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The title compounds, LiKB(4)O(7) and LiRbB(4)O(7), are newly developed non-linear optical crystals containing two kinds of anionic groups, namely (B(3)O(8))(7-) and (B(5)O(10))(5-). The (B(3)O(8))(7-) groups form infinite spiral chains parallel to the [100] direction, which are interconnected by sharing O atoms with (B(5)O(10))(5-) groups.
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Lithium is the preferred treatment for bipolar affective disorder, yet its mechanism of action is poorly understood. Our study was designed to investigate the effect of lithium on the 5-HT2A or 5-HT2C (5-HT2A/2C) receptor subtypes, by comparing the consequences of chronic pre-treatment of rats with lithium on 5-HT2A/2C receptor-mediated behavioural responses, Fos expression, and the density of these receptors in the brain. In addition, the time-course and persistence of the effect of chronic lithium on 5-HT2A/2C receptor-mediated Fos expression was examined. Furthermore, the acute action of lithium on Fos expression was also examined. In an investigation of the dose response of Fos to the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), rats received saline or 1, 2, 4, 8, 12, 16, 24 or 32 mg/kg DOI, then were sacrificed 3 h later for immunocytochemical localisation of Fos. In a chronic lithium study, rats received either control or lithium-containing (0.1% LiCO3) chow for 3 weeks prior to challenge with 8 mg/kg DOI. DOI-induced locomotor activity was measured for 30 min immediately following the drug challenge, then 150 min later, the animals were sacrificed for Fos immunocytochemistry. The brains of another group of rats, also receiving either control or lithium-containing diet for 3 weeks, were analysed for the distribution and density of 5-HT2A receptor binding sites by quantitative [3H]ketanserin autoradiography. One group of chronic lithium treated rats received ritanserin (0.4 mg/kg), a 5-HT2A/2C receptor antagonist, 40 min before DOI challenge and were sacrificed 3 h later for Fos localisation. In the time-course experiment, rats received lithium-containing diet for 3 weeks followed by normal, control diet for 48 h, 1, 2 or 4 weeks prior to DOI or saline challenge. A further group of animals received an injection of LiCl (3 mM/kg) before being challenged with DOI or saline 12, 24, 36 or 48 h later. The dose-response experiment revealed that little Fos-like immunoreactivity was evident above basal levels following administration of 1 mg/kg DOI. However, at all other doses examined, Fos-like immunoreactivity was elevated in a number of brain areas, particularly in cerebral cortex, olfactory tubercle and amygdala. Following 24 mg/kg DOI, the number of Fos-positive nuclei appeared to have reached a plateau level. Treatment of rats with chronic lithium significantly enhanced DOI-induced locomotor activity and Fos-like immunoreactivity throughout the cerebral cortex. This elevation in Fos-like immunoreactivity was completely abolished by prior treatment with ritanserin. In contrast, chronic lithium treatment had no effect on the density of [3H]ketanserin binding to 5-HT2A receptors in any brain region examined. The results of the time-course experiment demonstrated that the enhancing effect of lithium on 5-HT2A/2C receptor-mediated Fos expression was short-lived such that Fos-like immunoreactivity returned to untreated levels within 48 h. In the acute lithium experiment, administration of lithium to rats 12 or 24 h before DOI resulted in a similar elevation of Fos-like immunoreactivity to that seen in chronically treated animals. Administration of acute lithium 36 or 48 h before DOI had no effect. The effects of lithium on 5-HT2A/2C receptor function thus appear to be complex. In particular, the results of this study indicate that the enhancing effects of lithium on DOI-induced locomotor activity and Fos-like immunoreactivity are not accompanied by any alteration in the density of 5-HT2A receptor binding sites. If changes in receptor numbers therefore do not account for the physiological effect of chronic lithium, other explanations must be sought. The study also suggests that the inositol depletion hypothesis of lithium's therapeutic action does not adequately explain the mechanism of action of lithium in man.
Genetic factors play an important role in drug metabolism and drug response. In order to investigate genetic variables in lithium prophylaxis and lithium distribution across the erythrocyte in manic-depression, we have examined forty-two pairs of twins monozygotic (n = 25) and dizygotic (n = 17) with manic-depression. Concordant twins as a group show better lithium prophylaxis than do discordant twins. These results are consistent with previously published family studies of affective illness suggesting a positive relationship between genetic background and success of lithium prophylaxis. Lithium distribution across the red blood cell (RBC) was assessed by estimating lithium RBC/plasma ratios. The lithium ratio's intrapair differences in both groups of twins were minimal with a high heritability index suggesting that genetic factors play a role in lithium ion distribution. A high linear correlation was found between lithium ratio and plasma lithium and there was no difference in lithium ratios according to sex, affective state and response to lithium. The distribution of lithium ratios was homogenous in the lithium responders' population but this was not the case in the non-responders, suggesting biological heterogeneity of lithium distribution in lithium failures. The implications of these results are discussed as they relate to the genetic determinates of lithium prophylaxis in manic-depressive illness. These results indicate that lithium ratios are of limited value in lithium maintenance therapy. Our lithium kinetic data, however, are consistent with the concept of a lithium extrusion mechanism from red blood cells.
BACKGROUND: Several authors have recently described the development of lithium toxicity after the addition of angiotensin-converting enzyme inhibitors to a stable lithium regimen. This pilot study was designed to systematically investigate the effects of enalapril, an angiotensin-converting enzyme inhibitor, on the serum level of lithium. METHOD: In a 26-day outpatient study, nine healthy men took lithium for 10 days, lithium and enalapril for 10 days, and lithium alone again for 6 days. Serum lithium levels were measured while patients were taking lithium alone and while they were taking the lithium/enalapril combination. RESULTS: There were no statistically significant differences between mean serum lithium level during treatment with lithium alone and during treatment with the lithium/enalapril combination. However, one subject showed a 31% increase in serum lithium level after enalapril was added. CONCLUSION: Although no statistically significant differences between mean serum lithium level during treatment either with lithium alone or with lithium/enalapril were found, it is possible that the low dose of enalapril and low serum lithium levels employed for subject safety may have resulted in a type II statistical error. If enalapril doses or initial serum lithium levels were similar to those described in case reports, a significant difference in mean serum lithium levels may have been observed. While a predictable interaction between lithium and enalapril probably does not occur in all patients, factors such as enalapril dose, serum lithium level before addition of enalapril, or the presence of heart disease may make such an interaction more likely. At the levels of lithium and enalapril used in this study, elevated serum lithium concentration does not appear to be a universal event, but physicians must exercise appropriate caution.
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.
BACKGROUND: Lithium compounds have been widely used in the treatment of manic-depressive illness. Several electrocardiogram (ECG) abnormalities, including ventricular arrhythmias, atrioventricular conduction abnormalities, T wave changes and QT interval prolongation, have been reported to be associated with lithium. However, the correlation between serum lithium levels and ECG changes has never been characterized in a systematic way. METHODS: This retrospective study included 76 patients undergoing lithium treatment with available records of lithium levels. Eleven patients (4 men) had serum lithium levels >1.2 mEq/l and were diagnosed as lithium over range. Clinical characteristics and various ECG changes were analyzed in patients with and without lithium over range. RESULTS: Patients with lithium over range had a slower heart rate and longer PR, QT and corrected QT (QTc) intervals. QTc interval >440 ms was more commonly found in patients with lithium over range (55 vs. 8%, p < 0.001). Similarly, diffuse T wave inversion was more commonly associated with lithium over range (73 vs. 17%, p < 0.001). The daily dosage of lithium was similar between patients with and without over-range lithium levels. When these two ECG changes were combined, the sensitivity and specificity in predicting lithium over range were 64 and 97%, respectively. These findings were independent of the concomitant use of beta-blockers. CONCLUSIONS: QTc interval >440 ms and diffuse T wave inversion were significantly more common in patients with lithium over range, and were good predictors of lithium over range. More liberal checkup of the ECG in patients undergoing lithium treatment may be of help in the early detection of lithium over range.
1. During a prospective and outpatient study the correlation between the lithium ratio and the incidence of lithium side effects and type of comedications was studied in 51 Iranian bipolar patients by using new direct method of measuring erythrocyte lithium concentration. 2. Results revealed that patients who received lithium alone the incidence of lithium side effects was extremely lower than those with lithium and neuroleptics in combination. Both neurological and renal side effects of lithium were higher in patients who received lithium in combination with neuroleptics. 3. In patients on lithium alone the lithium ratio among patients with side effects were significantly lower than those without side effects, and the plasma lithium concentrations were significantly higher in those with side effects. In patients who received neuroleptics in combination with lithium, the lithium ratios were also significantly lower in those with serious side effects than those with slight side effects, but there were no significant correlation in plasma lithium concentrations between them. 4. Previous studies about the correlation of the lithium ratio and incidence of side effects have yielded inconsistent results, and methodological problems may be a reason for these discrepancies. By using the new direct method of measuring erythrocyte lithium concentration, repetition of previous studies on lithium ratio may elucidate its value as a tool in daily practice.
Lithium has proved to be a highly effective preventive measure in mood disorders and an increasing number of patients are receiving long-term lithium carbonate therapy. Among other biologically and clinically important effects of lithium, the possible induction of hyperparathyroidism was first suggested in 1973 by Garfinkel et al. About thirty other case reports have since been described, but they could simply have represented the coincidental occurrence of primary hyperparathyroidism and lithium carbonate treatment in the same patients. Eleven cross-sectional studies of calcium metabolism in patients treated with lithium carbonate have been reported. Evidence of a causal relationship of lithium to hyperparathyroidism can lead to a loss of effectiveness of lithium in controlling the affective symptoms. Interestingly, coexistence with hypothyroidism is not uncommon. Low serum phosphate, high serum chloride are also observed. Bone mineral content may decrease. In addition, several studies have shown that lithium treatment increases serum magnesium level. Unusual metabolic features are associated with hyperparathyroidism and long-term lithium treatment: low urinary calcium excretion, absence of nephrolithiasis, and normal urinary cyclic AMP excretion. Lithium inhibition of PTH sensitive adenylcyclase in the kidney would explain these features. In vitro studies suggested that lithium is a potent inhibitor of several hormone responsive adenylcyclase systems. It is possible that the tissue susceptibility to adenylcyclase inhibition in an individual may decide the nature of endocrine dysfunction seen during lithium treatment. Information about the time course with which abnormalities may develop is derived from longitudinal studies. Several months to several years are needed for lithium inducing primary hyperparathyroidism. In vitro studies provide strong evidence that lithium can induce a shift in the set-point for inhibition of PTH secretion by calcium and a direct stimulation of PTH secretion. The extent to which we can extrapolate these data to the clinical situation is discussed. In vivo data from Shen an Seely are compatible with these two mechanisms. These alterations should cause parathyroid hyperplasia. The possibility that a generalized parathyroid stimulus might lead to formation of a single adenima is not proved. Several recommendations regarding parathyroid function in patients receiving lithium have been suggested. Measurement of total calcium and serum proteins or of serum calcium ion values when available should be performed before therapy is begun. If elevated values are obtained, lithium treatment should be deferred and evaluation for hyperparathyroidism performed. Serum calcium should be monitored periodically during lithium treatment. Sustained hypercalcemia or true hyperparathyroidism require parathyroidectomy. If hypercalcemia is mild without complication and psychiatric symptoms well controlled, perhaps surgery should not be employed.
Intermittent hemodialysis is considered the modality of choice when enhanced lithium removal is indicated. However, postdialysis rebound in serum lithium concentration is frequently observed after the dialysis sessions and results from incomplete intracellular removal. Continuous renal replacement therapy could provide a more gradual and complete lithium removal since it is performed over longer time periods, thus avoiding rebound following therapy. Seven patients presenting with symptomatic lithium intoxication were treated by continuous renal replacement therapy (continuous arteriovenous and venovenous hemodiafiltration [CAVHDF and CVVHDF]). For CAVHDF, the dialysate flow rate was increased to 4 L/hr to optimize solute clearances. Five intoxicated patients (four acute and one chronic) were treated by high dialysate flow rate (HDFR) (4 L/hr) CAVHDF and two patients with chronic poisoning were treated by CVVHDF, one with a dialysate flow rate of 1 L/hr and one with a dialysate flow rate of 2 L/hr. Serum lithium concentrations for the four acute poisoning cases were 4.0, 4.6, 4.4, and 3.2 mEq/L, at initiation of HDFR CAVHDF, and decreased respectively to 1.2, 0.8, 1.2, and 1.1 mEq/L after 15, 19, 35, and 21 hours of treatment. No lithium rebound was observed over 24 to 36 hours following CAVHDF. For the three chronic intoxication cases, serum lithium concentrations dropped from 1.7, 2.2, and 3.8 mEq/L to 0.7, 0.17, and 0.4 mEq/L, respectively, after 18, 42, and 44 hours of HDFR CAVHDF or CVVHDF. The chronic case treated for only 18 hours presented a slight rebound in lithium level (0.3 mEq/L), whereas no significant rebound was observed for the two other cases treated for longer periods. Mean +/- SEM dialyser urea, lithium, and creatinine clearance during HDFR CAVHDF were 50.5 +/- 5.0, 41.4 +/- 4.6, and 37.6 +/- 3.7 mL/min, respectively (number of measurements = 41). Dialyser lithium clearance during CVVHDF was 48.4 +/- 1.4 mL/min (n = 10) and 61.9 +/- 2.3 mL/min (n = 7), with dialysate flow rates of 1 and 2 L/hr, respectively. Mean dialyzer lithium removal for the seven cases was 106.4 mEq, while mean renal lithium removal was 21.5 mEq during the same period. We conclude that HDFR CAVHDF and CVVHDF are effective alternatives to intermittent hemodialysis for treatment of lithium poisoning. They provide excellent lithium clearances (60 to 85 L/d); in addition, because of their continuous nature, they prevent posttherapy lithium rebound by allowing a more gradual and complete removal from intracellular compartments, and they may be particularly useful in chronic poisoning in which intracellular lithium accumulation is more extensive.
BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them lithium. OBJECTIVES: To review the effects of lithium for the treatment of schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's register (March 2002). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted pharmaceutical companies and authors of relevant studies to identify further trials and to obtain original patient data. SELECTION CRITERIA: All randomised controlled trials comparing lithium to antipsychotics or to placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted independently by at least two reviewers. Dichotomous data were analysed using relative risks (RR) and the 95% confidence interval (CI) estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics were calculated. Continuous data were analysed using weighted mean differences (WMD). MAIN RESULTS: The review currently includes 20 studies with a total of 611 participants. Most studies were small, of short duration and incompletely reported, but a number of authors were willing to share their data with us. Three studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed. In eight studies comparing lithium with antipsychotic drugs as the sole treatment more participants in the lithium group left the studies early (n=270, RR 1.8, CI 1.2 to 2.9, NNT 9, CI 5 to 33). Several of the outcomes relating to these studies suggested that lithium is less effective than antipsychotic drugs, but it was difficult to summarise the data, because a variety of rating scales were used in the studies. Eleven studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (n=244, RR 0.8, CI 0.7 to 0.96, NNT 8, CI 4 to 33). However, statistical significance became borderline when participants with schizoaffective disorders were excluded in a sensitivity analysis (n=120, RR 0.8, CI 0.6 to 1.0, p=0.07). Furthermore, more participants in the lithium augmentation groups left the studies early (n=320, RR 2.0 CI 1.3 to 3.1, NNT 7, CI 4 to 14), suggesting a lower acceptability of lithium augmentation compared to those on antipsychotics alone. No superior efficacy of lithium augmentation in any specific aspect of the mental state was found. While based on very little data, there were no differences between groups for adverse events. REVIEWER'S CONCLUSIONS: There is no randomised trial based evidence that lithium on its own is an effective treatment for people with schizophrenia. The evidence available on augmentation of antipsychotics with lithium is inconclusive, but it justifies further, large, simple and well-designed trials. These should concentrate on two target groups: 1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, 2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use.
The potential effects of lithium chloride on the neuromuscular transmission and muscular contraction were studied using in vitro and in vivo nerve-muscle preparations of rats. Addition of lithium chloride to the fluid bathing the isolated rat diaphragm produced a concentration-dependent inhibition of diaphragmatic contractions elicited by either indirect or direct electrical stimulation. The threshold concentrations were 1 mmol l(-1)and 3 mmol l(-1), respectively. Similarly, the intravenous administration of lithium chloride as bolus injections, produced a dose-dependent progressive inhibition of the indirectly- and directly-induced gastrocnemius muscle contractions during the 2-h period of investigation. The indirectly-induced contractions were much more sensitive to the inhibitory effect of lithium chloride than directly-induced contractions. Also, lithium chloride was found to be capable of enhancing the paralysis of the indirectly stimulated rat diaphragm in vitro and gastrocnemius muscle in vivo induced by either pipecuronium or succinylcholine. The combination of lithium chloride and pipecuronium led to a synergistic inhibition of the neuromuscular transmission, while the combination of lithium chloride and succinylcholine led to additive inhibition. Pretreatment with lithium chloride at the threshold concentrations enhanced the inhibitory effects of verapamil on diaphragmatic contractions elicited either indirectly or directly. The inhibitory effects of verapamil on the indirectly- and directly-induced rat gastrocnemius muscle contractions were potentiated by lithium chloride administration to rats. Glibenclamide was found to be capable of inhibiting the relaxant effects of lithium chloride on the indirectly- and directly-elicited contractions of rat diaphragm in vitro and rat gastrocnemius muscle in vivo, in a concentration- and dose-dependent manner, respectively. Doubling the concentration of magnesium in the bathing fluid potentiated the inhibitory effects of the threshold concentrations of lithium chloride on the diaphragmatic contractions induced either indirectly or directly. Pretreatment with 4-aminopyridine or barium chloride inhibited the relaxant effects of lithium chloride on the indirectly- and directly-elicited diaphragmatic contractions. The inhibitory effects of diazoxide on the indirectly-evoked contractions of rat diaphragm in vitro and rat gastrocnemius muscle in vivo were potentiated by lithium chloride. Pretreatment with glibenclamide inhibited markedly the combined effects of lithium chloride and diazoxide on the contractions of the diaphragm and gastrocnemius muscles induced indirectly. Additionally, the intravenous administration of lithium chloride into rats as bolus injections produced a dose-dependent progressive increase in plasma potassium level and a dose-dependent progressive decrease in the intracellular levels of adenosine triphosphate in the sciatic nerve and gastrocnemius muscle. It is concluded that lithium chloride, via activation of adenosine triphosphate- sensitive potassium channels, acts presynaptically to inhibit the neuromuscular transmission and acts at the muscle membrane to inhibit the muscular contraction.
Rats were treated with lithium administered either via the food or by intraperitoneal injection. Lithium administration via the food results in a rather stable serum lithium concentration, whereas lithium injection results in a varying serum lithium concentration whereby a sharp increase shortly after the injection is followed by an exponential decline until the next injection (Plenge et al. 1981). After 5 months of lithium treatment the 5HT transport protein, the beta-adrenergic receptor and several other brain proteins were determined. The 5HT transport protein, labelled with [3H]paroxetine, was found to be decreased in the lithium-injected rats (Bmax = 347 fmol/mg protein) but was unchanged in the lithium-fed rats (Bmax = 389 fmol/mg protein), as compared with control rats (Bmax = 396 fmol/mg protein), and therefore probably is a specific effect only seen with varying lithium concentration. In contrast, the neuronal membrane marker protein D3 was decreased in the lithium-fed rats (88% of the control value), and showed a trend towards decrease in the lithium-injected rats. The decrease in D3 in the lithium-fed rats may indicate some neuronal damage due to the continuous presence of lithium. This damage may be more pronounced than in rats, where periods of low lithium concentration enable repair to take place. The beta-adrenergic receptor and the neural cell adhesion molecule NCAM were unaffected by the different lithium treatment regimens. Lithium has been reported to inhibit the 5HT1B receptor (the serotonin autoreceptor).(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVES: To study the prophylactic efficacy of lithium administered every second day to patients with bipolar disorder or recurrent unipolar depressive disorder. METHODS: The study was carried out as a WHO multicentre study in five different psychiatric clinics: Russia (Moscow), Canada (Montreal), India (Lucknow), Germany (Munich) and South Korea (Pusan), with the lithium tablets being supplied from Denmark (Copenhagen). Participation in the study was conditional on the patient having been in prophylactic lithium treatment for the preceding 2-year period and having been free of depressive or manic phases during the preceding 6 months. After a 2-month baseline period during which lithium was administered every day, the treatment was changed to lithium intake every second day, this regimen in most cases being continued for 22 months. RESULTS: Forty-seven patients, 42 with a diagnosis of bipolar disorder and five with a diagnosis of recurrent unipolar depressive disorder, participated in the study. The number of patients from each centre ranged from six to 11. The mean lithium dose every second day was 36 mmol lithium, leading to a mean 12-h standard serum lithium concentration during the last month of treatment at 0.78+/-0.16 mmol/L. Lithium intake every second day was effective in 38 out of 47 patients. The remaining nine patients had recurrences, a number not differing from the 16 patients in the same group of 47 patients who, during the 2-year period preceding the study, had recurrences. The mean 12-h standard serum lithium concentration was lower in the patients who had recurrences than in those who stayed euthymic. The results suggest that to be effective when administered every second day, lithium must be given in a dose leading to a 12-h standard serum lithium concentration at 0.8 mmol/L or above. CONCLUSIONS: In the dose administered, lithium intake every second day was as effective as lithium intake every day. The amount and severity of lithium-related side effects were apparently not influenced by the change to lithium intake every second day.
BACKGROUND: Analyzing 24-h urine for lithium after consumption of lithium-tagged foods or supplements provides a validated compliance marker but is laborious. OBJECTIVE: Most studies involve blood sampling; therefore, we tested whether serum lithium concentration could be used as a compliance marker. DESIGN: We used serum lithium as a compliance marker in a dietary trial and an evaluation study. RESULTS: In the dietary trial, 78 volunteers consumed 500 mL yogurt tagged with lithium (250 micromol/d) for 6 wk. Serum lithium increased from 0.9+/-0.3 to 6.6+/-1.5 micromol/L, which was close to the predicted concentration, indicating that the subjects were highly compliant. However, the interindividual variability in serum lithium concentration was large. To test whether this variability resulted from compliance differences or natural variability, we performed an evaluation study: 12 subjects took a lithium supplement (250 micromol/d) for 13 d under supervision. Serum lithium increased from 0.14+/-0.03 to 3.9+/-0.8 micromol/L (range: 2.6-5.4 micromol/L); thus, there was wide interindividual variation in serum lithium despite 100% compliance. However, within-subject variability was small, with a CV of 7% for serum lithium measured on 4 different days. We checked whether taking half the dose on each of 2 d (125 micromol lithium/d) would significantly lower serum lithium. Indeed, serum lithium dropped in all subjects, by a mean of 1.0 micromol/L on the first day (P<0.0001) and by another 0.3 micromol/L on the second day (P = 0.0004). Thus, changes in serum lithium concentration of > or =1.0 micromol/L suggest altered compliance. CONCLUSION: Serum lithium concentrations after intake of lithium-tagged foods or supplements can be used to assess compliance in dietary trials.