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PubMed1975

Acute effects of lithium on the renal concentrating mechanism in a primate.

Although chronic lithium therapy has been associated with a defect in the urinary concentrating mechanism, short-term renal effects of lithium have received little attention in the intact animal. Solute-free water reabsorption (T-cH2O) and free water clearance (CH2O) were measured in primates of the genus Galago under control conditions and while animals were receiving either 0.5 mmol/kg-h or 1.0 mmol/kg-h lithium chloride (135 mM) intravenously. CH2O was unchanged by lithium infusion (P greater than 0.10), whereas T-cH2O was significantly depressed at all levels of osmolal clearance (P smaller than 0.01). Spontaneous recovery of near-normal T-cH2O was documented in two animals within 1 wk following acute lithium infusion. In addition it was observed that lithium-induced depression of T-cH2O could be partially prevented by pretreatment with intravenous amiloride. These results suggest that alterations in the renal concentrating mechanism can occur rapidly following the onset of lithium administration. They also imply that impairment of the renal concentrating mechanism by lithium is due at least in part to antagonism of the action of vasopressin on the collecting duct.

Amiloride↗
PubMed1976

Lithium-induced diuretic effect of antidiuretic hormone in rats.

The effect of a low dose of lithium (1 meq/kg per day) on renal function and its response to antidiuretic hormone (ADH) was studied in unanesthetized rats. This dose of lithium itself had no influence on renal water and electrolyte excretion, but lithium-treated rats responded paradoxically to exogenous ADH by increases in urinary volume, excretion of total solutes, sodium, potassium, and phosphate. Administration of ADH in the presence of lithium led to a lowering of urine osmolality, but free water clearance was not significantly reduced. Adenylate cyclase from the renal medulla of animals treated with ADH and lithium had a lower response to synthetic vasopressin in vitro than in animals treated with lithium alone. The results suggest that exogenous ADHis diuretic in the presence of a low concentration of lithilm. The predominant mechanism for this diuresis is probably inhibition of electrolyte and isomotic water reabbsorption in various nephron segments, including those proximal to the collecting ducts. ADH also markedly increased urinary excretion of lithium and appears to promote accumulation of lithium in the renal medulla.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

A micropuncture study of renal lithium reabsorption: effects of amiloride and furosemide.

The validity of the lithium clearance technique as a measure of end-proximal fluid delivery was assessed using micropuncture in sodium-replete, Inactin-anesthetized Sprague-Dawley rats. Three groups of animals were used: controls, amiloride treated, and furosemide treated. Diuretic-induced salt and water losses were replaced. Fractional lithium excretion (FELi) was 0.23 +/- 0.01, 0.24 +/- 0.02, and 0.40 +/- 0.03 in the control, amiloride, and furosemide groups, respectively. In each group, the tubular fluid-to-plasma lithium concentration ratio at the end of the proximal convoluted tubule (PCT) was significantly greater than unity (control, 1.16 +/- 0.03; amiloride, 1.16 +/- 0.02; furosemide, 1.17 +/- 0.02). In the control group, fractional lithium delivery (FDLi) at the late PCT was 0.50 +/- 0.02, while FDLi at the early distal tubule was 0.25 +/- 0.01; the latter did not differ significantly from FDLi at the late distal tubule or from FELi. Values in amiloride-treated rats were almost identical. Furosemide had no effect on FDLi at the late PCT, but raised that at the early distal tubule to 0.37 +/- 0.03. We conclude that 1) lithium reabsorption in the PCT lags slightly behind that of water, 2) substantial furosemide-sensitive lithium reabsorption occurs beyond the PCT, and 3) no significant lithium reabsorption occurs in nephron segments beyond the loop. These findings call into question the use of lithium clearance as a quantitative measure of end-proximal fluid delivery in sodium-replete animals.

Absorption↗
PubMed2000

Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study.

In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients' satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients' satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients.

Adult↗
PubMed1984

Erythrocyte lithium transport in bipolar affective disorders. The effect of membrane transport inhibitors.

Erythrocyte lithium influx and efflux were investigated in vitro in patients with bipolar affective disorders and in age- and sex-matched healthy controls. To explore the components of lithium influx and efflux five selected inhibitors (ouabain, phloretin, p-chloromercury benzene sulfonate [PCMBS], 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene, and lanthanium chloride) were employed. The mean values of lithium influx were similar in both populations of erythrocytes. The addition of ouabain and phloretin reduced lithium influx, but this effect was comparable in both patients and controls. PCMBS had an accelerating effect, and this was more pronounced in patients. Total erythrocyte lithium efflux from lithium-containing erythrocytes was comparable in both patients and controls. The addition of phloretin reduced RBC lithium efflux, the magnitude of this parameter, however, was similar in patients and controls. Erythrocyte lithium efflux was accelerated in the presence of PCMBS, and this effect was greater in patients. The relevance of these findings to the postulated cell membrane defect in affective disorders is evaluated.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1986

Effects of lithium on visual perception in manic-depressive patients without acute symptomatology.

Within a psychological theory of depression it is postulated that lithium influences the rigid and irregular patterns of psychic processes characterizing the premorbid state of patients with affective psychoses. Visual perception as a basic psychic function was, therefore, investigated in 16 patients, under long-term lithium treatment (= A), after 6 weeks of placebo (= B), after 6 weeks of reinstituted lithium (= A'). Series of clear, masked, and mixed stimuli (4 digit numbers) were presented tachistoscopically. It was found that lithium raises the perceptual threshold for all kinds of stimuli. Under lithium total performance for masked, i.e. complex stimuli was significantly changed, though not unidirectionally, if these stimuli were presented mixed with clear stimuli in randomized order. This finding of a lithium-induced increased variance of total performance, implying recognition and resolution of complex stimuli, was confirmed by a replication study in 6 patients having participated in the main study and being reexamined under continuous lithium medication without a placebo period. It is concluded that lithium modifies visual perception, and that possibly it influences the individual's expectancy towards the next stimulus during repeated exposures of mixed simple and complex targets.

Adult↗
PubMed1986

Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain.

The effects of lithium treatment on serotonin (5-HT) receptors in rat frontal cortex and hippocampus were investigated. Long-term lithium treatment strongly blocked 5-hydroxytryptophan-induced head twitches, while acute lithium administration by itself induced head twitches in rats, and ketanserin blocked this acute lithium action. Long-term administration of lithium decreased the number of not only 5-HT2 receptors in the frontal cortex but also 5-HT1 and 5-HT2 receptors in the hippocampus in rats. Decreases in 3H-5-HT binding to hippocampal 5-HT1 receptors and 3H-spiperone binding to frontal cortical 5-HT2 receptors, caused by chronic lithium treatment, were abolished by co-administration of p-chlorophenylalanine, and were enhanced by co-administration with methiothepin. The turnover of 5-HT in either frontal cortex or hippocampus was facilitated by lithium, and co-administered methiothepin enhanced this facilitation. These results suggest that long-term lithium treatment causes the down-regulation of postsynaptic 5-HT1 and 5-HT2 receptors, in part probably through its action on presynaptic nerve terminals.

5-Hydroxytryptophan↗
PubMed1993

Effect of lithium in murine immunodeficiency virus infected animals.

Murine AIDS (MAIDS) is a disease that shows many similarities to human HIV infection. The etiological agent of MAIDS is a defective murine leukemia virus that seems to be able to induce disease in the absence of viral replication. This animal model has been useful in stimulating the search of answers to questions and the formation of new hypotheses related to human AIDS. The monovalent cation lithium can influence a number of immunohematopoietic cell types and cellular processes where proliferation and differentiation occur. We describe here the result of in vivo studies investigating the effect of lithium treatment on MAIDS-infected mice. Viral control and lithium-treated animals were monitored for survival and development of MAIDS pathology. MAIDS animals treated with lithium demonstrated a marked reduction in their development of lymphadenopathy and splenomegaly. Both MAIDS control and lithium-treated virus-infected mice developed evidence of lymphoma; however, the involvement was much more massive both at the gross and microscopic levels in the MAIDS control compared with the lithium-treated mice. These data suggest that lithium may be effective in modulating murine immunodeficiency virus infection and raise important questions related to the potential role lithium may play in the pathophysiological processes associated with retroviral infections.

Animals↗
PubMed1983

Effects of lithium on the structure of the rat kidney.

Light and electron microscopy were used to study the effects of a lithium-supplemented diet on renal structure in the rat. At the end of a 7-week experimental period serum lithium levels were 1.14 +/- 0.20 mM. Lesions consisting of groups of dilated tubules were found in the immediate vicinity of the interlobular arteries in all experimental animals. These tubules were identified as the connecting tubule or the initial portion of the collecting tubule. The epithelium of these tubules was generally flattened but was punctuated by markedly swollen epithelial cells. PAS-positive deposits found in both types of cells were identified as glycogen. Electron microscopy revealed considerable lithium-induced damage in the swollen cells including increased numbers of mitochondria, many of which were swollen or otherwise damaged, dilated cisternae of endoplasmic reticulum and vacuolization of the apical cytoplasm. The flattened cells of these tubules were similar to the dark or intercalated cells of normal collecting tubules. Some detachment of epithelial cells from their basement membrane was evident in these tubules. Damage was less severe in distal convoluted tubules. Lithium-induced changes were not observed in glomeruli, proximal tubules or ascending thick limbs of Henle. In medullary collecting tubules damage was less severe than in cortical collecting tubules, but detachment of epithelial cells was a common finding. The interstitial tissue of the papilla exhibited histochemical and ultrastructural changes consistent with lithium blockade of the action of antidiuretic hormone. The ultrastructural damage to cortical tubules is similar to that found in patients receiving therapeutic lithium for long periods of time. The anatomic sites of lithium-induced pathology correspond to the location of lithium-induced pathophysiology.

Animals↗
PubMed1980

The relative prophylactic efficacy of lithium against manic and depressive recurrences in bipolar patients.

The relative prophylactic efficacy of lithium against manic and depressive recurrences was examined in 61 patients (22 males, 39 females) with bipolar manic-depressive disorders by comparing the number of manic and depressive episodes for each patient during equally long periods before and during lithium treatment. In all the patients, the percentage of depressive episodes during lithium was smaller than that of manic episodes. The better antidepressive than antimanic prophylactic effect of lithium was significant only in male patients, while the reduction of manic episodes during lithium was greater in females. The fraction of patients without depressive episodes on lithium was greater in the male group. The results obtained with this study design indicate that lithium is an effective antidepressive prophylactic agent in bipolar patients. Sex differences are also implicated in response to lithium prophylaxis.

Adult↗
PubMed1981

Effects of lithium on rat tail nerve conduction velocity.

Orthodromic and antidromic conduction velocities were measured in the tail nerve of rats given lithium throughout life. Lithium at nontoxic levels failed to influence nerve conduction velocities. Lithium at toxic levels (2 X 2.5 mmol/kg/day for 7 days) produced overt signs of lithium intoxication and reduced both orthodromic and antidromic nerve conduction velocities. The reductions in conduction velocities were related inversely to the level of lithium in serum and red blood cells. Conduction velocities returned to normal levels after cessation of the toxic lithium treatment. The findings show life-long administration of lithium at nontoxic levels to be without adverse effects on peripheral nerves in rats, while toxic lithium levels caused reversible impairment in conduction properties in peripheral nerves.

Animals↗
PubMed1989

Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age.

Case-control studies suggest that increased erythrocyte sodium-lithium countertransport may predict increased susceptibility to the development of essential hypertension. To characterize interindividual variation in sodium-lithium countertransport and its relation to blood pressure levels in the general population, we studied 1,475 Caucasians between 5 and 89 years of age (711 males and 764 females) ascertained through 266 households with children in the schools of Rochester, Minnesota. Individuals who were taking antihypertensive agents or combinations of estrogen and progesterone were not included in the sample. A third-order polynomial regression on age accounted for only a small fraction of variability in sodium-lithium countertransport (2.8% in males, p less than 0.001; 2.1% in females, p less than 0.01), whereas a fourth-order regression on age accounted for a large proportion of variability in systolic blood pressure (45.7% in males, p less than 0.001; 52.5% in females, p less than 0.001) and diastolic blood pressure (39.8% in males, p less than 0.001; 33.0% in females, p less than 0.001). Mean sodium-lithium countertransport was higher in males than females at all ages; but the rank order of male and female means for systolic and diastolic blood pressure was age dependent. Positively skewed distributions for age-, height-, and weight-adjusted sodium-lithium countertransport in male and female cohorts between 5-19.9, 20-49.9, and 50-89.9 years of age were explained significantly better by postulating a mixture of two partially overlapping sodium-lithium countertransport distributions rather than a single normal distribution (p less than 0.01). Among men in the 20-49.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with higher systolic and diastolic blood pressure (mean +/- SD) than values in the lower distribution (for systolic blood pressure: 115 +/- 11 vs. 111 +/- 11 mm Hg, p less than 0.07; for diastolic blood pressure: 71.2 +/- 8.0 vs. 68.4 +/- 8.6 mm Hg, p less than 0.08). Among females in the 50-89.9-year-old cohort, adjusted sodium-lithium countertransport values in the upper distribution were associated with significantly greater diastolic blood pressure than values in the lower distribution (77 +/- 10 vs. 70 +/- 9 mm Hg, p less than 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla.

Lithium, a widely used treatment for bipolar affective disorders, often causes nephrogenic diabetes insipidus. The effect of chronic lithium therapy on the expression of the vasopressin-regulated water channel Aquaporin-2 (AQP2) in rat kidney was examined. Membranes were prepared from inner medulla of one kidney from each rat, while the contralateral one was fixed for immunofluorescence and immunoelectronmicroscopy. Immunoblotting revealed that lithium treatment reduced AQP2 expression dramatically, to 31 +/- 8% after 10 d and to 4 +/- 1% after 25 d, coincident with development of severe polyuria. Immunofluorescence and immunogold quantitation confirmed the lithium-induced decrease in AQP2 expression (from 11.2 +/- 1.0 to 1.1 +/- 0.2 particles/microns 2). The downregulation was only partly reversed by return to lithium-free diet for 1 wk (40 +/- 8% of control). Furthermore, immunoblotting and immunogold quantitation revealed that 2 d of thirsting or 7 d of dDAVP treatment, in the continued presence of lithium, increased AQP2 expression by six- and threefold, respectively, coincident with increased urinary osmolality. Thirsting increased AQP2 immunolabeling mainly of vesicles, whereas dDAVP caused accumulation of AQP2 predominantly in the subapical region and plasma membrane. Thus, lithium causes marked downregulation of AQP2 expression, only partially reversed by cessation of therapy, thirsting or dDAVP treatment, consistent with clinical observations of slow recovery from lithium-induced urinary concentrating defects.

Animals↗
PubMed1991

Less frequent lithium administration and lower urine volume.

OBJECTIVE: This study was designed to determine whether patients maintained on a regimen of lithium on a once-per-day schedule have lower urine volumes than do patients receiving multiple doses per day. METHOD: This was a cross-sectional study of 85 patients from a lithium clinic who received different dose schedules. Patients were admitted to the hospital for measurement of lithium level, creatinine clearance, urine volume, and maximum osmolality. RESULTS: Multiple daily doses of lithium were associated with higher urine volumes. The dosing schedule, duration of lithium treatment, and daily dose of lithium did not affect maximum osmolality or creatinine clearance. CONCLUSIONS: Urine volume can be reduced by giving lithium once daily and/or by lowering the total daily dose. Lithium-induced polyuria seems to be related to extrarenal as well as to renal effects.

Depressive Disorder↗
PubMed1991

Comparison of the effects of hydrochlorothiazide and furosemide on lithium disposition.

OBJECTIVE: This study examined the interaction between lithium and diuretics, comparing both the pharmacokinetic and the pharmacodynamic variable of hydrochlorothiazide, furosemide, and placebo. METHOD: The study, which took place in an outpatient research clinic of a university hospital, used a double-blind, placebo-controlled crossover design. The subjects were normal, healthy male volunteers who responded to recruitment announcements. Thirteen subjects entered and completed the study. All subjects took lithium, 300 mg b.i.d., for 6 weeks. Hydrochlorothiazide, 25 mg b.i.d.; furosemide, 20 mg b.i.d.; and placebo were given during weeks 2, 4, and 6 in a random order of assignment. Serum lithium levels and indices of diuretic activity were measured during each week. RESULTS: The subjects' serum lithium levels after 5 days of taking hydrochlorothiazide were significantly higher than after 5 days of taking furosemide and placebo. At the doses studied, hydrochlorothiazide was also more potent than furosemide in increasing plasma renin activity, increasing sodium excretion, and decreasing lithium excretion. CONCLUSIONS: The observed differences between diuretics in effects on serum lithium may have been due to differences in the potency of the diuretics at the doses studied as well as in the site of action of the diuretic effect. The results must be interpreted cautiously, however, because the effects were small and of questionable clinical significance, and the study used healthy volunteers and low doses of lithium instead of psychiatric patients and the usual therapeutic levels of lithium.

Adult↗
PubMed2001

Lithium levels and toxicity among hospitalized patients.

OBJECTIVE: Although psychiatrists in the United States have used lithium for nearly 30 years, toxicity still occurs frequently. The authors report an attempt to reduce the incidence of lithium toxicity in hospitalized psychiatric patients and to identify factors associated with toxicity. METHODS: Serum lithium levels were monitored by the drug use evaluation committee at a psychiatric hospital between 1990 and 1996. Each laboratory result showing a serum lithium level of 1.5 mmol/L or more was promptly investigated, and the results were reported quarterly to the hospital staff association. RESULTS: The study found that in 6.8 percent of the 2,210 admissions during which lithium was administered, patients had serum levels of 1.5 mmol/L or higher. The number of excessive serum lithium levels decreased over the course of the study period. Only 27.8 percent of patients with excessive levels had signs and symptoms of toxicity. Of the excessive serum lithium levels that were investigated, 43.3 percent were detected in blood samples drawn at the time of admission. Women and elderly persons were significantly more likely to have excessive serum levels. Psychiatric diagnosis was not significantly associated with excessive serum levels. CONCLUSIONS: Education by the drug use evaluation committee may have helped to reduce the number of patients who experienced excessive lithium levels while hospitalized. Vigilance should be emphasized for women and elderly persons.

Adolescent↗
PubMed1995

Disabling parkinsonism due to lithium: a case report.

Two cases of disabling parkinsonism have been previously reported in association with lithium treatment and only one occurred without other signs of lithium toxicity. We report a case of an elderly female who suddenly developed disabling parkinsonism, apparently as a side effect from treatment with lithium carbonate without other signs of lithium toxicity. All neurologic symptoms completely resolved on discontinuation of lithium. Resuming lithium at serum levels below 0.7 mmol/L resulted in no further neurologic side effects, but serum levels of 0.7 to 0.9 mmol/L resulted in the return of mild Parkinson's symptoms. Older age, longer duration of lithium treatment, and high therapeutic levels of lithium may be risk factors for this side effect. Implications for clinicians are discussed.

Aged↗
PubMed1995

Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine.

BACKGROUND: This study was designed to establish whether (as suggested in a number of open and relatively small controlled trials) lithium augmentation is more effective than continued antidepressant alone, where response to a standard course of antidepressant treatment has been absent or partial. METHOD: Lithium or placebo was added on a double-blind basis for six weeks to the drug regime of 62 patients with major depressive illness (in both hospital and primary care settings) who had failed to respond to a controlled trial of fluoxetine or lofepramine. Response was defined as a final Hamilton Depression Rating Scale (HDRS) score of < 10. RESULTS: Response was seen more frequently in patients taking lithium (15/29) than in those remaining on antidepressant alone (8/32; P < 0.05). Rapid response to lithium augmentation (LA) was not consistently observed in this cohort. Mean HDRS scores after six weeks were significantly lower (P < 0.01) in the lithium group after excluding those who had not achieved significant exposure to lithium (arbitrarily defined as two or more lithium levels > or = 0.4 mmol/l). No differences in the efficacy of LA were apparent between fluoxetine and lofepramine. CONCLUSIONS: Our results confirm that LA is a useful strategy in the treatment of antidepressant-resistant depression. Partial response was, however, frequently observed with continued antidepressant treatment alone, and the superiority of LA appears to depend on achieving adequate serum lithium levels.

Adolescent↗