Elevations in thyroid-stimulating hormone in normal subjects after receiving short-term lithium carbonate

Nine normal, healthy male subjects had significantly elevated thyroid-stimulating hormone (TSH) concentrations while receiving oral lithium carbonate for two weeks. The mean minimum lithium serum concentration was 0.765 mEq/L. The TSH concentrations after 15 days on lithium were significantly correlated to the TSH concentration at baseline. No correlation was found between mean minimum lithium steady-state concentration and TSH concentration after 15 days on lithium. Further research is necessary to determine if a high baseline TSH concentration or an early rise in TSH will predict those patients who will eventually develop hypothyroidism after long-term lithium therapy.     

Zinc Concentrations in Human Plasma and in Rat Plasma and Tissues during Lithium Administration

Abstract: Zinc concentrations, determined with atomic absorption spectrophotometry, did not differ significantly in plasma from manic-depressive patients about to start lithium treatment and in patients having been in lithium treatment for six months or 1-2 years. Plasma zinc concentrations and zinc concentrations in liver, muscle, kidney, bone, and skin did not differ in control rats and rats given lithium with the food for four weeks.     

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.     

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.     

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.     

Prediction of lithium carbonate dosage in psychiatric inpatients using the repeated one-point method

A repeated one-point pharmacokinetic model of predicting lithium carbonate doses was evaluated. Six psychiatric inpatients with normal renal function who required lithium therapy were given two 600-mg lithium carbonate test doses 12 hours apart. Serum lithium concentrations were determined 11 hours after each test dose. Based on these determinations, the patients were then given individualized lithium doses to reach a minimum steady-state serum concentration of 1.0 meq/liter. The measured and predicted minimum steady-state concentrations were compared. The mean +/- S.D. measured and predicted minimum steady-state serum concentrations for all patients were 1.03 +/- 0.06 meq/liter and 0.97 +/- 0.08 meq/liter, respectively. While further studies are needed to evaluate the method, the repeated one-point pharmacokinetic model provided accurate predictions of lithium carbonate doses in these patients.     

Acute and chronic effects of lithium chloride on physiological and psychological measures in normals

In the acute experiment six healthy volunteers were given orally two doses of lithium chloride, 16 and 32 mmol, and placebo sodium chloride 32 mmol in a double-blind standardized procedure, with a 1-week interval between treatments. Compared to sodium, lithium produced a decrease in subjective well-being, decrease of skin conductance fluctuations, and increase in plasma calcium concentrations. Dose-related effects were maximal at the first hour after ingestion, decreasing or disappearing at 3–5h. Most effects did not correlate with plasma or erythrocyte lithium concentrations, but drug effects and feelings of nausea were highly correlated. Accordingly, most acute effects seemed due to peripheral drug effects.In the chronic experiment six healthy volunteers were given orally 16 mmol of lithium chloride or sodium chloride (placebo) twice a day for 1 week in a double-blind standardized procedure with a 2-week interval between treatment weeks. Compared to placebo, lithium produced feelings of subjective impairment, an increase in EEG slow waves and of auditory evoked response variability, a deficit in long-term memory, and an increase in plasma magnesium concentrations. Most lithium effects did not correlate with plasma or erythrocyte lithium concentrations.     

Steady-state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam

AIMS: This open, controlled study investigated the effect of concomitant 15 mg oral meloxicam on the pharmacokinetics of lithium in healthy male volunteers. METHODS: On days 1-14 lithium was coadministered with meloxicam to 16 volunteers; on days 10-14 lithium was administered in individualized dosage regimes to achieve stable lithium plasma concentrations in the lower therapeutic range of 0.3-0.7 mmol l(-1). A 12 h steady-state concentration profile for lithium was obtained at day 14, after which meloxicam was withdrawn. The lithium dose remained unchanged from day 15 to day 22, at which time a second lithium concentration profile was determined. RESULTS: Lithium and meloxicam were well tolerated throughout the study and all 16 volunteers completed the study. Lithium predose concentrations (Cpre,ss) and area under the curve (AUCss) values both increased by 21% (paired t-test P = 0.0002; 90% confidence intervals for test/reference ratios: 113-130% and 115-128%, respectively) when lithium was coadministered with meloxicam compared with values obtained for lithium alone. The geometric mean lithium Cpre,ss was 0.65 mmol l(-1) when coadministered with meloxicam and 0.54 mmol l(-1) for lithium alone. Lithium Cmax,ss values were increased by 16% by coadministration of meloxicam, from 0.97 mmol l(-1) to 1.12 mmol l(-1). The total plasma clearance of lithium was lower with concomitant meloxicam administration (82.5% of value for lithium alone). CONCLUSIONS: Meloxicam (15 mg) moderately increased the plasma concentration of lithium in healthy volunteers, but by a magnitude thought to be of low clinical relevance. Nevertheless, lithium plasma concentrations should be closely monitored in patients receiving concomitant meloxicam and lithium therapy.     

Alcohol and Malt Liquor Availability and Promotion and Homicide in Inner Cities

We investigated the role of the alcohol environment in explaining disparities in homicide rates among minorities in 10 cities in the United States using 2003 data from the Malt Liquor and Homicide study. We hypothesized that (a) higher concentrations of African Americans would be associated with higher homicide rates, as well as higher alcohol and malt liquor availability and promotion, and (b) the relationship between neighborhood racial/ethnic concentration and homicide would be attenuated by the greater alcohol and malt liquor availability and promotion in African American neighborhoods. Hypotheses were tested using separate Poisson, linear, and logistic regression models that corrected for spatial autocorrelation. Census block groups served as the unit of analysis (n = 450). We found that higher concentrations of African Americans were associated with higher homicide rates as well as greater alcohol availability, especially malt liquor availability. The promotion of malt liquor on storefronts was also significantly greater in African American than in other neighborhoods. However, none of the measures representing alcohol or malt liquor availability and promotion variables changed the effect of neighborhood racial/ethnic concentration on homicide. Limitations and implications of our findings are discussed.     

Chronic treatment with lithium,but not sodium valproate,increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients

Previous studies have found that treatment with lithium over a 4-week period may increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients and controls. In view of other findings indicating that NAA concentrations may be a good marker for neuronal viability and/or functioning, it has been further suggested that some of the long term benefits of lithium may therefore be due to actions to improve these neuronal properties. The aim of the present study was to utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects of both lithium and sodium valproate upon NAA concentrations in treated euthymic bipolar patients. In the first part of the study, healthy controls (n =18) were compared with euthymic bipolar patients (type I and type II) who were taking either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios were determined. In the second part, we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n =9) and compared these to age- and sex-matched healthy controls (n =11), and we quantified the exact concentrations of NAA using an external solution. The results from the first part of the study showed that bipolar patients chronically treated with lithium had a significant increase in NAA concentrations but, in contrast, there were no significant increases in the sodium valproate-treated patients compared to controls. The second part of the study also found no effects of sodium valproate on NAA concentrations. These findings are the first to compare NAA concentrations in euthymic bipolar patients being treated with lithium or sodium valproate. The results support suggestions that longer-term administration of lithium to bipolar patients may increase NAA concentrations. However, the study suggests that chronic administration of sodium valproate to patients does not lead to similar changes in NAA concentrations. These findings suggest that sodium valproate and lithium may not share a common mechanism of action in bipolar disorder involving neurotrophic or neuroprotective effects.     

Multiple-Dose Sodium Polystyrene Sulfonate in Lithium Intoxication: An Animal Model

Abstract: Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N=144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full-Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half-Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post-treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose-related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.     

Determination of Trace Lithium in Human Erythrocytes by Electrothermal Atomic-absorption Spectrometry with Pyrocoated Graphite Tubes and Integrated Platform

Electrothermal graphite-furnace atomic-absorption spectroscopy with pyrocoated graphite tubes, integrated platform and matrix modification was used to determine submicromolar concentrations of trace lithium in human red blood cells. Matrix-matched samples were used to establish calibration curves for concentrations up to 0.58 μM. (addition-calibration method) with satisfactory linearity (r² > 0.99) and intra-and inter-day variability (CV < 11.4%). The median concentration of trace lithium in the cells of 40 healthy Caucasian volunteers devoid of medical or psychiatric history was 0.23 μM (inter-quartile range 0.20–0.30). The levels of trace lithium in the red blood cells correlated (r² = 0.83) with plasma concentrations (median 0.13 μM, inter-quartile range 0.11–0.19) measured in the same blood sample. Dietary factors (e.g. consumption of lithium-containing mineral water) affected both levels. The red blood cell/plasma lithium ratio had a median value of 1.57 (inter-quartile range 1.16–2.07), implying that trace lithium is accumulated in erythrocytes. This contrasts with most reports of red blood cell/plasma ratio, measured during therapeutic treatment with lithium, for which the average value is 0.5–0.8, albeit for much higher concentrations of lithium (approx. 500–800 μM). The proposed analytical method has the required sensitivity and accuracy for determination of trace lithium in red blood cells and makes it possible to perform epidemiological studies to assess human exposure to environmental lithium in diet and beverages, and inter-individual variations in trans-membrane and renal lithium kinetics at the submicromolar level.     

Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate.

A recent study by Kling et al (1978) noted the finding of higher lithium concentrations in serum and brain of rats after an intraperitoneal injection (2 mmol lithium kg-1) of lithium orotate as a slurry than of lithium carbonate in solution. The authors suggested that lithium orotate might offer advantages in the treatment of patients. We repeated the experiments of Kling et al but in addition examined the kidney function of the rats. Glomerular filtration rate and urine flow were markedly lower in rats given lithium orotate than in rats given lithium carbonate, sodium chloride or a sham injection. The renal lithium clearance was significantly lower, the kidney weight and the lithium concentrations in serum, kidney and heart significantly higher after injection of lithium orotate than after injection of lithium carbonate. The higher lithium concentrations could be accounted for by the lower kidney function. It seems inadvisable to use lithium orotate for the treatment of patients.     

Multiple-dose sodium polystyrene sulfonate in lithium intoxication: an animal model.

Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N = 144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full-Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half-Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post-treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose-related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.     

Alcohol and malt liquor availability and promotion and homicide in inner cities

We investigated the role of the alcohol environment in explaining disparities in homicide rates among minorities in 10 cities in the United States using 2003 data from the Malt Liquor and Homicide study. We hypothesized that (a) higher concentrations of African Americans would be associated with higher homicide rates, as well as higher alcohol and malt liquor availability and promotion, and (b) the relationship between neighborhood racial/ethnic concentration and homicide would be attenuated by the greater alcohol and malt liquor availability and promotion in African American neighborhoods. Hypotheses were tested using separate Poisson, linear, and logistic regression models that corrected for spatial autocorrelation. Census block groups served as the unit of analysis (n = 450). We found that higher concentrations of African Americans were associated with higher homicide rates as well as greater alcohol availability, especially malt liquor availability. The promotion of malt liquor on storefronts was also significantly greater in African American than in other neighborhoods. However, none of the measures representing alcohol or malt liquor availability and promotion variables changed the effect of neighborhood racial/ethnic concentration on homicide. Limitations and implications of our findings are discussed.     

Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.     

Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate

A recent study by Kling et al (1978) noted the finding of higher lithium concentrations in serum and brain of rats after an intraperitoneal injection (2 mmol lithium kg^?1) of lithium orotate as a slurry than of lithium carbonate in solution. The authors suggested that lithium orotate might offer advantages in the treatment of patients. We repeated the experiments of Kling et al but in addition examined the kidney function of the rats. Glomerular filtration rate and urine flow were markedly lower in rats given lithium orotate than in rats given lithium carbonate, sodium chloride or a sham injection. The renal lithium clearance was significantly lower, the kidney weight and the lithium concentrations in serum, kidney and heart significantly higher after injection of lithium orotate than after injection of lithium carbonate. The higher lithium concentrations could be accounted for by the lower kidney function. It seems inadvisable to use lithium orotate for the treatment of patients.     

Effect of co-administration of lithium and reboxetine on extracellular monoamine concentrations in rats

We investigated the effect of reboxetine, a selective noradrenaline reuptake inhibitor, 7 days after treatment with subchronic lithium on extracellular noradrenaline, dopamine and serotonin (5-HT) concentrations in the medial prefrontal cortex. Acute treatment with reboxetine significantly increased extracellular concentrations of noradrenaline and dopamine, but did not alter 5-HT concentrations. Subchronic lithium increased basal levels of extracellular 5-HT, but not noradrenaline or dopamine. Co-administration of reboxetine and lithium treatment increased the extracellular concentrations of noradrenaline, dopamine and 5-HT, though reboxetine alone increased the extracellular levels of noradrenaline and dopamine only. Thus, combined lithium and reboxetine produces an additive effect neurochemically rather than their interaction.     

Effect of ibuprofen on lithium plasma and red blood cell concentrations

The effect of ibuprofen on steady-state lithium plasma and red blood cell concentrations was studied in 11 normal volunteers. During the seven-day control phase, sustained-release lithium carbonate 450 mg was administered every 12 hours. Lithium plasma and red blood cell concentrations were determined on days 5, 6, and 7. During the treatment phase (days 7-15), ibuprofen 400 mg was administered four times a day concurrently with lithium. Lithium plasma and red blood cell concentrations were obtained on days 14, 15, and 16. Multiple blood samples were obtained over a 12-hour period on days 6 and 15. Urine samples were collected from six subjects. The mean minimum lithium concentration increased 15% when ibuprofen was added. Mean maximum lithium concentration, area under the curve, red blood cell concentrations, and the lithium red blood cell to plasma ratio were significantly higher during the treatment phase. Mean lithium total body and renal clearance values were significantly lower during the treatment with ibuprofen. The administration of ibuprofen can increase steady-state plasma lithium concentrations and decrease lithium clearance.     

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.