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PubMed2006

Lithium as adjuvant to radioiodine therapy in differentiated thyroid carcinoma: clinical and in vitro studies.

OBJECTIVE: Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS). DESIGN: In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mM for 0-48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well. RESULTS: Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed. CONCLUSIONS: The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.

Adjuvants, Pharmaceutic↗
PubMed1976

Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats.

1 The pharmacokinetics of the lithium ion administered as lithium orotate were studied in rats. Parallel studies were carried out with lithium carbonate and lithium chloride. 2 No differences in the uptake, distribution and excretion of the lithium ion were observed between lithium orotate, lithium carbonate and lithium chloride after single intraperitoneal, subcutaneous or intragastric injections (0.5-1.0 mEq lithium/kg) or after administration of the lithium salts for 20 days in the food. 3 The findings oppose the notion that the pharmacokinetics of the lithium ion given as lithium orotate differ from lithium chloride or lithium carbonate. 4 Polyuria and polydipsia developed more slowly in rats given lithium orotate than in those given lithium carbonate or lithium chloride, perhaps due to an effect of the orotate anion.

Animals↗
PubMed2002

Lithium in bipolar disorder: can drug concentrations predict therapeutic effect?

The evidence is reviewed for effective serum lithium concentrations for the acute and prophylactic treatment of mania and depression in patients with bipolar disorder. The efficacy of lithium in the treatment of acute manic episodes has been recognised for several decades, primarily using concentrations in the range of 0.8 to 2 mmol/L. The number of patients responding increases as the serum lithium concentration increases, although individual patients may respond at lower concentrations (<0.8 mmol/L). Lithium doses and serum concentrations similar to those used to treat acute mania have been studied in bipolar depression, with no evaluation of a relationship between concentration and clinical response. Several prospective controlled trials have evaluated this relationship in the prophylactic treatment of bipolar disorder. Maintaining higher serum lithium concentrations (0.8 to 1 mmol/L) improves the likelihood of good effect in prophylactic treatment, although individual patients may do well on lower concentrations. Despite the paucity of evidence to specifically support the efficacy of lithium at lower serum lithium concentrations in the elderly, lower target ranges (0.5 to 0.8 mmol/L) are commonly recommended due to an increased sensitivity to adverse effects, particularly neurotoxicity. The serum lithium concentrations recommended in adults have been applied to children; however, this has not been studied. Overall, the evidence suggests a relationship between serum lithium concentration and therapeutic effect, although the exact nature of this relationship is not clear. For example, it is not known why some people respond to lower concentrations and others do not. There are many factors that influence studies trying to elucidate this relationship. Many of these factors are related to the interpretation of the serum lithium concentration. In summary, patients have an increased chance of responding to lithium if 12-hour serum lithium concentrations at steady state are above 0.8 mmol/L. Many patients will respond to lower concentrations (0.4 to 0.7 mmol/L), but we are unable to identify these patients a priori. The relationship between serum lithium concentrations and adverse effects is also very important in determining appropriate target lithium concentrations. The current best advice is to individualise the target serum lithium concentrations based on efficacy and tolerability and to optimise the interpretation of these concentrations by ensuring within-patient consistency with respect to dosage schedule, lithium preparation and the timing of blood sampling.

Adolescent↗
PubMed1994

24-hour lithium concentration in human brain studied by Li-7 magnetic resonance spectroscopy.

Brain and serum lithium concentrations were measured every second hour during a 24-hr period following lithium intake, and again 48-hr later in two normal subjects in steady state lithium treatment receiving lithium carbonate (Priadel Synthelabo) once every evening. The brain-lithium concentration was measured by 7Li magnetic resonance spectroscopy (MRS). The brain lithium level was found to undulate in a peak-trough pattern that followed the serum lithium profile, although in an attenuated form. The brain/serum lithium concentration ratio varied considerably during the 48-hr period, ranging from 0.5 to 1.3, but the ratio was independent of the serum-lithium concentration. The median half-life for lithium was 28 hr in the brain, and 16 hr in serum. The brain lithium concentration in the morning was about 75% of the clinically relevant standard 12-hr serum lithium concentration. The finding that brain lithium undulates during the day means that MRS measurements of brain lithium can only be compared if carried out under standard conditions that include a fixed interval following lithium intake and an identical treatment regimen.

Adult↗
PubMed2004

7Li MR measures of blood lithium--correlation with chemical analysis data.

Lithium is used in the treatment and prophylaxis of manic-depressive illness. A narrow therapeutic range of lithium (0.4-1.2 meq/l) requires constant monitoring of these levels to avoid neurotoxicity and overdose. It is general practice to measure plasma lithium levels as a guide to monitor the therapy. Efforts to predict the concentration of Li at its active sites in the brain have led to the use of red blood cells (RBCs) because they are similar to neuronal cells. Thus RBC lithium is a very relevant clinical parameter for monitoring therapy and to observe the changes at intracellular levels under varying treatment conditions. A measure of both plasma and RBC lithium may be of significant value to physicians and researchers as lithium profile for RBCs correlate more closely with the brain lithium than plasma lithium. Although methods to measure lithium in blood such as atomic absorption or flame photometry exist, a complete quantitation of both plasma and RBC lithium requires a tedious physical separation of the two components prior to chemical analysis. On the other hand, lithium MR technique, via the use of shift reagents, can provide both plasma and RBC lithium in a single study. Here we have performed a correlation study of lithium results obtained from MR with the vitros dry-slide method on blood samples from rats treated with lithium. The results show a high degree of correlation between the two methods. Additionally, the MR measurements made on dilute samples of blood indicate that small blood samples with lithium concentration in the neighborhood of 0.08 meq/l can be measured with high accuracy and reproducibility needed for clinical purposes.

Animals↗
PubMed1989

Evaluation of lithium clearance as a marker of proximal tubule sodium handling.

Estimations of proximal tubule sodium reabsorption with the FELi method come closer to direct measurements than any other indirect method. There is little doubt that most lithium reabsorption takes place in the proximal tubules, very likely in proportion to the reabsorption of sodium and water. It is also likely that changes in proximal tubule sodium reabsorption due to changes in volume status are paralleled by changes in proximal tubule lithium reabsorption, at least in the superficial nephrons. Nonetheless, changes in FELi probably do not purely reflect changes in proximal reabsorption, since lithium is also handled beyond the proximal tubules. Acknowledged problems are lithium reabsorption in Henle's loop and in the late distal and collecting tubules. The latter occurs in the rat and the dog, but not or much less in men. Sodium restriction enhances this lithium transport considerably. It is as yet uncertain whether other conditions, such as increased vasopressin activity or lowering of renal perfusion pressure, also influence this transport. Amiloride appears to prevent this reabsorption of lithium. Therefore, this drug can be used in lithium clearance studies whenever unwanted "distal" lithium reabsorption is expected. Lithium reabsorption in Henle's loop forms a greater problem as it cannot be prevented by any drug without influencing proximal tubule reabsorption. It is estimated that about 7% of the filtered lithium (one-tenth of total lithium reabsorption) is normally taken up here, preferentially in deep nephrons. In view of studies with furosemide, this reabsorption probably varies with sodium intake, but the proportion of this variation to that of proximal tubule lithium reabsorption is obscure. This remains an uncertain factor in any circumstance where the lithium clearance method is used. In some conditions the change in FELi may be so large relative to the expected changes in proximal reabsorption, that use of FELi as marker of end-proximal solute delivery seems unjustified. Disproportionately large suppression is likely during mineralo-corticoid-induced volume expansion, and stimulation during prostaglandin synthesis inhibition and vasopressin. Based on observations in these conditions the potential range of lithium reabsorption in the loop of Henle would be 0 to 15% of filtered load. In this review attention was paid mainly to the validity of lithium clearance as a pure "proximal marker". Many of our interpretations suffer from incomplete certainty with respect to the renal effects of tested maneuvers, a problem which is acknowledged.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Lithium toxicity: an iatrogenic problem in susceptible individuals.

OBJECTIVE: Lithium toxicity, manifesting primarily as neurotoxicity, is a significant health problem and is primarily iatrogenic in nature. Despite 50 years of medical experience with lithium, factors contributing to the development of severe neurotoxicity remain poorly documented. We hypothesized that severe neurotoxicity represents the most clinically significant manifestation of lithium toxicity. We proposed that this occurs primarily in the context of chronic therapeutic administration ('chronic poisoning'), rather than in the context of an overdose. Furthermore we hypothesized that patients who developed chronic poisoning did so in the presence of identifiable factors which predictably impair lithium clearance. METHOD: A retrospective analysis of 97 cases of lithium poisoning, treated at a regional centre over a 13-year period was performed. Demographic data and factors considered likely to relate to the risk of developing lithium toxicity were recorded. Patients were classified according to mode of poisoning (acute, acute on chronic, or chronic) and according to severity of neurotoxicity (nil, mild, moderate, severe). The risk of developing severe neurotoxicity as a result of each mode of poisoning was assessed. The association between various risk factors and the development of chronic poisoning was assessed using a logistic regression model. RESULTS: Twenty-eight cases were rated as suffering severe neurotoxicity; in 26 this developed in the context of chronic poisoning and in two in the context of acute on chronic poisoning. All patients who developed severe neurotoxicity had at least one putative risk factor present, regardless of mode of poisoning. Length of stay was significantly longer for cases with severe neurotoxicity compared to those without severe neurotoxicity (12 vs. 2 days, P < 0.001). Peak serum lithium concentrations were significantly higher in cases with severe neurotoxicity compared to those without (2.3 vs. 1.6 mmol/L, P = 0.02). Patients presenting with chronic poisoning had a substantially higher risk of severe neurotoxicity than those presenting after an overdose of lithium (Odds Ratio [OR] 136, 95% CI 23-1300). A logistic regression model showed three factors contributed independently to the risk of chronic poisoning. These were: nephrogenic diabetes insipidus (adjusted OR 26.96, 95% CI 2.89-251.94), age over 50 years (adjusted OR 6.20, 95% CI 1.36-28.32) and thyroid dysfunction (adjusted OR 9.30, 95% CI 1.36-63.66). A fourth factor, baseline endogenous creatinine clearance below normal limits, was significant at the P = 0.05 level (adjusted OR 6.49, 95% CI 0.98-43.01). Hyperparathyroidism was noted in three cases of chronic poisoning suffering severe neurotoxicity. CONCLUSION: Severe lithium neurotoxicity occurs almost exclusively in the context of chronic therapeutic administration of lithium, and rarely results from acute ingestion of lithium, even in patients currently taking lithium. As such it is an iatrogenic illness, occurring in patients who have identifiable clinical risk factors: nephrogenic diabetes insipidus, older age, abnormal thyroid function and impaired renal function. Although administration of drugs which impair lithium clearance appeared to contribute minimally to chronic lithium poisoning in the absence of other factors, these drugs may well 'uncover' the predisposing risk factors and certainly should not be considered safe to use as a consequence of this study. The serious morbidity suffered by lithium toxic patients, and the cost to society due to long hospital stays, might be reduced by careful prescribing, vigilant monitoring and awareness of these factors, as they develop in otherwise stable patients. Review of existing therapeutic guidelines may be warranted.

Aged↗
PubMed1998

Effect of over-the-counter dosages of naproxen sodium and acetaminophen on plasma lithium concentrations in normal volunteers.

Prescription doses of nonsteroidal antiinflammatory agents have been shown to decrease clearance and increase plasma concentrations of lithium. This study was designed to evaluate whether over-the-counter (OTC) doses of naproxen sodium or acetaminophen have the same potential to affect lithium concentration. This was a prospective, crossover, 3-phase study conducted at the Clinical Pharmacology Studies Unit of the Albany Medical Center Hospital during July and August of 1995. The 3-phase study comprised the following: phase 1, lithium carbonate (300 mg every 12 hours) alone for 7 days; phase 2, lithium and either naproxen sodium (220 mg every 8 hours) or acetaminophen (650 mg every 6 hours) for 5 days; and phase 3, a 2-day washout period followed by a crossover to lithium with the alternate drug (acetaminophen or naproxen sodium) for 5 days. Twelve healthy male volunteers were recruited, nine of whom completed the study and were included in the statistical analysis. Mean (+/-SD) plasma lithium concentrations for subjects in treatment group 1 (lithium in phase 1, lithium and naproxen sodium in phase 2, lithium and acetaminophen in phase 3) were 0.38 (+/-0.11), 0.40 (+/-0.07), and 0.36 (+/-0.11) mEq/L, respectively. Mean plasma lithium concentrations for subjects in treatment group 2 (lithium in phase 1, lithium and acetaminophen in phase 2, lithium and naproxen sodium in phase 3) were 0.43 (+/-0.05), 0.48 (+/-0.10), and 0.48 (+/-0.05) mEq/L, respectively. One-way repeated-measures analysis of variance and paired t-test showed no statistically significant differences (p>0.05) in plasma lithium concentrations during any phase of the study. The results of this study demonstrated that OTC doses of naproxen sodium and acetaminophen did not increase plasma lithium concentrations in these volunteers when taken for short periods of time.

Acetaminophen↗
PubMed1988

Sodium-lithium exchange in sarcolemmal vesicles from canine superior mesenteric artery.

Exchange of intracellular sodium for extracellular lithium readily occurs in vascular smooth muscle, but the mechanism of this exchange is not known. These studies examined whether a sodium-lithium countertransport system was present in the cell membrane of vascular smooth muscle. A sarcolemmal-enriched vesicle preparation was obtained from canine superior mesenteric artery via a magnesium aggregation and differential centrifugation technique. An outwardly directed gradient for lithium stimulated 22Na uptake by the vesicles, and an inwardly directed gradient for lithium stimulated 22Na efflux. These effects were not due to an alteration in membrane potential, and sodium uptake was not stimulated by lithium in the absence of a gradient for lithium. The lithium gradient-stimulated component of sodium uptake was not affected by a change in membrane potential and was insensitive to ouabain. Both sodium-lithium exchange and sodium-proton exchange in sarcolemmal-enriched vesicles were inhibited by two compounds that inhibit the sodium-lithium countertransport system in red cells, phloretin and quinidine. Ethylisopropylamiloride also inhibited both sodium-lithium exchange and sodium-proton exchange in the vesicles. In support of the possibility that sarcolemmal sodium-lithium exchange and sodium-proton exchange are mediated by a single cation exchange mechanism with affinity for sodium, lithium, and protons, we found that an inwardly directed sodium or lithium gradient stimulated proton efflux, and that the stimulation of sodium efflux by external lithium or protons was not additive. It is concluded from these studies that sarcolemmal vesicles from canine superior mesenteric artery contain an electroneutral, phloretin, quinidine, and ethylisopropylamiloride inhibitable sodium-lithium exchange transport system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed2005

Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy.

OBJECTIVE: Lithium has been used during pregnancy for more than four decades, but quantification of fetal lithium exposure and clinical correlations of such exposure are limited. The study objectives were to 1) quantify the rate of lithium placental passage, 2) assess any association between plasma concentration of lithium at delivery and adverse perinatal events, and 3) determine whether lithium concentrations can be reduced by briefly suspending therapy proximate to delivery. METHOD: Maternal blood and umbilical cord blood were obtained at delivery for assay of lithium concentrations, and obstetrical outcome data were collected prospectively for 10 participants. These data were combined with results from MEDLINE and PsycINFO searches that identified 32 cases in which maternal lithium was administered throughout delivery. Statistical analysis of the pooled data was conducted. RESULTS: The ratio of lithium concentrations in umbilical cord blood to maternal blood (mean=1.05, SD=0.13) was uniform across a wide range of maternal concentrations (0.2-2.6 meq/liter). Significantly lower Apgar scores, longer hospital stays, and higher rates of CNS and neuromuscular complications were observed in infants with higher lithium concentrations (>0.64 meq/liter) at delivery. Withholding lithium therapy for 24-48 hours before delivery resulted in a 0.28 meq/liter reduction in maternal lithium concentration. CONCLUSIONS: Lithium completely equilibrates across the placenta. Higher lithium concentrations at delivery are associated with more perinatal complications, and lithium concentrations can be reduced by brief suspension of therapy proximate to delivery. Treatment guidelines are proposed to improve neonatal well-being when lithium use is indicated in late pregnancy.

Apgar Score↗
PubMed2003

Risk factors of thyroid abnormalities in bipolar patients receiving lithium: a case control study.

BACKGROUND: Lithium-induced thyroid abnormalities have been documented in many studies. They may occur despite normal plasma lithium levels. The objectives of this study were: 1) to determine possible relationship between lithium ratio, defined as erythrocyte lithium concentrations divided by plasma lithium concentrations, and thyroid abnormalities in bipolar patients receiving lithium and 2) to find other possible risk factors for developing thyroid abnormalities in the subjects. METHODS: Sixty-eight bipolar patients receiving lithium therapy were enrolled in a cross-sectional evaluation of thyroid function test and thyroid size. Patients were divided into two groups based on their thyroid function tests and thyroid sizes. Erythrocyte and plasma lithium concentrations were determined by atomic absorption spectrometry for each patient. Lithium ratio was then calculated. RESULTS: No significant differences were found between age, positive family history of affective disorder, plasma lithium concentration, erythrocyte lithium concentration, and lithium ratio comparing the two groups. Thyroid abnormalities was significantly higher in women than in men (p < 0.05). CONCLUSIONS: Lithium ratio does not appear to have a predictive role for thyroidal side effects of lithium therapy. Female gender was the main risk factor. We suggest more frequent thyroid evaluation of bipolar women who are treated with lithium.

Adult↗
PubMed2000

Differential pharmacokinetics of lithium in elderly patients.

The pharmacotherapeutic use of lithium in the elderly as acute and maintenance therapy in bipolar disorder and augmentation therapy for major depression is well documented. Differences in the response to lithium are explained, in part, by the effect of age-related physiological changes, comorbid conditions, and concurrent medications on the pharmacokinetics of lithium in the elderly. The pharmacokinetic profile of lithium has been studied for many years, primarily in younger adult populations. Lithium pharmacokinetics may be influenced by a number of factors including age. It was first noted several years ago that elderly individuals required lower doses of lithium to achieve serum concentrations similar to those observed in younger adults. This is due to the combination of a reduced volume of distribution and reduced renal clearance. The composition of the human body changes with aging producing an increase in body fat, a decrease in fat-free mass and a decrease in total body water. Lithium clearance decreases as the glomerular filtration rate decreases with increasing age. The effects of other medical conditions in the elderly on the pharmacokinetics of lithium are less well delineated. Reduced lithium clearance is expected in patients with hypertension, congestive heart failure or renal dysfunction. Larger lithium maintenance doses are required in obese compared with non-obese patients. The most clinically significant pharmacokinetic drug interactions associated with lithium involve drugs which are commonly used in the elderly. Thiazide diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs can increase serum lithium concentrations. The tolerability of lithium is lower in the elderly. Neurotoxicity clearly occurs in the elderly at concentrations considered 'therapeutic' in general adult populations. There are no placebo-controlled randomised trials of lithium in old age and recommendations for clinical use are based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed age populations and clinical experience in old age psychiatry. Serum concentrations of lithium need to be markedly reduced in the elderly population and particularly so in the very old and frail elderly.

Aged↗
PubMedDate not supplied

Reversible hypercalcemia and hyperparathyroidism associated with lithium therapy: case report and review of literature.

OBJECTIVE: To present a case of reversible hypercalcemia and hyperparathyroidism associated with lithium therapy and to discuss the pathophysiology and management of this condition. METHODS: The clinical and laboratory findings in a patient with lithium-induced hypercalcemia are presented. A PubMed search for associated English language articles (with use of the key words lithium, hypercalcemia, and hyperparathyroidism) was conducted, and the relevant literature to date was reviewed. An approach to the management of patients with lithium-induced hypercalcemia is suggested. RESULTS: A 56-year-old man was referred for management of incidentally discovered hypercalcemia. The serum parathyroid hormone (PTH) level was increased; serum phosphorus and 24-hour urine calcium excretion were both normal. For 5 years, he had been treated with lithium carbonate for bipolar affective disorder. The laboratory features were consistent with lithium-induced primary hyperparathyroidism. Discontinuation of lithium treatment resulted in normalization of serum calcium and PTH levels. Review of the literature suggests that hypercalcemia and hyperparathyroidism are common consequences of lithium therapy. CONCLUSION: Hypercalcemia associated with lithium-induced hyperparathyroidism is a common, but underrecognized, complication of lithium therapy. Most patients have mild asymptomatic hypercalcemia. The long-term consequences of mild lithium-induced hypercalcemia are unknown. After discontinuation of lithium, the hypercalcemia may not always resolve; thus, parathyroidectomy may be necessary in some cases. Measurement of the serum calcium and PTH levels before and periodically after the initiation of lithium treatment is advisable. The appropriate monitoring of patients with lithium-induced hypercalcemia and decisions regarding parathyroidectomy are unclear. The decision to continue lithium therapy in the presence of hypercalcemia should be individualized.

Bipolar Disorder↗
PubMedDate not supplied

Intensive treatment with lithium carbonate "once a day" in bipolar patients.

Lithium carbonate is the treatment of choice in the prevention of recurrences of bipolar mood disorders. The aim of this study is the evaluation of the pharmacokinetics of a new lithium compound to be administered "once a day", with a half-life of 32.4 hours. The present study investigates plasma lithium levels in patients treated with the novel vs. standard preparation of lithium carbonate to assess whether the new preparation may be associated with lithium plasma accumulation. The authors studied twenty-two bipolar patients whose standard lithium treatment was replaced by the new one. The total duration of the new treatment was 57 days. During this period, lithium plasma levels were monitored 7 times, 12 hours post-lithium administration. Lithium plasma level 24 hours following administration was evaluated in seven patients. The average dose of "once a day" lithium was 821 (+/- 250) mg/day, the corresponding plasma level was 0.45 (+/- 0.11) mEq/L, and the dose (g) to plasma level ratio was 1.96 (+/- 0.66). Differences between average lithium plasma levels at time T1 and successive times were not statistically significantly. Moreover, the average lithium level at 12 hours after lithium administration was not different from that after 24 hours (0.45 +/- 0.11 and 0.47 +/- 0.0.29 respectively). These results demonstrate that the new preparation, "once a day", maintains steady lithium plasma levels during our times of observation without accumulation in body fluids and tissues. "Once a day" lithium carbonate appears to be a useful alternative to the standard preparation, and may potentially improve treatment compliance by simplifying patients' medication.

Adult↗
PubMed2003

[Neuroprotective actions of lithium].

Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.

Animals↗
PubMed1990

Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus.

Lithium lengthens the period of free-running circadian rhythms in a variety of species, but this effect has not been demonstrated unequivocally in primates. Because of the possible link between lithium's action on the circadian clock and its therapeutic action in human mood disorders, we tested the ability of lithium to lengthen circadian period in a diurnal primate with circadian properties similar to those of humans. Lithium carbonate was administered in food pellets to 8 adult male squirrel monkeys (Saimiri sciureus) for at least 27 consecutive days. Serum lithium levels on the last day of lithium administration ranged from 0.76 to 2.02 mEq/liter, comparable to the therapeutic range for treatment of bipolar disorder in humans (0.6-1.2 mEq/liter). Circadian periods of perch-hopping activity were longer during lithium treatment than during baseline in 7 of the 8 monkeys (changes of -0.08 to +1.41 hr, mean +0.55 hr, p = 0.01), and returned toward baseline values when lithium was discontinued. In most cases, the period change was evident within a few days after beginning full lithium dose, and was not accompanied by changes in level or pattern of activity, nor in amplitude of the circadian rhythm. Food consumption and body weight were reduced during lithium treatment, and rebounded on return to lithium-free diet. Period change was related to lithium dose (p less than 0.05), but did not correlate with food consumption, body weight, or baseline circadian period. These results, by establishing that lithium lengthens circadian period in primates, suggest that studying the cellular mechanisms of this circadian effect may be relevant to understanding lithium's therapeutic effect on mood in humans.

Animals↗
PubMed1995

Modulation by inositol of cholinergic- and serotonergic-induced seizures in lithium-treated rats.

Hippocampal and cortical EEG recordings in rats were used to monitor the in vivo modulation by lithium of responses to agonists for 5HT2/5HT1c serotonergic (DOI) and cholinergic (pilocarpine) receptors and the influence of inositol administration. Administration of DOI (8 mg/kg) or pilocarpine (30 mg/kg) to rats pretreated with lithium acutely (3 mmol/kg) or chronically (dietary, 4 weeks) resulted in seizures, whereas these doses did not cause seizures without lithium pretreatment. This indicated that lithium most likely affects a signal transduction process common to both systems, which is the phosphoinositide second messenger system. To examine the potential influence of altered inositol levels on these responses, we tested the effects of infusions (10 mg, i.c.v.) of myo-inositol, a precursor of phosphoinositide synthesis, and of epi-inositol, an isomer not used for phosphoinositide synthesis. Administration of myo-inositol (10 mg) slightly reduced the incidence of seizures induced by acute lithium plus DOI but almost completely blocked seizures induced by acute lithium plus pilocarpine. This was surprising since seizures induced by acute lithium plus DOI were less severe than those after acute lithium plus pilocarpine, but myo-inositol was more effective in blocking the latter. Epi-inositol also blocked seizures under both conditions but it was less effective than myo-inositol after treatment with acute lithium plus pilocarpine. The latencies to seizures and/or severity of seizures were potentiated more by chronic than acute lithium pretreatment with both DOI and pilocarpine, but attenuation by myo-inositol was less with each agonist after chronic lithium compared with acute lithium treatment. Peripheral administration of a high dose of myo-inositol blocked seizures induced by acute lithium plus pilocarpine, but the inositol treatment itself was toxic and caused seizures prior to pilocarpine administration, so the mechanism of action cannot simply be attributed to increased brain inositol levels. These results demonstrate that lithium modulates the in vivo responses to DOI and pilocarpine, most probably through an effect on the phosphoinositide signal transduction system. They also show that centrally administered myo-inositol modifies responses to these agents, but the effectiveness of epi-inositol and other results leave unclear the mechanistic basis of its actions.

Amphetamines↗
PubMed1987

Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy.

From the analysis of several studies published from 1979 to 1986 comprising 1,172 patients, we estimated that glomerular filtration rate (GFR) was normal in 85% of unselected patients on chronic lithium therapy. The remaining 15% of patients displayed only mild reduction in GFR, clustering at approximately 60 mL/min. Thus, the data available to date do not support earlier concerns that long-term lithium therapy could eventuate into renal insufficiency. The most prevalent renal effect of lithium is impairment of concentrating ability, which we estimated to be present in at least 54% of 1,105 unselected patients on chronic lithium therapy. This defect translated into overt polyuria in only 19% of unselected cases. A renal lesion confined to the collecting tubule has been described in humans who have taken lithium for short periods of time. This lesion may represent the collecting tubule's response to the intracellular accumulation of lithium, which interferes with cAMP formation and results in an early and probably reversible inhibition of antidiuretic hormone (ADH)-mediated water transport. However, long-term lithium therapy may induce a progressive and partly irreversible defect in concentrating ability. The potential risk for dehydration associated with lithium-induced polyuria, as well as the discomfort inherent to this side effect, deserves evaluation and consideration for therapeutic intervention. Amiloride has additional advantages over conventional treatment of nephrogenic diabetes insipidus using thiazide diuretics. The action of amiloride on ADH-mediated water transport seems specific in as much as it is capable of preventing the uptake of lithium in high resistance epithelia and thereby prevents the inhibitory effect of intracellular lithium on water transport. Unlike thiazides, amiloride has a weak natriuretic effect and is less likely to increase plasma lithium levels by causing volume contraction. In addition, amiloride, by conserving potassium, obviates the need for potassium supplementation that is usually required to prevent hypokalemia when thiazides are used to treat lithium-induced polyuria. Since amiloride may prevent chronic intracellular lithium accumulation in the collecting tubule, future studies should elucidate whether amiloride also has a role in preventing lithium-induced chronic tubulo-interstitial damage.

Acidosis, Renal Tubular↗