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PubMed2006

Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium.

Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 (3 outbred) mouse strains. In our initial screening, mice received either (1) no drugs, (2) LiCl only, (3) d-amphetamine only, or (4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the d-amphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function.

Animals↗
PubMed1992

Lithium clearance in dogs: effects of water loading, amiloride and lithium dosage.

1. The influences of lithium dosage, urine flow rate and acute administration of amiloride on the renal handling of lithium in normal conscious dogs were investigated. 2. Lithium was administered in the diet at daily doses of 100 mg or 2 mg of lithium carbonate for the 2 days preceding the investigation. Urine flow rate was altered by water loading with and without arginine vasopressin infusion (5 pg min-1 kg-1). Amiloride was administered as an intravenous bolus (130 micrograms/kg) followed by a continuous infusion (1.22 micrograms h-1 kg-1). 3. Glomerular filtration rate (exogenous creatinine clearance) did not change within series and was not different between series; it averaged 3.27 ml min-1 kg-1. Control levels of fractional lithium excretion (12.4 +/- 1.2%, mean +/- SEM) were not influenced by hydration, hydration plus arginine vasopressin administration or the lithium dosage. However, in hydrated dogs having a plasma lithium concentration of 130-140 mumol/l, amiloride administration was associated with a 5% increase in fractional lithium excretion (P less than or equal to 0.01). 4. It is concluded that distal tubular lithium reabsorption may take place in sodium-replete conscious dogs undergoing water diuresis. The low fractional lithium excretion even during amiloride infusion (14.1-16.8%) may well be due to a high fractional reabsorption of lithium in the proximal tubules; however, a significant reabsorption of lithium distal to the proximal straight tubules by amiloride-insensitive pathways cannot be excluded.

Amiloride↗
PubMed2005

Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat.

Bipolar affective disorders can be successfully treated with long-term use of the mood stabilizer lithium. However, discontinuation of lithium treatment is followed by a high incidence of manic episodes. In the present study, we attempted to identify neurobiological changes that might mediate this rebound mania. In vivo microdialysis in the anaesthetized rat and in situ hybridization histochemistry were used to study the effect of chronic lithium treatment and withdrawal from chronic lithium treatment on presynaptic dopamine (DA) function. Rats were maintained for 28 days on a lithium diet or control diet. The lithium-withdrawn treatment group had their lithium diet substituted for control diet from day 25 of the treatment period. Microdialysis probes were implanted in the shell of the nucleus accumbens and both basal extracellular DA levels and DA levels in the presence of the DA uptake inhibitor bupropion (1 microM) were collected. Basal DA levels did not differ between any of the treatment groups. However, during local perfusion of bupropion, the increase in DA was significantly attenuated in the lithium-treated animals compared to controls or lithium-withdrawn animals. In situ hybridization of DA transporter mRNA in the ventral tegmental area revealed no difference in the abundance of this mRNA in any of the groups. These data suggest that there is impaired DA release in rats during chronic lithium treatment, but DA release returns to normal levels on withdrawal from lithium treatment, and is therefore unlikely to underlie the rebound mania associated with lithium withdrawal.

Animals↗
PubMed1994

Study of lithium absorption by users of spas treated with lithium ion.

This study examines the possible dermal absorption of lithium ion into the blood serum of spa/hot tub bathers. Fifty-three participants (28 males and 25 females) spent 20 minutes per day, 4 days per week for 2 consecutive weeks in one of two assigned spas. The participants were randomly assigned to one of the two spas after matching based on sex, age, and use of oral contraceptives. The test spa contained 40 +/- 5 ppm lithium ion, while the control spa contained no additional lithium ion above the background levels of approximately 0.02 ppm. The exposure in the spa treated with lithium ion (from lithium chloride) simulated the maximum exposure that would be expected in a spa sanitized with lithium hypochlorite. The two spas were maintained at 101 +/- 2 degrees F. Serum lithium ion levels before and after spa use were determined using graphite-furnace atomic absorption spectroscopy with a minimum detectable level of lithium ion in serum of 2 micrograms l-1 (ppb). There was no statistically significant difference in serum lithium levels between the control and treatment group at any stage. We conclude that dermal exposure to lithium ion (as would be present after treatment of a spa with lithium hypochlorite) did not result in a detectable increase in the serum lithium ion level.

Baths↗
PubMed1983

Effect of lithium carbonate plus oxymetholone vs. lithium alone on chemotherapy-induced myelosuppression.

To evaluate the possible additive leukocyte count-enhancing properties of lithium and oxymetholone, patients (1-21 years old) were randomized to receive lithium or lithium plus oxymetholone after chemotherapy. Seventy-one trials with lithium, 63 with both drugs, and 79 in the control group, were compared. White blood cell count and neutrophil nadirs were better in both treatment groups than in the controls (p = 0.001) but an additive effect of oxymetholone above and over lithium alone was seen only in patients under 15 years old (p = 0.05). The median duration of severe neutropenia (absolute neutrophil count less than 1000/cm3) was 6.2 days/patient in the control group but only 4.5 days/patient and 3.8 days/patient in the lithium and lithium plus oxymetholone groups, respectively (p = 0.0001). Both the lithium and lithium plus oxymetholone treatments had a modest platelet-sparing effect (p = 0.03). No difference in the hemoglobin nadirs was observed in the three groups. While the majority of the patients lost weight in the control and lithium-treated group, the patients on oxymetholone gained weight (median 1.25 kg) p = 0.00001. Lithium reduces the period of neutropenia after chemotherapy during which the patients may acquire infection. The addition of oxymetholone does not substantially lessen myelosuppression in most patients but improves the patients' appetite and weight.

Adolescent↗
PubMed2007

Astroglia growth retardation and increased microglia proliferation by lithium and ornithine decarboxylase inhibitor in rat cerebellar cultures: Cytotoxicity by combined lithium and polyamine inhibition.

Lithium, the most prevalent treatment for manic-depressive illness, might have a neuroprotective effect after brain injury. In culture, lithium can exert neurotoxic effects associated with reduction in polyamine synthesis but neuroprotective effects as cultured neurons mature. Cumulative evidence suggests that lithium may exert some of its effects on neurons indirectly, by initially acting on glial cells. We used rat cerebellar cultures to ascertain the effects of lithium on ornithine decarboxylase (ODC) activity, the enzyme catalyzing the first step in polyamine synthesis, and to compare effects of lithium with those of the ODC inhibitor alpha-difluoromethylornithine (DFMO) on neuron survival and glial growth. Switching cultures from high (25 mM) to low (5 mM) KCl concentrations served as the traumatic neuronal insult. The results indicate the following. 1) Whereas high depolarizing KCl concentration enhances neuron survival, it inhibits astroglial growth. 2) Lithium (LiCl; 1-5 mM) enhances neuronal survival but inhibits astroglial growth. 3) Lithium treatment leads to reduced ODC activity. 4) DFMO enhances neuron survival but inhibits astroglial growth. 5) Lithium and DFMO lead to transformation of astroglia from epithelioid (flat) to process-bearing morphology and to increased numbers of microglia. 6) Combined lithium plus DFMO treatment is cytolethal to both neurons and glia in culture. In conclusion, lithium treatment results in growth retardation and altered cell morphology of cultured astroglia and increased microglia proliferation, and these effects may be associated with inhibition of polyamine synthesis. This implies that direct effects on astrocytes and microglia may contribute to the effects of lithium on neurons.

Animals↗
PubMed1992

Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements.

The lithium content of human hair shows an approximately linear response to extradietary lithium supplementation at dosage levels of up to 2000 micrograms/d. From the mean hair lithium concentration of 0.063 micrograms/g in 2648 predominantly American adults, and the reference hair lithium concentrations determined in the present study, the mean lithium intakes were calculated to be 730 micrograms/d. Hair lithium concentrations were extremely low in nearly 20% of the American samples, and in samples collected in Munich, Germany and Vienna, Austria. Hair lithium levels are low in certain pathological conditions, e.g., heart disease, in learning-disabled subjects, and in incarcerated violent criminals. The highest levels were observed in samples of a lithium-treated psychiatric patient. A statistically highly significant direct association was observed between the hair lithium and cobalt concentrations, which suggests a role of lithium in the transport and distribution of vitamin B12. Interactions of lithium with other trace elements are also discussed.

Adult↗
PubMed1982

Lithium and electrolytes plasma/RBC ratio and paradoxical lithium neurotoxicity.

1. Although lithium neurotoxicity and EEG disturbances are known to be associated with toxic plasma lithium levels, it may also be paradoxically manifested when plasma lithium levels are within the therapeutic range. 2. Plasma and RBC lithium and electrolytes levels were measured in 50 patients with affective disorders during the course of lithium therapy. Seventeen of them suffered from lithium neurotoxicity. 3. It is suggested that in the course of lithium treatment, in the manic and depressed phases as well as during prophylaxis, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone, even when the plasma lithium levels are within the therapeutic range. 4. In addition, an increase in the intra-erythrocyte sodium/potassium ratio was observed in toxic patients in comparison to non-toxic patients.

Adult↗
PubMed1983

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system.

Preliminary reports suggested that the addition of lithium carbonate to the regimen of patients treated with, but not responding to, a tricyclic antidepressant (TCA) drug can induce a rapid alleviation of depression. We examined the effect of lithium carbonate addition in 39 patients with unipolar depression whose conditions were not improved by at least three weeks' TCA drug administration. In 30 of 42 observations, lithium carbonate brought about a greater than 50% improvement within 48 hours. In a second study, the effects of lithium carbonate addition were compared in five amitriptyline hydrochloride-pretreated and five placebo-pretreated patients who showed no improvement after a three-week treatment. All five patients receiving amitriptyline showed a greater than 50% improvement 48 hours after lithium carbonate addition, whereas only one patient in the placebo group showed a marked response. In a third study the effect of lithium carbonate withdrawal was studied in nine TCA-resistant patients who had shown a marked improvement 48 hours after lithium addition. Only five of these patients had a relapse five days after lithium discontinuation. Since animal studies have shown that TCA drugs sensitize forebrain neurons to serotonin and that lithium enhances the activity of serotonin-containing neurons, we propose that the antidepressant effect of lithium addition in TCA-resistant patients might be mediated by enhancing serotonin neurotransmission.

Adult↗
PubMed2005

Effect of lithium and lithium withdrawal on potassium-evoked dopamine release and tyrosine hydroxylase expression in the rat.

The mood stabilizer lithium is used successfully in the treatment of bipolar affective disorder. However, treatment compliance is frequently poor and sudden withdrawal from lithium therapy is associated with a significantly increased risk of rebound mania. In this study we have used rodents to identify neurobiological changes in dopamine function occurring during chronic lithium treatment and withdrawal from chronic lithium treatment. Rats were maintained for 28 d on a lithium diet or a control diet. A subgroup had their lithium diet substituted with a control diet from day 25 of the treatment period. In-vivo microdialysis was used to study both basal dopamine release and potassium-evoked dopamine released in the shell of the nucleus accumbens. In-situ hybridization histochemistry was used to study the abundance of mRNA coding for dopamine's synthetic enzyme, tyrosine hydroxylase in the ventral tegmental area. Basal dopamine levels did not differ across any of the three treatment groups. However, the potassium-evoked dopamine release was significantly attenuated in lithium and lithium-withdrawn rats compared to control rats. Tyrosine hydroxylase mRNA abundance in the ventral tegmental area did not differ between any of the three treatment groups. These data suggest that decreased dopamine release may mediate the mood stabilizing action of lithium. However, in this paradigm a rebound increase in dopamine release was not found after withdrawal from lithium treatment.

Animals↗
PubMed1979

The erythrocyte lithium-plasma lithium ratio in patients with primary affective disorder.

Increasing attention has been given to the significance of intra-cellular concentrations of the lithium ion in patients treated with this drug. The erythrocyte has been the most common cell investigated because of its accessibility and certain similarities between the ion transport mechanisms of this cell and the neuron. Intraerythrocyte lithium is expressed as the ratio of lithium in the cell to the plasma lithium concentration (lithium ratio). The lithium ratio has been reported to be related to a number of clinical variables, including treatment response, clinical state, side-effects, toxicity, diagnosis, and electrophysiological effects. We have investigated the lithium ratio in a large series of patients with a primary affective disorder and in a smaller control group. We found a significantly higher mean lithium ratio in the bipolar diagnostic group than in the unipolar and control groups. There was a trend, not statistically significant, in the unipolar and bipolar groups for females to have higher lithium ratios than males. While not diagnostic, the lithium ratio appears to be another biological variable where bipolar patients, as a group, differ from normals and others with an affective disorder.

Bipolar Disorder↗
PubMed1978

Lithium effects on rat brain glucose metabolism in long-term lithium-treated rats studied in vivo.

The time course of lithium effects on several brain energy metabolites has been investigated in rats. The rats were injected once daily with lithium chloride and killed by freezing in liquid nitrogen 1--8 h after the last injection. The effect of lithium was most marked in the period in which the brain lithium concentration was increasing, whereas the effect was wearing off when the brain lithium concentration had stabilized, even though the lithium concentration was higher. These results led to the hypothesis that the effect of lithium on several parameters depends on the increase in lithium concentration following the administration of lithium, rather than on the absolute concentration of lithium.

Animals↗
PubMed1976

Effect of lithium on cardiovascular performance: report on extended ambulatory monitoring and exercise testing before and during lithium therapy.

To assess the effect of long-term lithium therapy on cardiac arrhythmias and cardiovascular performance, extended ambulatory electrocardiographic monitoring was performed in 12 patients, and rest and exercise electrocardiograms in 10 of 12, before and during lithium therapy. Lithium increased the frequency of premature ventricular contractions in three patients, decreased it in one, and produced no change in eight. Three of four patients with atrial arrhythmias showed improvement during lithium therapy. Exercise performance was unchanged. Although 7 of the 12 patients manifested T wave flattening in the resting electrocardiogram, none had S-T segment displacement at rest or on treadmill exercise. Before lithium therapy, arrhythmias on exercise included premature atrial contractions in four patients, ventricular arrhythmias in four (premature ventricular contractions in four, with couplets in two and with ventricular tachycardia in one). During lithium therapy, exercise did not provoke premature atrial contractions or ventricular tachycardia in any of the patients, but three patients had premature ventricular contractions (with couplets in one case). We conclude that lithium at therapeutic levels may precipitate or aggravate ventricular arrhythmias. When administered to patients with heart disease, factors that interfere with renal clearance of lithium (heart failure, salt restriction, long-term diuretic therapy) must be recognized and doses must be adjusted accordingly. Careful follow-up and electrocardiographic monitoring are advisable if lithium is to be used in the presence of ventricular arrhythmias. Cardiovascular performance as assessed by treadmill exercise testing was not affected by long-term lithium therapy.

Adult↗
PubMed1986

Acute lithium treatment suppresses the proestrous LH surge in mice: chronic lithium leads to constant diestrus.

Although the therapeutic usefulness of lithium in manic-depressive psychosis is now well-established, a number of basic and clinical studies in recent years have shown that the administration of this anti-manic drug produces a wide range of adverse endocrine and metabolic effects. The present study was undertaken in order to examine (a) what effects acute lithium administration might have on the preovulatory surge of luteinizing hormone (LH) during proestrus, and (b) whether chronic lithium administration has any adverse effect on the estrous cycle in C57BL/6 mice. Acute injections of lithium on the day of proestrus (at 10.00, 16.00 and 18.00 h; LD 14:10; lights on at 05.00 h CST) at a dosage of 5 mEq/kg b. wt. led to a significant (P less than 0.01) suppression of the LH surge that normally occurs in the evening of proestrus at 21.00 h. Chronic administration of lithium, on the other hand, resulted in a complete disruption in the regularity of the estrous cycle. This was characterized by an increasing number of mice showing a continuous diestrous vaginal smear during the first week of exposure to lithium, after which all of the lithium-treated mice completely stopped cycling and entered into constant diestrus. These results represent for the first time that lithium has significant adverse effects on the reproductive function in the female, especially in regard to the proestrous LH surge and estrous cyclicity in mice. Since these adverse effects were manifested under conditions when plasma lithium concentrations were within or around the therapeutic range, our results provide important conceptual information concerning possible adverse effects of lithium on the reproductive function in the human female.

Animals↗
PubMed1983

Effect of combined haloperidol-lithium treatment on vitro RBC lithium uptake in patients with affective disorders.

Combined treatment with haloperidol and lithium is a frequently employed strategy for the treatment of acute psychoses. Although this combination regime is safe in most clinical situations, under certain circumstances it has resulted in neurotoxicity, with organic brain syndrome, and ultimately, in some patients, irreversible brain damage and death. Plasma lithium levels in these neurotoxic patients are generally within the clinically acceptable range of 0.7 - 1.5 mEq/l, but RBC-lithium levels, when reported are abnormally elevated. To account for these observations we hypothesized that in vivo haloperidol will alter the transport of lithium across the RBC membrane and thus cause an increase in RBC lithium levels. We report preliminary results from a study that tested this hypothesis by measuring RBC lithium transport in vitro, in patients treated with a) haloperidol only, b) haloperidol, followed by haloperidol and lithium, c) combined haloperidol and lithium. In eight manic depressive patients in vivo haloperidol alone, or in combination with lithium resulted in a statistically significant (p less than 0.0001) reduction of the in vitro RBC Li+ uptake values. These results are interpreted as supportive of our hypothesis, that in vivo haloperidol alters the transport of lithium across the RBC membrane, and this effect can be detected by the use of a sensitive in vitro test. Work is currently in progress to evaluate, whether the RBC Li+ transport alteration is due to a direct effect of the drug on the cell membrane or secondary to some circulating factor, and to extend these findings to a larger sample of patients.

Bipolar Disorder↗
PubMed2004

Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder.

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithium-regulated genes, including alpha1B-adrenoceptor (alpha1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMP-dependent 3',5'-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that alpha1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that alpha1B-AR may play an important role in the mechanism of action of lithium treatment.

Adult↗
PubMed2005

Is the prophylactic antidepressant efficacy of lithium in bipolar I disorder dependent on study design and lithium level?

In the 1970s, several randomized controlled trials demonstrated significant antimanic and antidepressant properties of lithium in the prophylactic treatment of bipolar disorder. However, a recent meta-analysis of randomized, placebo-controlled trials of lithium in bipolar disorder found that its protective effect against depressive relapse/recurrence was equivocal. By examining potentially relevant parameters of recent randomized controlled trials with regard to lithium's prophylactic antidepressant efficacy, we try to identify factors which might help to explain these discrepant results across the different trials. Lithium's efficacy against manic relapse/recurrence appears rather robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment. Furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response. A lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence. To provide evidence-based guidelines on this issue, large prospective, randomized, double-blind, placebo-controlled trials are needed comparing the efficacy of lithium at different plasma levels against manic and depressive relapse/recurrence. In these trials, factors previously associated with predicting response to lithium should also be assessed.

Antidepressive Agents↗
PubMed1998

Comparison of 2 treatment strategies for depressed inpatients: imipramine and lithium addition or mirtazapine and lithium addition.

BACKGROUND: The purpose of this study was to compare the overall effectiveness of 2 treatment strategies for inpatients with severe major depressive episode (DSM-III-R): (1) mirtazapine (phase 1) and subsequent lithium addition (phase 2) or (2) imipramine (phase 1) and subsequent lithium addition (phase 2). We previously reported the results of phase 1. METHOD: In phase 1, patients were randomly assigned to treatment with either mirtazapine or imipramine, and doses were adjusted to obtain predefined blood drug levels. Nonresponders had lithium added to the double-blind mirtazapine or imipramine medication. The dose was adjusted to obtain a blood lithium level of 0.5-1.0 mmol/L. Treatment effects were evaluated weekly by the Montgomery-Asberg Depression Rating Scale for up to 2 weeks on this blood lithium level. RESULTS: Data for 100 patients were available for comparison of the 2 treatment strategies. 80 patients received no comedication. By the end of phase 2, 24 (48%) of 50 had responded to mirtazapine and 32 (64%) of 50 had responded to imipramine (intent-to-treat analysis). A survival analysis of the total patient group intent-to-treat showed a significant difference in favor of the treatment strategy with imipramine and subsequent lithium addition. CONCLUSION: Efficacy of imipramine and subsequent lithium addition for nonresponders is superior to the same treatment strategy with mirtazapine. This applies to the patient sample studied, which consisted of 100 severely depressed inpatients, 29 of whom were psychotically depressed. More serious side effects of imipramine, however, led to discontinuation of imipramine in 5 patients. No serious side effects were observed during the phase of lithium addition to either imipramine or mirtazapine. We, therefore, prefer to start treatment with imipramine and test for fixed blood drug levels, and, if necessary, add lithium. In the case of prohibitive side effects, patients are switched to a modern antidepressant such as mirtazapine, and, if necessary, lithium is added to this antidepressant.

Adult↗