17) score by > or =50% and an end point score of 9 or less, were determined by weekly HDRS ratings. The DST revealed a statistically significant increase of the post-dexamethasone cortisol values (P = 0.021) and an increase in the post-dexamethasone ACTH values (P = 0.051) during lithium augmentation as compared to pre-treatment baseline evaluations. The pre-dexamethasone hormone values were unchanged. The number of non-suppressors at baseline was one and increased to three at follow-up. Results of DST did not predict response to lithium augmentation, which occurred in 40% of subjects. Results suggest that lithium augmentation increases HPA system activity, as indicated by the increase of post-dexamethasone cortisol and ACTH levels measured by the DST. This is in contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants.

Adolescent↗
PubMed2007

Lithium therapy for unipolar and bipolar depression among the middle-aged and older adult patient subpopulation.

Affective disorders are a major cause of morbidity and disability among middle-aged and older people. Thus, the prophylaxis of both unipolar depression and bipolar disorder in this patient subpopulation is an important task of psychiatrists and other physicians. Although lithium remains an effective prophylactic and treatment agent in younger individuals with bipolar disorder, its prophylactic efficacy and tolerability has not been thoroughly investigated among middle aged and older people with unipolar depression and bipolar disorder. Our study is based on a mirror-image design that compared the clinical course with lithium treatment and the clinical course prior to lithium treatment based on a retrospective chart review. We examined the results obtained with long-term lithium maintenance in a group of 60 middle-aged and older adult patients (age >60 years) with unipolar depression and bipolar disorder. More specifically, we analyzed changes of frequency, severity, and duration of depressive or manic relapses, rate and duration of hospitalizations and suicidal behavior (thoughts or attempts), and various assessments of outcome. A significant reduction was found on all indices during lithium therapy compared to before lithium treatment, attesting to the prophylactic efficacy of long-term lithium in unipolar depression and bipolar disorder. The range of side effects in our sample was similar to that found in other reports in this age group. The probability of relapse and recurrence in patients with bipolar disorder and with unipolar depression can be significantly decreased by lithium prophylaxis. Further investigation is mandated to confirm these findings under double-blind conditions.

Adult↗
PubMed1995

Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells.

Lithium, which is used to treat bipolar psychiatric disorders, can stimulate proliferation of a number of cells in tissue culture. Proliferation of MCF-7 human breast cancer cells, which also respond to EGF and estrogens, was stimulated by LiCl (1-5 mM) within the concentration range that is encountered during human therapy with lithium. Stimulation of growth was specific for lithium; rubidium, potassium, and sodium showed no such effect. In the presence of antiestrogen, lithium stimulated the growth of hormone-dependent breast cancer cells MCF-7, ZR-75-1, and T47D but not hormone-independent MDA-MB-231 cells or an estrogen-independent clone of MCF-7 cells. Lithium-stimulated proliferation was limited by cytotoxicity which could be moderated by added potassium chloride (5-20 mM) in the medium. Each of the mitogens lithium, 17 beta-estradiol, and EGF increased the rate of uptake of myo-inositol into MCF-7 cells. Whether normalized to inositol lipids, to protein, or to DNA, steady-state levels of inositol phosphates were elevated by each of the mitogens including lithium, which inhibits the breakdown of inositol phosphates in the phosphoinositide signaling pathway. These data indicate that therapeutic concentrations of lithium can stimulate the proliferation of human breast cancer cells by a mechanism that may involve the phosphoinositide pathway.

Breast Neoplasms↗
PubMed2003

Dietary lithium induces regional increases of mRNA encoding cysteine string protein in rat brain.

Lithium salts are used to treat manic-depressive disorders; however, the mechanism by which lithium produces its therapeutic benefit remains obscure. The action of lithium may involve alterations of proteins important for regulating synaptic function. In this context, we observed recently that lithium at therapeutically relevant concentrations enhanced expression of cysteine string protein (csp) at the level of both mRNA and protein, in cell culture and in rat brain. Several lines of evidence have shown that csps are vital components of the regulated secretory pathway. We were interested whether lithium modulates expression of csp in specific brain regions. To study this issue, we analyzed the effects of chronic lithium administration (21 days) on csp mRNA levels in rat brain using in situ hybridization. Densitometric analysis revealed that lithium upregulated csp mRNA in several brain areas that are important for mood and behavior. This effect may be germane to understanding the beneficial action of lithium in mood disorders.

Animals↗
PubMed1991

Differential effect of lithium on fos protooncogene expression mediated by receptor and postreceptor activators of protein kinase C and cyclic adenosine monophosphate: model for its antimanic action.

Lithium salts are the most effective agents used in treating manic-depressive illness. It has been suggested that lithium's therapeutic efficacy could be due to an inhibitory effect on either inositol phospholipid (IP) and/or cyclic nucleotide metabolism. We have investigated the effect of lithium on these two signal transduction pathways in PC12 pheochromocytoma cells by studying a common effector target, expression of the fos protooncogene. We find that lithium, at therapeutic doses, has an augmenting effect on phosphatidylinositol (PI)-mediated fos expression induced by activating a muscarinic cholinergic pathway, whereas it has no effect, at tenfold the therapeutic dose, on fos expression induced by receptor or postreceptor activators of cyclic adenosine monophosphate (cAMP). The lithium augmenting effect is also observed when the cells are treated with phorbol esters, which directly activate protein kinase C (PKC), suggesting that the level of lithium's interaction with the IP pathway is at the postreceptor level. We also show that phorbol esters induce extensive down regulation of subsequent cholinergic and phorbol ester responsiveness as well as heterologous down regulation of cAMP responses. Treatment of down-regulated cells with lithium leads to an enhanced responsiveness when cells are rechallenged with agonists that activate PKC but not by agonists that stimulate cAMP. We also show that carbamazepine, another antimanic agent, has an inhibitory effect on cAMP-mediated fos but no effect on the IP pathway. The opposite effects of lithium and carbamazepine on two critical transducing systems suggest a model for the antimanic action of these agents.

Adrenal Gland Neoplasms↗
PubMed1995

Induction of apoptosis in HL-60 cells by lithium.

It has been established that lithium, a preferred drug for the treatment of manic depression, affects the growth of HL-60 cells. Concentrations of lithium above 10 mM were shown to be cytotoxic to these cells. However, the mechanism by which lithium induces its cytotoxicity is still obscure. In this study, we examined whether programmed cell death was involved in lithium cytotoxicity. Our findings show that lithium induced apoptosis in a time- and concentration-dependent manner. Morphological features and DNA fragmentation revealed that with 10 mM lithium, apoptosis was maximal at 72 hours of treatment. Interestingly, other monovalent ions were unable to elicit DNA fragmentation, suggesting that this phenomenon is specific for lithium. Cell cycle studies revealed that lithium arrested the cells at the G2/M phase.

Apoptosis↗
PubMed2001

Lithium suppresses signaling and induces rapid sequestration of beta2-adrenergic receptors.

Lithium is a monovalent cation used therapeutically to treat a range of affective disorders (1), although the cellular mechanisms of lithium regulation that might contribute to its therapeutic effects at the level of neurotransmitter receptors are not known. Herein we report the ability of lithium to stimulate the internalization of beta2-adrenergic receptors. Lithium treatment of A431 human epidermoid carcinoma cells resulted in a rapid, prominent desensitization and internalization of beta2-adrenergic receptors. The ability of these receptors to generate a cyclic AMP response was strongly inhibited by lithium, at concentrations therapeutic in humans. Receptors for the serotonin (5HT1c) and for opiates (mu-opioid), in sharp contrast, resisted the effects of lithium on internalization. These data provide the first receptor-based mechanism to be described for lithium that could explain, in part, the therapeutic effects of lithium on affective disorders.

Adrenergic beta-2 Receptor Antagonists↗
PubMed1988

Short-term lithium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding.

Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The Vmax of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (Vmax) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (Km) of [3H]-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients.

Adult↗