Sodium-dependent lithium efflux from red cells in affective disorders

Steady state red blood cell/plasma lithium concentration ratios were determined simultaneously with the in vitro sodium-dependent downhill lithium efflux from red cells during maintenance lithium treatment in 22 bipolar depressed patients, 17 unipolar depressed patients, and 28 psychiatric control patients. The values of the sodium-dependent lithium efflux were significantly correlated with the steady-state lithium levels in red blood cells and plasma. A profound difference in sodium-dependent lithium efflux from red cells was found between controls and bipolar patients and to a lesser degree between controls and unipolar patients.     

碳酸锂治疗的躁狂发作患者血锂浓度与肾小球滤过率的关系

目的探讨锂盐代谢与肾小球滤过率的关系。方法收集52例接受碳酸锂治疗的躁狂发作患者,检测治疗前血肌酐、尿素氮、体表面积、血钠浓度等指标,同时根据肾脏病膳食改善(the modification of diet in renaldisease,MDRD)方程估算肾小球滤过率(estimated glomerular filtration rates,eGFR);在给予口服碳酸锂1.0 g/d 1周后测定稳态血锂浓度。对上述各项指标与血锂浓度进行相关分析。结果患者组的稳态血锂浓度为0.2～1.0 mmoL/L,平均(0.52±0.18)mmoL/L。单因素分析显示,血锂浓度与体表面积、eGFR负相关(r=-0.33,P=0.02;r=-0.30,P=0.03)。多元线性回归分析也显示血锂浓度与体表面积、eGFR间负相关(β=-0.31,P=0.02;β=-0.28,P=0.03),未发现血锂浓度与血肌酐、尿素氮相关(P>0.05)。结论本研究结果提示eGFR可以作为个体代谢锂盐能力的预测指标之一。     

Lithium distribution in mania: plasma and red blood cell lithium, clinical state, and monoamine metabolites during lithium treatment

We examined red blood cell (RBC) and plasma lithium concentrations and RBC/plasma lithium ratios in 14 manic patients during lithium treatment as part of the National Institute of Mental Health's Collaborative Program on the Psychobiology of Depression, Biological Studies. All of the lithium measures increased during treatment, especially RBC lithium. There were positive correlations between the RBC lithium concentration and the RBC/plasma lithium ratio and their maximal values in a single-dose pharmacokinetic experiment before treatment. After 5 and 16 days of treatment, patients with good subsequent outcome had higher RBC/plasma lithium ratios than did patients with poor outcome. Early in treatment, there was a negative correlation between lithium concentrations and severity of mania. During treatment, there was a negative correlation between RBC lithium and urinary MHPG excretion. There was a positive correlation between RBC or plasma lithium during the first few days of treatment and subsequent reduction in norepinephrine excretion during treatment. At 3 weeks, there were negative correlations between reductions in catecholamine measures and lithium concentrations. These data suggest that there are changes in the sensitivity of behavior and catecholamine function to lithium during treatment. RBC concentrations of lithium appear to be a potentially useful indicator of its behavioral and neurochemical effects.     

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

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

The effect of lithium on pupillary response to pulses of light in sheep

Administration of lithium carbonate to sheep in the dose range of 600–1800 mg/day resulted in a linearly described rise in lithium levels in plasma and red blood cells. In contrast to the rodent model but in agreement with the human condition, plasma lithium levels exceeded those of red blood cells. Polydipsia and body weight changes were not evident. At plasma levels of 0.70– 0.8 mM/1, lithium attenuated the ability of the pupil to constrict in response to 30-sec pulses of light in the 25–150 μW/cm² intensity range but not the ability to dilate in the dark. Thus, similar to observations in normal human volunteers and bipolar patients, lithium reduces sensitivity to light. The sheep is proposed as a useful model for studying the actions of lithium.     

Lithium side effects in relation to dose and to levels and gradients of lithium in plasma

The relation between lithium dose, lithium concentrations, and lithium gradients in plasma and the side effects tremor, nausea, abdominal pains, and loose bowels was studied in 19 subjects. Rapidly dissolving lithium carbonate tablets were used. Tremor was related to higher doses, to higher concentrations, and to higher gradients of lithium in plasma. Nausea was related to higher gradients. Abdominal pain and loose bowels showed no relation to doses, levels or gradients. Concentrations of lithium were dose-dependent, while gradients were relatively independent of dose.     

A novel, point-of-care test for lithium levels: description and reliability

BACKGROUND: Lithium is a highly effective agent for numerous psychiatric disorders but requires therapeutic monitoring because of its narrow therapeutic index. This article describes a novel instant blood test that will facilitate the routine monitoring process. METHOD: This instant blood test allows the clinician to take a finger-stick sample of whole blood and determine the plasma lithium level in a 2-minute period. This new test is compared with standard laboratory measurements for lithium in human subjects. The reliability of the new test is reported as agreement with standard laboratory values in 3 studies involving a total of 269 subjects. RESULTS: The test demonstrates extremely high reliability (r = 0.962, 0.928, 0.983 for studies 1-3, respectively) for the measurement of serum and plasma lithium levels as compared with standard laboratory measures. CONCLUSION: This new test is reliable and offers unique advantages over standard laboratory procedures for measuring lithium levels in patients.     

Plasma renin concentration during lithium therapy.

Plasma renin concentration was determined in patients given lithium treatment. In longitudinal study plasma renin concentration was determined in nine patients before the start of lithium treatment and at intervals during 3 months of treatment. In a transversal study, 18 patients given lithium treatment for 2--20 years were compared with 11 control persons. In the longitudinal study, plasma renin concentrations did not, during lithium treatment, deviate significantly from pre-treatment values. In the transversal study, values in the lithium treated patients did not differ significantly from values in the control group. There were no correlations, in the transversal study, between serum lithium concentrations and plasma renin concentrations. Our study indicates that the plasma renin concentration remains unaffected by lithium administered in nontoxic doses.     

Serum lithium minimum and diuresis

Serum lithium was analyzed over a 24-hour period in patients who were receiving lithium in one daily dose. Linear regression was performed with urine volume as the independent variable and lithium dose, maximum serum lithium concentration. 12-hour serum lithium, minimum serum lithium, length of treatment, and age of patients as the dependent variables. Only minimum serum lithium and urine volume showed a good positive correlation.     

Pharmacokinetics and toxicology of lithium

The pharmacokinetics of lithium is reviewed in regard to the pattern of lithium concentration in plasma, red blood cells, saliva and urine and to a four-compartmental model of lithium distribution. An overview of lithium toxicology is given summarizing the gastrointestinal, cardiovascular, endocrine, hematological, dermatologic, teratogenic and neurological side effects of lithium. The results of two controlled studies are described in detail. The investigation of thyroid function in 88 patients under lithium treatment revealed abnormally high values of TSH and/or of TSH response to TRH in 50% of the subjects. By use of daily protocols of eating and drinking over a period of 14 days, a distinctly higher caloric intake (from solid food, not fluids) was found in 10 patients who gained weight during lithium therapy as compared to 10 lithium-treated patients without weight gain.     

Erythrocyte lithium transport during lithium treatment in patients with affective disorders

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

Relationship between plasma, RBC, and CSF lithium concentrations in human subjects

Simultaneous measurement of plasma, RBC, and plasma lithium concentrations took place with 17 inpatients chronically treated with lithium, at various times after the last lithium dose. RBC lithium levels were significantly higher than CSF lithium levels. Specimens drawn 10 or more hours after the last dose showed higher RBC and CSF lithium and lower plasma lithium than specimens drawn 4 or less hours after the last lithium dose. None of the lithium measurements differentiated manic-depressives from schizophrenics or schizoaffectives. Plasma, RBC, and CSF lithium all intercorrelated highly and equally.     

Lithium effects: relation to lithium dose and to plasma peak levels.

In a 24-hour study, plasma peak lithium was determined in manic-melancholic patients who routinely had their entire lithium dose at night. A correlation analysis was undertaken of the relation of plasma peak level and the dose of lithium to a number of lithium induced changes: Increase in urine volume, weight gain, decrease in plasm phosphate, increase in plasma magnesium, decrease in plasma urea, increase in plasma alkaline phosphatase, increase in urinary pH. Only the changes in plasma phosphate and in urine pH were significantly correlated to the peak value of plasma lithium. The increase in urine volume was significantly correlated to the dose of lithium.     

Seasonal variations of lithium plasma levels

The aim of this study was to investigate the seasonal time course of lithium blood levels. We analyzed lithium plasma and red blood cell (RBC) levels in 186 subjects affected by bipolar (n=134) and major depressive (n=52) disorder, with stable oral dosage, followed in our lithium clinic for an average of 36 months. We observed a significant elevation of lithium plasma levels in summer with a more marked variation among early-onset subjects, bipolar subtype, and females. Lithium levels in plasma peaked in summer, and levels in RBC showed a trend in the same direction. Possible stratification factors such as presence of affected relatives or psychotic features did not significantly influence results. In conclusion, we observed a significant variation of lithium plasma levels according to seasons. If confirmed, this finding could have both clinical and research implications.     

Effects of bipolar affective disorder and lithium administration on the cholinergic system in human blood

Several processes relating to the cholinergic system that are present in human blood were measured in samples obtained from patients with bipolar affective disorder, both before and during treatment with lithium, and from controls. The biochemical measurements include RBC and plasma choline concentrations, the kinetics of RBC choline uptake, plasma non-specific cholinesterase and RBC and plasma acetylcholinesterase. The RBC choline level is increased and the Vmax of the RBC choline uptake system is decreased in samples from lithium-free bipolar patients during manic episodes. There are no differences from control in the plasma choline levels or in the acetylcholinesterase enzyme activities in blood samples from the lithium-free or lithium-treated patients. Plasma non-specific cholinesterase is below control levels in all patients. Lithium treatment increases the RBC choline concentration to more than ten-times control levels and reduces the Vmax and the affinity for choline of the RBC choline transport system. In vitro addition of lithium does not replicate the effects of in vivo administration of lithium. Possible mechanisms for these effects of lithium are discussed.     

Renal insufficiency in long-term lithium treatment

OBJECTIVE: To compare long-term lithium patients who developed renal insufficiency (RI) with those who did not, and to examine what characterized these groups. METHOD: One hundred fourteen subjects with DSM-IV bipolar, major depressive, or schizoaffective disorder who had been taking lithium for 4 to 30 years from 1968 to 2000 were studied retrospectively. Subjects with blood creatinine levels > or = 1.5 mg/dL were defined as RI patients, and creatinine levels < 1.5 mg/dL indicated no renal insufficiency (NRI). Ninety-four unmedicated subjects, matched for sex and age, served as a comparison group and had 2 measures of creatinine with a mean interval of 11.88 years. RESULTS: Twenty-four (21%) of the lithium-treated patients were defined as RI patients. These subjects exhibited the "creeping creatinine" phenomenon as their creatinine levels increased progressively. The NRI subjects showed no increase of creatinine levels in up to 30 years and remained comparable to the comparison group. RI was associated with episodes of lithium intoxication and diseases or medicines that could affect glomerular function, but not with sex, psychiatric diagnosis, age at onset of diagnosed disorder, duration of lithium therapy, serum lithium concentration, and cumulative lithium dose. CONCLUSIONS: Long-term lithium therapy did not influence glomerular function in an overwhelming majority of patients. However, about 20% of long-term lithium patients exhibited "creeping creatinine" and developed renal insufficiency.     

Interdependency of lithium ratio, plasma lithium level and clinical state in patients with affective disorders

The interrelationship between lithium ratio, lithium plasma level and the different clinical phases of 31 patients with bipolar affective disorder has been investigated. the interdependency of these variables was followed longitudinally during different phases of the illness while under lithium therapy. Although positive correlations between lithium ratio and lithium plasma levels were evident, the lithium ratio values in the euthymic group were significantly higher than those in the manic and depressive groups, independently of the plasma lithium level. Our data suggested that RBC/plasma lithium ratio might be a sensitive state dependent index in affective bipolar illness.     

Endocrine aspects of lithium therapy in Tourette's syndrome

The use of Lithium Carbonate (Li₂CO₃) therapy in Gilles de la Tourette syndrome is reported in one patient. The patient, a 22-year-old male, was treated with a daily dose of 900 mg of Li₂CO₃ to attain therapeutic blood serum lithium concentration between 0.76 and 0.87 mEq/L. Renal function tests, urine analysis and thyroid function tests were monitored in addition to determinations of serum gonadotropins and testosterone concentrations throughout the 8 months of the study. The neuroendocrine measurements indicate blunting of Thyrotropin Stimulating Hormone (TSH) response, to Thyrotropin Releasing Hormone (TRH) stimulation test, which may be due to lithium therapy. The patient's growth and development were normal. This case represents the first report of blunting of TSH response to TRH in Tourette's disease. The fact that this disease has an onset during childhood suggests the importance of monitoring various endocrine functions during lithium therapy.     

Accuracy of the Pepin method to determine appropriate lithium dosages in healthy volunteers

OBJECTIVE: To assess if the lithium dosage prescribed according to the Pepin method leads to therapeutic serum concentrations of lithium. METHODS: For 13 healthy volunteers, the initial daily doses of lithium were calculated according to the Pepin formula with a view to obtaining a serum lithium level of 0.8 mmol/L. Lithium was administered twice daily for 21 days, and blood samples were drawn daily, 12 hours after the last dose was taken. Dosage was adjusted if serum concentrations were below 0.6 mmol/L or above 1.0 mmol/L or if major side effects were reported. RESULTS: Daily lithium doses ranged from 1050 mg to 1950 mg (mean 1569 mg, standard deviation [SD] 291 mg), The mean serum lithium concentrations for weeks 1, 2 and 3 were 0.74 mmol/L (SD 0.19 mmol/L), 0.67 mmol/L (SD 0.22 mmol/L) and 0.69 mmol/L (SD 0.13 mmol/L), respectively. Within-subject variance was negligible. Sixty-eight percent of the serum lithium concentration measurements fell between 0.57 mmol/L and 0.83 mmol/L, and 84% fell within the recommended therapeutic range of 0.60 mmol/L and 1.20 mmol/L. CONCLUSIONS: The Pepin method is a safe but conservative method for predicting the appropriate daily dose of lithium.     

Comparison between saliva and serum lithium concentrations in patients treated with lithium carbonate.

The relation between serum and saliva lithium concentration was studied in patients treated with lithium carbonate. In 23 patients a highly variable saliva/serum ratio was found in simultaneous saliva and serum samples. In five patients studied during a period of 4-8 weeks three patients showed a high fluctuation in saliva/serum lithium ratio. In 20 patients saliva lithium concentrations varied unexpectedly in a second sample produced after 15 min. Although some authors report a high and stable relation between saliva and serum lithium concentration, we consider the saliva lithium level unreliable as a prediction of the serum lithium level in patients treated with lithium carbonate.