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PubMed1999

Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons.

This report describes a modulatory action of lithium and glutamate on the activity of serine/threonine kinase Akt-1. Lithium is most commonly used to treat bipolar disorder, but the mechanism of its therapeutic action remains unknown. We have recently demonstrated that lithium protects against glutamate-induced excitotoxicity in cultured brain neurons and in an animal model of cerebral ischemia. This study was undertaken to investigate the role of Akt-1, activated by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating glutamate excitotoxicity and lithium protection in cerebellar granule cells. High levels of phosphorylation and activity of Akt-1 were detected in cerebellar neurons cultured in the presence of serum. Protracted treatment with selective PI 3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced neuronal death that could be reduced by long-term lithium pretreatment. Exposure of cells to glutamate induced a rapid and reversible loss of Akt-1 phosphorylation and kinase activity. These effects were closely correlated with excitotoxicity and caspase 3 activation and were prevented by phosphatase inhibitors, okadaic acid and caliculin A. Long-term lithium pretreatment suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery toward the control levels. Lithium treatment alone induced rapid increase in PI 3-K activity, and Akt-1 phosphorylation with accompanying kinase activation, which was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt. Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of glutamate excitotoxicity and lithium neuroprotection.

Androstadienes↗

PubMed2004

Alteration of lithium pharmacology through manipulation of phosphoadenosine phosphate metabolism.

Bisphosphate 3'-nucleotidase (BPNT1 in mammals and Met22/Hal2 in yeast) is one of five members of a family of signaling phosphatases united through a common tertiary structure and inhibition by subtherapeutic doses of the antibipolar drug lithium. Here we report a role for 3'-nucleotidase and its substrate, 3'-phosphoadenosine 5'-phosphate (PAP), in mediating the cellular effects of lithium. Lithium-induced inhibition of growth in yeast cells may be overcome by dose-dependent heterologous expression of human BPNT1. Disruption of the yeast 3'-nucleotidase gene or treatment of cells with lithium results in a >80-fold accumulation of PAP and leads to potent growth inhibition. These data indicate that the accumulation of a 3'-nucleotidase substrate, such as PAP, mediates the toxicity of lithium. To further probe this model we examined the growth inhibitory effects of lithium under conditions in which PAP biosynthetic machinery was concomitantly down-regulated. Disruption of met3 or met14 genes (ATP sulfurylase or phosphosulfate kinase), transcriptional down-regulation of MET3 through methionine addition, or administration of chlorate, a widely used cell-permeable sulfurylase inhibitor, function to reduce lithium-induced intracellular PAP accumulation and lithium toxicity; all of these effects were reversed by heterologous expression of human sulfurylase and kinase. Collectively, our data support a role for 3'-nucleotidase activity and PAP metabolism in aspects of lithium's mechanism of action and provide a platform for development of novel pharmacological modulators aimed at improving therapies for the treatment of bipolar disorder.

Adenosine Diphosphate↗

PubMed1994

Lithium potentiates phosphoinositide-linked 5-HT receptor stimulation in vivo.

The therapeutic effect of lithium in manic-depressive illness may involve alterations in the activity of the phosphoinositide second messenger system. Lithium administration to rats potentiates responses to cholinergic agonists, as evidenced by the production of seizures in lithium-treated rats after normally nonconvulsant doses of cholinergic agonists. We now report that lithium also potentiates the response to a serotonin (5-HT) agonist, DOI, that activates 5-HT2/5-HT1C receptors coupled to phosphoinositide hydrolysis. EEG recordings showed that administration of DOI (8 mg kg-1) to lithium-treated, but not to lithium-naive, rats caused seizures which were blocked by ritanserin pretreatment. These results demonstrate that lithium pretreatment causes a normally subconvulsive dose of serotonergic, in addition to cholinergic, agonists to induce seizures. Since DOI, like cholinergic agonists, activates receptors coupled with phosphoinositide hydrolysis and lithium potentiates responses to each, this second messenger system is likely to be involved in this effect of lithium.

Amphetamines↗

PubMed1995

Untoward effects of lithium treatment in children aged four through six years.

OBJECTIVE: To explore the relationship between lithium dose and serum lithium level on the occurrence of untoward or toxic effects of lithium in the treatment of 20 hospitalized aggressive and/or mood-disordered children aged 4 through 6 years. METHOD: Clinical and research records of 20 children treated with lithium according to an established inpatient protocol were reviewed. Side effects as reported by psychiatric staff were categorized by organ system affected and severity. RESULTS: During the initial 2 weeks of lithium treatment, 60% of the children manifested one or more types of side effects, most commonly central nervous system effects. Side effects were seen at doses of 25.6 to 52.1 mg/kg per day and at serum levels from 0.65 to 1.37 mEq/L. In general, adverse effects were associated with higher lithium doses and lithium levels and were most common during the first week of treatment. A potential interaction between concurrent infection and more severe side effects was seen. CONCLUSIONS: Side effects occur frequently in children aged 6 years and younger during the initiation phase of lithium treatment; are related to higher milligram per kilogram doses, higher serum lithium levels, and phase of treatment; and may be related to concurrent medical illness.

Aggression↗

PubMed1985

A pharmacokinetic approach to the study of cell membrane lithium transport in vivo.

Although many previous investigations have focused on in vitro studies of lithium transport by erythrocytes (RBCs) of psychiatric patients, the extent to which such studies actually reflect the transport of this drug by other types of cells in vivo is unknown. To study lithium transport in vivo, pharmacokinetic analysis of plasma lithium concentration data was performed in four subjects who were given single oral doses of lithium carbonate (600 mg). The data were analyzed according to a two-compartment model, consisting of a central compartment (extracellular, including plasma) and a peripheral (intracellular) compartment. Rate constants for the transfer of lithium into (ki) and out of (ko) the intracellular compartment were calculated. In RBCs from the same subjects, lithium transport in vitro was also directly measured. Rate constants were determined for phloretin-sensitive transport (ks), which corresponds to Na+-Li+ countertransport activity, and residual passive "leak" diffusion (kr). In RBCs, these two pathways account for major components of lithium efflux and influx, respectively. To compare the in vivo and in vitro rate constant data, the ratios ko/ki and ks/kr were also calculated. There was a significant correlation between these two rate-constant ratios (r = 0.96, p less than 0.05), although the values observed in vitro were higher than those found in vivo. Because the in vivo rate constants reflect lithium transport by many types of cells in the peripheral compartment, this finding supports the idea that the RBC may provide a useful model for studying lithium transport processes that are also operative in other types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane Permeability↗

PubMed1998

Increased lithium serum and red blood cell concentrations during ketorolac coadministration.

Case reports of a lithium-ketorolac drug interaction have been published, but no formal investigation of this interaction has been conducted. The objective of the study presented here was to determine significant changes in lithium serum and red blood cell (RBC) concentrations after lithium and ketorolac (oral formulation) coadministration at steady-state conditions. Five healthy men participated in the study and received lithium 900 mg/day (300 mg in the morning and 600 mg at bedtime) for 13 days. Ketorolac 40 mg/day (10 mg four times a day) was added on days 8 through 12. Ten blood samples were obtained on days 7 and 13 to determine area under the concentration-time curve (AUC) lithium serum and RBC concentrations. Serum and RBC lithium concentrations were assayed by atomic absorption spectrophotometry with an intra-assay coefficient of variation (CV) of 1.2% on day 1 (range 0-1.0 microg/mL) and 4.9% (range 0-1.0 microg/mL) on day 2 and an interassay CV of 2.9% (range 0-1.0 microg/mL) on days 1 and 2 of serum analysis and a CV of 5.3% (range 0-0.3 microg/mL) of RBC concentrations. Total serum AUC lithium and RBC AUC values significantly increased by 24% (p < 0.02) and by 27% (p < 0.05) with the ketorolac coadministration, respectively. An increased incidence and severity of lithium-associated side effects were reported during concomitant administration. A clinically significant drug interaction can occur when ketorolac is added to lithium therapy.

Adult↗

PubMed1998

Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts.

One hundred patients who had attempted suicide before commencing lithium prophylaxis were followed up. Outcome was analyzed in terms of attempted or completed suicide after a mean of 10 years since admission to the lithium clinics. Of 10 patients who committed suicide, 9 had discontinued adequate lithium prophylaxis for a period ranging from 2 weeks to 7 years before death. Having discontinued lithium therapy was associated with suicide also in the subgroup of patients for whom lithium had not completely prevented episodes during lithium treatment. Suicide risk was 24 times as high during periods off compared with periods on adequate lithium prophylaxis. Incidence of attempting suicide was similar during the periods before receiving or after discontinuing lithium treatment, whereas it was 5 to 6 times lower during prophylaxis. Continuous and adequate lithium prophylaxis should be considered in the presence of high suicide risk, even if the prophylactic effect on the underlying mood disorder may be incomplete.

Adolescent↗

PubMed2002

Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine.

In a previous study, of 41 depressed patients who had not responded to fluoxetine 20 mg/day, 53% were treated with high-dose fluoxetine (40-60 mg/ day) and responded (i.e., their 17-item Hamilton Rating Scale for Depression [HAM-D-17] score was <7) versus 29% and 25% of patients treated with fluoxetine plus lithium (300-600 mg/day) or fluoxetine plus desipramine (25-50 mg/day), respectively. We wanted to assess whether these findings could be replicated in a larger sample of depressed outpatients. We identified 101 outpatients with major depressive disorder (52 men and 49 women; mean age, 41.6 + 10.6 years) who were either partial responders (n = 49) or nonresponders (n = 52) to 8 weeks of treatment with fluoxetine 20 mg/ day. These patients were randomized to 4 weeks of double-blind treatment with high-dose fluoxetine (40-60 mg/day), fluoxetine plus lithium (300-600 mg/day), or fluoxetine plus desipramine (25-50 mg/day). In the overall group of patients (N = 101), there was no significant difference in response rates across the three treatment groups (high-dose fluoxetine, 42.4%; fluoxetine plus desipramine, 29.4%; fluoxetine plus lithium, 23.5%). Dropout rates were also comparable, ranging from 9.1% (high-dose fluoxetine) to 14.7% (fluoxetine plus desipramine and fluoxetine plus lithium). There were also no significant differences in response rates across the three treatment groups among partial responders (high-dose fluoxetine, 50.0%; fluoxetine plus desipramine, 33.3%; fluoxetine plus lithium, 33.3%) and nonresponders (high-dose fluoxetine, 35.3%; fluoxetine plus desipramine, 26.3%; fluoxetine plus lithium, 12.5%). At the end of the study, the mean lithium level was 0.37 + 0.15 mEq/L (n = 27; range, 0.1-0.8 mEq/L) among lithium-treated patients, and the mean desipramine level was 104.7 + 58.8 ng/mL (n = 22; range, 25-257 ng/mL). There were no significant relationships between lithium or desipramine blood levels and degree of improvement (as measured by the change in HAM-D-17 score). We found no significant differences in efficacy among these three treatment strategies among patients who had failed to respond adequately to 8 weeks of treatment with fluoxetine 20 mg/day, although the high-fluoxetine group was associated with nonsignificantly higher response rates in both partial responders and nonresponders.

Adult↗

PubMed1986

Relations between erythrocyte lithium efflux, blood pressure and family histories of hypertension and cardiovascular disease: studies in a factory workforce and hypertension clinic.

Sodium-dependent lithium efflux was measured in erythrocytes from 399 factory workers and 125 patients attending a hypertension clinic. Thirty-two factory workers had unsuspected essential hypertension (diastolic blood pressure phase V greater than 90 mmHg). These subjects had the same average erythrocyte lithium efflux as those with normal blood pressure, whereas lithium efflux was increased on average in the clinic hypertensives. Lithium efflux was greater in those subjects from both groups who had a family history of high blood pressure. Our clinic hypertensives did not have raised lithium efflux when they were matched for family history; the increased lithium efflux in the group as a whole (and in analysis of published reports) was explained by an excess of subjects with a family history of hypertension. Furthermore, when a family history of hypertension was present, lithium efflux was increased on average only in those whose relatives also had a cardiovascular event associated with their high blood pressure. These results, in conjunction with detailed analysis of the distributions of lithium efflux within the groups, suggest that, though not linked to blood pressure itself, an increase in lithium efflux is an inherited marker for those at risk from the cardiovascular complications associated with high blood pressure.

Adolescent↗

PubMed2000

Lithium poisoning from a poison control center perspective.

The purpose of this study was to evaluate the severity of lithium poisoning from a poison control center-based population and the correlation of the Hansen and Amdisen classification with outcome and lithium levels in that setting. All lithium overdoses brought to the attention of the poison control center were prospectively observed during 1 year. Demographic data, amount ingested, coingestants, symptoms and signs, lithium levels, treatment, and outcome were recorded. There were 12 acute lithium overdoses: 5, 5, and 2 with grade 0, 1, and 2, respectively. No patients required hemodialysis or had sequelae or died. There were 174 acute-on-chronic overdoses: 66, 85, 15, and 8 with grade 0, 1, 2, and 3, respectively. Six patients underwent hemodialysis; none had sequelae but one died. There were 19 chronic poisonings: 9, 9, and 1 with grade 1, 2, and 3, respectively. Three patients underwent hemodialysis; one had sequelae and one died. Patients classified as grade 2 had higher lithium levels than those with grade 1 in patients with only lithium poisoning (3.08 +/- 0.77 vs. 2.09 +/- 0.91 mmol/L P = 0.03). The study concluded that morbidity (0.5%) and mortality (1%) associated with lithium poisoning are rarely observed. The Hansen and Amdisen classification does not appear to be a useful clinical tool to predict either morbidity or mortality and does not correlate well with lithium levels.

Acute Disease↗

PubMed1977

Age as a factor affecting lithium therapy.

1 We examined the case notes of 82 psychiatric out-patients (aged 21-84 years) receiving lithium prophylaxis and with steady-state plasma lithium levels. 2 The mean weight-related daily dose of lithium prescribed decreased by about 50% between the third and eight decades. 3 The corresponding steady-state plasma lithium levels showed a less marked tendency to decrease, this only being seen in the seventh and eighth decades. 4 In patients aged 50 years or over the daily lithium dose required to give a plasma level of 1 mmol l-1 (0.50 mmol kg-1) was significantly lower than that (0.65 mmol kg-1) in patients aged under 50 years (P less than 0¿5, Student's t-test). In patients aged 70-79 years this dose was 31% lower than in patients under 50 years. However, interindividual variation was great and it was estimated that age only contributed about 14% to the total interpatient variation. 5 Of the 36 patients under 50 years of age, 42% had minor lithium side-effects and 17% were not optimally controlled with lithium. The corresponding figures for the 46 'older' patients were 46% and 28%. 6 Generally the 50% dosage reduction seemed necessary to compensate for an age-related decrease in lithium excretion and to reduce lithium side effects to a level comparable to that acceptable in younger patients.

Adult↗

PubMed2004

The effect of inositol supplements on the psoriasis of patients taking lithium: a randomized, placebo-controlled trial.

BACKGROUND: Lithium carbonate is the most widely used long-term treatment for bipolar affective disorders, but its ability to trigger and exacerbate psoriasis can become a major problem in patients for whom lithium is the only treatment option. Inositol depletion underlies the action of lithium in bipolar affective disorders and there are good theoretical reasons why the use of inositol supplements might be expected to help this group of patients. OBJECTIVES: To determine whether inositol supplements improve the psoriasis of patients on lithium therapy. METHODS: Fifteen patients with psoriasis, who were taking lithium, took part in a randomized, double-blind, placebo-controlled, crossover clinical trial comparing the effect of inositol supplements with those of a placebo (lactose). Changes in the severity of their psoriasis were measured by Psoriasis Area and Severity Index scores recorded before and after the different courses of treatment. The effect of inositol supplements on the psoriasis of 11 patients who were not taking lithium was evaluated in the same way. RESULTS: The inositol supplements had a significantly beneficial effect on the psoriasis of patients taking lithium. No such effect was detected on the psoriasis of patients not on lithium. CONCLUSIONS: The use of inositol supplements is worth considering for patients with intractable psoriasis who need to continue to take lithium for bipolar affective disorders.

Adult↗

PubMed2005

Re-evaluation of randomized control trials of lithium monotherapy: a cohort effect.

OBJECTIVE: The reported reduction of lithium's efficacy in the prophylaxis of bipolar illness has been attributed to various factors, including diagnostic changes and heterogeneous study designs. We attempted to quantify the impact of pre-randomization enrichment designs and diagnostic drift on randomized controlled trials (RCTs) of lithium maintenance therapy. METHODS: Using the Cochrane RCT search filter, MEDLINE, EMBASE, and PSYCHINFO were searched (1966 to June 2004) for all available randomized studies using the text word 'lithium'. Studies of 1 year minimum duration in bipolar disorder involving lithium and placebo arms were identified. Superiority trials without a placebo arm, discontinuation and mirror image studies were excluded. Standardized scales were used to assess randomization and allocation concealment. RESULTS: Nine RCTs enrolling 1432 bipolar I and II patients, randomizing 341 to lithium and 386 to placebo were identified, with 705 reported pre-randomization dropouts. The pooled odds of remaining recurrence free in two non-enriched RCTS using Research Diagnostic Criteria (RDC) or Feighner criteria were 3.2:1 (95% CI 0.65--15.46) trending in favor of lithium over placebo, and 22.0:1 (95% CI 7.0--68.7) for three trials using lithium enrichment and excluding atypical bipolar disorder. The odds of remaining recurrence free using DSM-IV criteria and lamotrigine enrichment were 1.9:1 (95% CI 1.2-2.8). CONCLUSION: Lithium maintenance RCTs differ in patient selection, design, and outcome. A cohort effect can be associated with the use of pre-randomization enrichment phases and, to a lesser extent, with diagnostic drift, compromising straightforward comparisons across three decades of lithium monotherapy in bipolar illness.

Antipsychotic Agents↗

PubMed1993

Elevated phosphatidyl-CMP is not the source of diacylglycerol accumulation induced by lithium in NG108-15 cells.

Previous studies have shown that in the neuroblastoma x glioma hybrid cell line NG108-15 lithium is able to induce an increase in diacylglycerol levels. This effect was shown to be enhanced by the presence of bradykinin. Another striking effect of lithium was a marked gain in the level of the liponucleotide phosphatidyl-CMP. Increased phosphatidyl-CMP levels were detected in the presence of lithium alone but were considerably more pronounced in the presence of both lithium and bradykinin. These results are consistent with the inhibitory action of lithium on key enzymes of the degradation pathway of inositol phosphates, resulting in a decrease in cellular inositol content and in an elevation in levels of phosphorylated inositols. Comparison of the mass of the inositol phosphates and diacylglycerol showed that the lithium-induced diacylglycerol levels were substantially greater than would be expected from phosphoinositide hydrolysis alone. One possible reason for the increase in the level of diacylglycerol through the action of lithium is the reversal of the reaction for the formation of phosphatidyl-CMP. The resulting phosphatidic acid would then need to be further dephosphorylated to diacylglycerol. The lithium-induced elevation of phosphatidyl-CMP was prevented by addition of myo-inositol (10-30 mM), suggesting that the increase in liponucleotide level was due to depletion of cellular inositol. Under the same conditions the elevated diacylglycerol concentration remained unchanged. Consequently, phosphatidyl-CMP is not its source, and diacylglycerol may arise through an effect of lithium on the degradation of phospholipids other than phosphoinositides. The action of phospholipase C or D on phosphatidylcholine is the most likely mechanism.

Animals↗

PubMed1974

Effects of lithium ions on electrical activity in sympathetic ganglia of the bullfrog.

1 The mode of action of lithium on electrical activity in the sympathetic ganglia of the bullfrog has been studied by recording extracellular and intracellular potential changes. Changes in nerve conduction and various types of synaptic transmission were studied when sodium ions in the external solution were totally replaced by equimolar concentrations of lithium ions and also when lithium ions were added to the external Ringer solution.2 Nerve conduction and nicotinic transmission in sympathetic ganglia were completely blocked in sodium-free sucrose solution, but were restored when the preparations were transferred to a sodium-free lithium solution.3 In the sodium-free lithium solution, the slow excitatory postsynaptic potential (e.p.s.p.) and muscarinic acetylcholine-depolarization were restored while the slow inhibitory postsynaptic potential (i.p.s.p.) and the muscarinic acetylcholine-hyperpolarization were not restored. Furthermore, the early after-discharges were accelerated and the inhibition of after-discharges was eliminated. These results support the hypothetical concept that the slow i.p.s.p. is generated by an activation of the electrogenic sodium pump.4 In the sodium-free lithium solution, restoration of nerve conduction and synaptic transmission were transient phenomena; both conduction and transmission were gradually blocked when preparations were soaked in the solution for long periods. The blockade appeared to be due to membrane depolarization.5 When lithium ions (20 mM) were added to the Ringer solution, nicotinic transmission was depressed. The slow e.p.s.p. was also depressed, but less so than the slow i.p.s.p. The early after-discharge was, however, accelerated; presumably due to the marked depression of the slow i.p.s.p. in this solution.6 Changes in synaptic transmission in Ringer solution containing lithium ions could be explained by membrane depolarization, a reduction of acetylcholine release and a depression of the electrogenic sodium pump.7 All results obtained in the present experiments could be explained by supposing that lithium ions are able to substitute for sodium ions in passive ionic membrane transport dependent on electrochemical energy but not in active ionic membrane transport dependent on metabolic energy.

Action Potentials↗

PubMed1993

Lithium and peripheral nervous system function in manic-depressive patients.

INTRODUCTION: Lithium salts are widely used in treatment of affective disorders, but lithium may cause electrophysiologically detectable changes in peripheral nervous system even with lithium concentrations within recommended therapeutic limits. The risk of lithium treatment against other risks to peripheral nervous system in psychiatric patients with affective psychoses was tested in our study. MATERIAL AND METHOD: Electrophysiologic parameters of motor and sensory peripheral nerve fibre function were measured in two age-matched groups of psychiatric patients (20 lithium-treated and 20 affective psychotic patients without lithium treatment) and a group of 20 healthy age-matched volunteers. RESULTS: Lower amplitudes of M waves (p < 0.015) and sensory nerve action potentials (p < 0.020) on stimulation of the median nerve have been found in both groups of patients. On peroneal nerve stimulation lower M wave amplitudes have been found only in the group of lithium-treated patients (p < 0.055). No significant differences in conduction parameters of motor and sensory fibres were demonstrated. CONCLUSION: Our results demonstrate subclinical involvement of motor and sensory axons in affective-psychotic patients, which is only slightly more pronounced in lithium-treated patients. We suggest that lithium (within therapeutic plasma concentrations) is just one among the factors leading towards minor axonopathy in psychiatric patients.

Adult↗

PubMed1976

An evaluation of the double-blind design in a study comparing lithium carbonate with placebo.

As part of a study of drug treatment of aggressive behavior to be reported separately, we have evaluated the double-blind procedure in a recently completed comparison of the efficacy of lithium carbonate versus placebo in modifying aggressive behavior in nonpsychotic incarcerated delinquents. We conclude that the side effects of lithium carbonate are sufficient to reveal the medication to most subjects receiving it. Thus, while the study staff could not identify lithium-receivers at better than chance levels, and while subjects who received placebo could not identify their medication at better than chance levels, subjects who received lithium could accurately identify it. On a weekly symptom check list there was no difference between lithium and placebo groups on average lithium target symptoms reported during 4-week pre- and postmedication control periods; however, lithium-receivers reported significantly more target symptoms every week medication was administered. Of 16 subjects who quit the study, 14 had received lithium and nearly all of those who gave reasons for quitting specified side effects, most often nausea. The methodological problems of using lithium in a double-blind design might be overcome by employing a "discontinuation" design, or, speculatively, a double-blind, cross-over design utilizing an "active placebo".

Adolescent↗

PubMed1979

Lithium treatment and kidney function. A survey of 237 patients in long-term treatment.

Kidney function has been examined in 237 patients who in the autumn of 1977 were in lithium treatment at the Psychiatric Hospital in Risskov, most of them as outpatients. The average age was 42 years. The patients had been given lithium treatment for 0.5-17 years, mean duration 5 years. The mean lithium dosage was 33 mmol/day and the mean 12-hour serum lithium concentration 0.85 mmol/l. Glomerular filtration rate was assessed through determination of 24-hour creatinine clearance and serum creatinine, in some cases iothalamate clearance. Water excretion was assessed through determination of 24-hour urine volume and in some cases urine osmolality after 26 hours of fluid deprivation. Creatinine clearances, serum creatinine concentrations, and urine volumes were subjected to multiple regression analysis with various clinically relevant predictor variables. Affection of glomerular filtration rate was only moderate and progressed slowly. The data indicate that the risk of renal insufficiency and terminal azotemia is remote even when lithium is given for many years. A large number of the patients had altered water excretion with polyuria or lowered urine concentrating ability or both. Due to the extra fluid loss these patients are apt to develop dehydration, and they may then be in danger of lithium poisoning. We hypothesize that lithium-induced changes of kidney function may become less frequent and less pronounced if patients are maintained at serum lithium levels somewhat lower than those employed in the group studied here. We recommend careful monitoring of serum lithium levels, regular control of kidney function, and extra caution when physical illness or additional drug treatment may lead to disturbance of fluid and electrolyte balance.

Adult↗