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PubMed1975

[Mechanism of action and kinetics of lithium. I. Biochemical and experimental pharmacological findings after administration of lithium-conclusions on the mechanism of the therapeutic effect of lithium].

A comprehensive consideration of biochemical and pharmacodynamic lithium (Li) effects enabled an explanation of the Li mechanism (Fig 1). According to this concept, Li might possibly affect the activity of membrane-bound ATPases in dependence on the initial situation, dose and duration of application. Research into Li-kinetics suggested the participation of active process in the transport of the ion through the organism. Li-kinetics describes distribution within a multiple-compartment system and, with the exception of the resorption phase, its independent of the anion used. The elimination (half-life time 22 to 25 hrs) is limited by backward flow form the tissue.

Adenosine Triphosphatases↗
PubMed1982

Lithium effects on rat brain glucose metabolism in vivo. Effects after administration of lithium by various routes.

The effects of lithium on several brain energy metabolites were investigated in rats. Lithium was administered by three alternative routes: 1) in food, 2) via IP injection, or 3) intracisternally via the suboccipital route. Lithium given in food induced permanent changes, mainly in glycolytic processes and in glycogen content. Lithium injected IP induced, in addition, several changes which depended on the increase in brain lithium concentration following injection of lithium. These changes in brain metabolites disappeared as brain lithium concentration stabilized. Intracisternal injection of lithium produced brain lithium concentrations between 1 and 2 mmoles/kg wet wt., with a mean of about 1.6 mmoles/kg wet wt. Lithium concentrations below about 1.6 mmoles/kg wet wt. induced changes in brain metabolites which were similar to the changes seen after IP injection of lithium. Lithium concentrations above about 1.6 mmoles/kg wet wt. induced changes in several brain metabolites which were at variance with the changes induced by lower lithium concentrations. These changes were in many respects similar to changes in brain metabolites seen in rats exposed to convulsive treatment. It is hypothesized that such metabolic changes during lithium treatment, in discrete areas of the brain with higher concentration of lithium, e.g., hypothalamus, might be related to the prophylactic effect of lithium treatment in man.

Animals↗
PubMed2002

Effect of background serum lithium concentrations on the accuracy of lithium dilution cardiac output determination in dogs.

OBJECTIVES: To assess the effect of increasing serum lithium concentrations on lithium dilution cardiac output (LiDCO) determination and to determine the ability to predict the serum lithium concentration from the cumulative lithium chloride dosage. ANIMALS: 10 dogs (7 males, 3 females). PROCEDURE: Cardiac output (CO) was determined in anesthetized dogs by measuring LiDCO and thermodilution cardiac output (TDCO). The effect of the serum lithium concentration on LiDCO was assessed by observing the agreement between TDCO and LiDCO at various serum lithium concentrations. Also, cumulative lithium chloride dosage was compared with the corresponding serum lithium concentrations. RESULTS: 44 paired observations were used. The linear regression analysis for the effect of the serum lithium concentration on the agreement between TDCO and LiDCO revealed a slope of -1.530 (95% confidence interval [CI], -2.388 to -0.671) and a y-intercept of 0.011 (r2 = 0.235). The linear regression analysis for the effect of the cumulative lithium chloride dosage on the serum lithium concentration revealed a slope of 2.291 (95% CI, 2.153 to 2.429) and a y-intercept of 0.008 (r2 = 0.969). CONCLUSIONS AND CLINICAL RELEVANCE: The LiDCO measurement increased slightly as the serum lithium concentration increased. This error was not clinically relevant and was minimal at a serum lithium concentration of 0.1 mmol/L and modest at a concentration of 0.4 mmol/L. The serum lithium concentration can be reliably predicted from the cumulative lithium dosage if lithium chloride is administered often within a short period.

Animals↗
PubMed1986

Erythrocyte lithium transport during lithium treatment in patients with affective disorders.

Erythrocyte lithium transport mechanisms--lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium efflux (PLE)--were measured in 46 patients with bipolar affective disorder on prophylactic lithium therapy and in 20 healthy control subjects. Maximal velocity of LSC measured at saturating intracellular lithium concentration was lower in the patients than in the controls; this may concur with previous reports on possible links between impaired activity of LSC and bipolar affective illness. When measured at therapeutic lithium concentration, LSC was 4 times lower and Km for LSC was 5 times higher in lithium-treated affective patients than in control subjects. The in vivo erythrocyte:plasma lithium ratio was inversely correlated with LSC in lithium-treated patients; higher ratios were found in females than in males. No differences were found between affective patients and control subjects in other erythrocyte lithium transport measurements. The values for lithium transport were not related to age, duration of lithium therapy, concomitant neuroleptic treatment, hypertension or obesity. Lower activity of LSC was found in patients with lithium-induced thyroid enlargement than in the other patients. The results obtained are discussed in the light of contemporary findings concerning erythrocyte lithium transport mechanisms in affective disorders and other conditions.

Adult↗
PubMed1998

Long-term outcome of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients at a lithium clinic.

OBJECTIVE: In this prospective study, information was collected on all bipolar I patients who started lithium prophylaxis at a lithium clinic during more than 15 years. METHOD: Patients were evaluated bimonthly with standardized instruments for as long as they took lithium. Treatment surveillance conformed to internationally accepted guidelines. Five years after starting prophylaxis, each patient was contacted for a follow-up interview. RESULTS: Of the 402 enrolled patients, 27.9% were no longer taking lithium at follow-up; 38.1% were taking lithium and had had at least one recurrence of the disorder; and 23.4% were taking lithium and had had no recurrence. Among patients still taking lithium whose plasma lithium levels had been below 0.5 mmol/liter on no more than 10% of checks, 88.0% had at least a 50% reduction in mean annual time spent in the hospital compared to a reference pretreatment period, and 43.0% had had no recurrence. Patients not taking lithium at follow-up had a poorer outcome than those taking lithium, but patients no longer taking any psychotropic drug did not differ from those taking lithium. Patients no longer taking lithium had had a higher frequency of psychotic features in the index episode than those still taking lithium. CONCLUSIONS: The impact of lithium prophylaxis on the course of bipolar disorder is severely limited by the high dropout rate. In bipolar patients taking lithium regularly for several years, a drastic reduction of time spent in the hospital is almost the rule; these patients represent a self-selected population in which at least one group at high risk of poor outcome is under-represented.

Adolescent↗
PubMed1998

Use of sodium polystyrene sulfonate for reduction of plasma lithium concentrations after chronic lithium dosing in mice.

OBJECTIVES: Previous studies have shown that oral sodium polystyrene sulfonate lowers plasma lithium concentrations after acutely administered oral doses of lithium chloride. However, a significant proportion of lithium overdose cases resulting in morbidity and mortality are those in which exposure to lithium is chronic. This study was designed to determine whether multiple oral doses of sodium polystyrene sulfonate are effective in reducing plasma lithium concentrations after chronic dosing. DESIGN: Placebo-controlled animal study. INTERVENTIONS: One hundred thirty mice were given 75 mM lithium chloride in their drinking water for a period of 14 days. At the end of that period, half of the animals were given orogastric sodium polystyrene sulfonate at 5 g/kg/dose 0, 60, 120, 180, and 360 minutes after the cessation of lithium chloride; the remaining half received orogastric water at equivalent times. Subgroups of each group were sacrificed at 90, 150, 330, 480, 1440, and 2880 minutes after lithium chloride cessation and plasma analyzed for lithium content. Lithium concentrations were compared by analysis of variance and single degree of freedom contrasts. Significance was set at an alpha level of 0.05. RESULTS: Lithium concentration was lower overall in the animals treated with sodium polystyrene sulfonate (p < .0001) and specifically at 150, 330, and 480 minutes after lithium chloride cessation (p < .05). CONCLUSIONS: Repetitive oral doses of sodium polystyrene sulfonate effectively lowered plasma lithium concentrations. Further study may ultimately define a role for the use of sodium polystyrene sulfonate in the treatment of patients with chronic lithium toxicity.

Administration, Oral↗
PubMed2002

Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data.

OBJECTIVE: Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. METHOD: In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. RESULTS: In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence. CONCLUSIONS: The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels > or =0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder.

Adult↗
PubMedDate not supplied

[Long-term administration of lithium carbonate: experience based on a case of 25-year-long treatment with lithium].

In the beginning of 1960s, initial reports appeared pointing to a possibility of preventing depressive and manic recurrences in affective illness by means of long-term administration of lithium salts. Subsequent several years of controlled studies confirmed such prophylactic effect of lithium in affective illness beyond any doubt. Some patients in whom lithium administration was started in the beginning of 1970s may, by now, have received lithium for more than twenty years. The patient reported in the present paper, had began lithium treatment on April 1, 1971, after her third depressive episode since 1965. During 25 years of uninterrupted lithium carbonate administration in daily dose 1000 mg (for 5 years-750 mg) and with mean serum lithium concentration 0.6 mmol/l, the recurrences have not been observed, mental status was normal and professional (physician-ophthalmologist) and family functioning was good. Either somatic or mental side-effects have not occurred. Twenty five years of the patient's lithium treatment, was paralleled by important events for lithium therapy such as, i.a., autobiographies of prominent persons receiving lithium for porphylactic purposes, definition of a new category of psychotropic drugs (normothymic) with lithium as a prototype, establishing some mechanism of lithium action on intracellular transmission, discovery of antiviral and immunomodulatory effect of lithium as well as finding of decreased mortality of patients receiving long-term lithium therapy.

Depressive Disorder↗
PubMed1996

Twelve-hour brain lithium concentration in lithium maintenance treatment of manic-depressive disorder: daily versus alternate-day dosing schedule.

The 12-h brain lithium concentration was measured by lithium-7 magnetic resonance spectroscopy in ten manic-depressive patients receiving daily or alternate-day lithium carbonate treatment. The median dose of lithium carbonate was 800 mg in the daily treatment group and 1200 mg in the alternate-day group. Median 12-h serum lithium concentration in the two groups was 0.86 mmol l-1 and 0.55 mmol l-1, respectively, while the corresponding concentration in brain was 0.67 mmol l-1 and 0.52 mmol l-1, respectively. The 12-h brain lithium concentration was independent of lithium dosing schedule (multiple linear regression), but correlated significantly with the 12-h serum lithium concentration (P = 0.003; B = 0.53, 95% c.l. 0.24-0.82; beta = 0.83). Thus at identical 12-h serum lithium concentrations the 12-h brain lithium concentration is similar with both treatment regimes. As the risk of manic-depressive relapse during alternate-day lithium treatment is in our experience 3-fold greater than with daily treatment (at similar mean 12-h serum lithium concentration), the findings suggest that the difference in the prophylactic efficacy of the two dosing schedules is unrelated to differences in the 12-h brain lithium concentration.

Adult↗
PubMed1980

The influence of external sodium and potassium on lithium uptake by primary brain cell cultures at "therapeutic" lithium concentration.

The ionic regulating of lithium homeostasis and steady-state intra:extracellular lithium distribution in the brain can be approached by experimental methods using intact nerve cells in vitro. Primary cultures prepared from chick embryonic brain were applied to study the effect of extracellular sodium and potassium on the lithium uptake of nerve cells at 'therapeutic' lithium concentration (1.5 mM). Lithium influx and the level of steady-state intracellular lithium were significantly reduced by increasing the external sodium concentration. At physiological extracellular sodium level, the steady-state content of lithium in the brain cells was about half of that observed in the presence of 10 mM sodium in the incubation media and the value of the intra:extracellular lithium distribution ratio was below 1. External potassium (0.5 - 3mM) strongly inhibited lithium uptake of the nerve cells. Ouabain (10(-4)M) had no effect on this potassium-sensitive lithium uptake in Tyrode media. Sodium influx studied by isotope tracer methodology was higher in cultures preloaded with lithium as compared to that of the controls. It can be concluded that sodium and potassium ions, at physiological concentrations, significantly influence lithium uptake as well as the intra:extracellular lithium distribution in brain cell cultures.

Animals↗
PubMed1980

Renal concentrating capacity in long-term lithium treatment and after withdrawal of lithium.

The urinary concentrating capacity was estimated with the DDAVP test in 87 patients receiving lithium therapy, which was discontinued in all patients. The test was repeated three and eight weeks after withdrawal of lithium in 75 patients and one year after withdrawal in 27 patients. Of the 87 patients, 52 were also treated with neuroleptics, which treatment was continued throughout the study. Two control groups, consisting of 30 patients receiving only neuroleptics and 30 healthy subjects, were studied on one occasion with the DDAVP test. Lithium-treated patients had significantly lower concentrating capacity and higher serum creatinine than healthy subjects at all examinations. Small but statistically significant correlations were found between urinary osmolality and total dose of lithium, between urinary osmolality and duration of lithium treatment, between the highest serum lithium concentration recorded and urinary osmolality after withdrawal of lithium and between the daily dose of lithium and urinary osmolality, while patients were still on lithium. The concentrating capacity improved significantly during the first two months after withdrawal of lithium, but not later. One year after withdrawal of lithium, 17 of 27 patients still had a concentrating capacity below 800 mOsm/kg. Patients receiving lithium and neuroleptics had lower concentrating capacity than patients treated with lithium alone, and patients treated with neuroleptics alone had lower concentrating capacity than healthy subjects.

Adult↗
PubMed1998

Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels.

The purpose of the study was to examine the outcome of long-term lithium treatment in consecutively admitted affective disorder patients assigned to high and low serum lithium levels. A total of 91 patients were diagnosed according to DSM-III criteria and randomly allocated to two open treatment groups in which prophylactic lithium was administered in high (serum lithium 0.8-1.0 mmol L-1) and low (serum lithium 0.5-0.8 mmol L-1) doses, respectively. The patients were followed for 2 years or until discontinuation of lithium treatment or readmission to hospital for recurrence of affective illness. The main outcome of the treatment groups was compared with Kaplan-Meier survival curves and by Cox regression analysis. A total of 31 patients (34%) completed 24 months of prophylactic lithium treatment without recurrence and readmission to hospital. In total, 18 patients (20%) suffered a recurrence on lithium, and 42 patients (46%) discontinued lithium or were lost to follow-up. No effect of treatment group was seen, either for the total patient group or for the large subgroup of bipolar patients when analysed separately. A number of patients did not maintain their original assignment to the high serum lithium levels group. The results were analysed both according to assignment and according to actual serum lithium levels. Abuse of alcohol or medication was associated with a poor outcome. Only one third of the patients completed 2 years of lithium prophylaxis successfully. No difference in the protection against recurrences was observed between patients maintained on high and low serum lithium levels.

Adult↗
PubMed1978

Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate.

Eight hours after intraperitoneal injections of 1.0, 2.0, and 4.0m equiv Li kg-1, the serum and brain lithium concentrations of rats were significantly greater after lithium orotate than after lithium carbonate. While little serum lithium remained at 24 h after injection of 2.0 m equiv kg-1 lithium carbonate, two-thirds of the 2 h serum lithium concentration was present 24h after lithium orotate. Furthermore, the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate. These data suggest the possibility that lower doses of lithium orotate than lithium carbonate may achieve therapeutic brain lithium concentrations and relatively stable serum concentrations.

Animals↗
PubMedDate not supplied

Alterations of lithium clearance in rats by different modes of lithium administration.

This study examines the effects of acute versus dietary lithium administration on proximal tubular fluid output (Vprox) and sodium clearance in 6 groups of unrestrained, conscious rats. Vprox was estimated on the basis of the renal lithium clearance. The aim was to find the mode of lithium administration which least influences the proximal and distal reabsorption of sodium. The lithium doses used resulted in serum lithium concentrations between 0.2 and 0.3 mmol/l with no difference between the groups. Acute intravenous lithium administration increased lithium clearance by 40% and sodium clearance by 109%. Administration by gastric tube increased lithium clearance by 22% and sodium clearance by 78% in comparison to dietary administration of lithium. Potassium excretion did not change by acute lithium administration. The data presented indicate that prior to measurements of lithium clearance, lithium should be administered in the diet for 2 days, since acute lithium administration, intravenously or by gastric tube, causes great changes in renal tubular reabsorption.

Administration, Oral↗
PubMed1993

Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses.

Thirty-four patients with tricyclic-resistant depressive illness took part in a nine-week, double-blind, placebo-controlled trial of lithium augmentation. In addition to the maximum tolerated doses of their tricyclic antidepressant, the experimental group (n = 16) received 250 mg lithium daily for three weeks, followed by 750 mg lithium daily for six weeks, while the controls (n = 18) received placebo for three weeks followed by three weeks each of 250 mg lithium daily and 750 mg lithium daily. There was no significant difference between placebo and 250 mg lithium for weeks 0-3 of the trial. However, there was a significantly greater improvement on the MADRS for weeks 3-6 for those subjects on 750 mg lithium than for those on 250 mg lithium. In addition, using a 50% fall in the HRSD as a criterion of drug responsiveness, 22% responded to placebo, 18% to 250 mg lithium, and 44% to 750 mg lithium. Thus, lithium in normal, but not in low, dose has a significant antidepressant effect in TCA-resistant depression. Further controlled studies using lithium in normal dose in trials which have a greater duration of placebo exposure are required to confirm the lithium augmentation effect.

Adult↗
PubMed1979

Syncope caused by lithium treatment. Report on two cases and a prospective investigation of the prevalence of lithium-induced sinus node dysfunction.

Lithium salts have been widely used for several years in the treatment of manic-depressive psychosis. Various side-effects of lithium salts have been described. The present case report present two patients in whom sinus node dysfunction leading to syncope was caused by lithium. One of the cases showed signs of depressed sinus node function even when not on lithium, but no symptoms arose until lithium treatment was commenced. The second case showed no signs of depressed sinus node function when lithium was withdrawn. To study the prevalence of sinus node dysfunction in patients on lithium therapy, 97 consecutive patients on lithium were examined. The examination included case history, ECG and carotid massage. In two patients lithium could not be ruled out as being responsible for sinus node depression and in one patient the same was true for the atrioventricular node. None of these patients had any symptoms. It is concluded that lithium treatment may result in sinus node dysfunction. This side-effect is, however, not common. Lithium treatment can obviously be instituted in all patients without a history suggesting sinus node dysfunction. Patients with a history of dizziness and/or syncope should not be given lithium until thorough cardiological examination has been carried out. Likewise, a cardiological examination should be performed if patients on lithium develop symptoms of this type.

Aged↗
PubMed1979

The relationship of the lithium erythrocyte: plasma ratio to plasma lithium level.

The relationship of the lithium erythrocyte:plasma ratio to plasma lithium concentration was reviewed in inpatients and outpatients with affective disorders. For some patients, there was a linear correlation between the erythrocyte lithium:plasma lithium ratio and the plasma lithium concentration. For these patients a graph of the slopes and intercepts of the lithium erythrocyte:plasma ratio vs. plasma lithium data formed a line that was not significantly different from the data of Lee et al. (1975). Significant correlations were found between the slopes and intercepts of the lithium erythrocyte:plasma ratio vs. plasma lithium data and the magnitude of active lithium efflux (Ko) from the erythrocyte. Our data confirm the finding of Lee et al. (1975) that the lithium erythrocyte:plasma ratio is dependent on the plasma lithium concentration. We relate this finding to lithium efflux from the erythrocyte.

Adult↗
PubMedDate not supplied

Kinetics of erythrocyte lithium-sodium countertransport in patients with affective illness before and during lithium therapy.

Previous investigations have elucidated an erythrocyte lithium-sodium countertransport (LSC) system as the primary mechanism for extruding lithium from the cell, and this activity has been described in terms of Michaelis-Menten kinetics. In most clinical studies the maximum velocity (Vmax) of the LSC has been measured by estimating the rate of lithium efflux from lithium-loaded cells. To date, few studies have examined whether the affinity (Km) of the LSC for lithium might be altered in patients with affective disorders. In the present study we examined LSC kinetic parameters (Vmax, leak, Km, and in vitro lithium ratio) at baseline in 80 patients with affective disorder and 25 healthy control subjects, and after 6 weeks of lithium administration in 33 of the patients. No differences in Vmax were observed between any patient and control group, although Vmax was significantly lower in unipolar depressed men compared to bipolar men (P = 0.043). The affinity (Km) of the transport 'carrier' for lithium did not differentiate between patient and control groups. Chronic lithium administration caused a decreased Vmax in bipolar men (P = 0.015), an increase in the in vitro lithium ratio in bipolar men (P = 0.002) and bipolar women (P = 0.002), and a marginal increase in Km in bipolar men (P = 0.08) and bipolar women (P = 0.06). Although the present data do not demonstrate an underlying difference for Km between affectively ill patients and controls, they do indicate a decrease in the affinity of the transport 'carrier' for lithium after chronic lithium administration.

Adult↗