Days Of Lithium Treatment Research Articles

Dose optimization of lithium to increase the uptake and retention of I-131 in rat thyroid

The present study was undertaken to optimize the dose of lithium, with an aim to increase the retention of I-131 in the thyroid follicles while maintaining the euthyroid state. 24 female Wistar rats weighing 110 ± 20g were segregated into four groups. Animals in group I were fed standard laboratory feed and water throughout the period of experimentation. Animals in group II, III and IV were additionally fed with lithium in the form of lithium carbonate orally, at a dose of 10mg/kg body weight, 20mg/kg body weight, 30mg/kg body weight respectively. The dose of lithium was started 1 week prior to radioiodine administration and continued thereafter for another 8 days. After 7 days of lithium treatment, 0.48MBq of carrier-free I-131 was injected intraperitoneally into each rat, of the four groups. I-131 thyroidal uptake and biokinetics, as well as serum TSH, T3, T4 levels were estimated in all the treatment groups. A significant increase in the thyroid and whole body counts was observed after 4 and 24h of I-131 aministration in lithium treated rats, compared to control animals. An increase in thyroidal effective t1/2 and serum TSH levels, along with decrease in the levels of serum T3 and T4 was observed with a dose of 20mg/kg or higher. In Conclusion, a Lithium dose of 10mg/kg body weight in rats could increase the uptake of I-131 in the thyroid, without disturbing the control circulating levels of thyroid hormones.

Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment

Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

Mortality study indicates importance of persisting with lithium treatment regimen

The Brown University Psychopharmacology UpdateVolume 26, Issue 9 p. 4-4 What's New in Research Mortality study indicates importance of persisting with lithium treatment regimen First published: 13 August 2015 https://doi.org/10.1002/pu.30077Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract A nationwide cohort study of Veterans Health Administration (VHA) records has found significantly reduced nonsuicide mortality over the first 90 days of lithium treatment compared with valproate treatment, but increased mortality over 180 days relative to valproate in individuals discontinuing lithium treatment. Study authors stated that their findings point to the importance of emphasizing persistence with lithium treatment and engaging in close monitoring of patients who stop treatment. Volume26, Issue9September 2015Pages 4-4 RelatedInformation

Mitotic Figures in the Median Eminence of the Hypothalamus

The median eminence of the hypothalamus is part of the avenue by which neurosecreted hormones from the hypothalamic nuclei reach the pars nervosa (neural lobe) of the pituitary and eventually the bloodstream. Lithium treatment and osmotic stress increases the transport of neurosecretory hormones to the pituitary in the adult rat. Specialized astrocytes termed pituicytes in the pars nervosa of the pituitary participate in the secretory process and also develop considerable mitotic activity. The present work reveals similar mitotic figures in cells within the median eminence following 3 days of lithium treatment. The location and appearance of these mitoses add to the evidence that pituicytes are present in the median eminence. Moreover, mitoses occur within the ependymal (tanycyte) layer of the median eminence. Thus, the present results suggest that the tanycyte layer may contain pituicytes, indicating that the hypothalamus possesses specialized cells for modulating neurosecretion in response to osmotic challenges.

Expression of transporters involved in urine concentration recovers differently after cessation of lithium treatment

Patients receiving lithium therapy, an effective treatment for bipolar disorder, often present with acquired nephrogenic diabetes insipidus. The nephrotoxic effects of lithium can be detected 3 wk after the start of treatment and many of these symptoms may disappear in a few weeks after lithium use is stopped. Most patients, however, still have a urine-concentrating defect years after ending treatment. This prompted an investigation of the transporters involved in the urine concentration mechanism, UT-A1, UT-A3, aquaporin-2 (AQP2), and NKCC2, after discontinuing lithium therapy. Sprague-Dawley rats fed a Li2CO3-supplemented diet produced large volumes of dilute urine after 14 days. After lithium treatment was discontinued, urine osmolality returned to normal within 14 days but urine volume and urine urea failed to reach basal levels. Western blot and immunohistochemical analyses revealed that both urea transporters UT-A1 and UT-A3 were reduced at 7 and 14 days of lithium treatment and both transporters recovered to basal levels 14 days after discontinuing lithium administration. Similar analyses demonstrated a decrease in AQP2 expression after 7 and 14 days of lithium therapy. AQP2 expression increased over the 7 and 14 days following the cessation of lithium but failed to recover to normal levels. NKCC2 expression was unaltered during the 14-day lithium regimen but did increase 14 days after the treatment was stopped. In summary, the rapid restoration of UT-A1 and UT-A3 as well as the increased expression of NKCC2 are critical components to the reestablishment of urine concentration after lithium treatment.

Insulin-like growth factor binding protein-2 expression is decreased by lithium

Lithium has been shown to possess cytoprotective properties in both cellular and animal models. Moreover, previous studies indicate that lithium treatment alters the expression of insulin-like growth factor binding protein-1 (IGFBP-1), a critical modulator of insulin-like growth factor bioactivity. Given the critical roles played by insulin-like growth factors in cellular mitogenesis, differentiation, and cell death, and that IGFBP-2 is the major brain resident IGFBP, we assessed IGFBP-2 expression in primary cortical neuroncultures subsequent to lithium treatment. We report that 7 days of lithium treatment at therapeutically relevant doses attenuates the expression of IGFBP-2 mRNA and protein in a dose and time-dependent manner. Therefore, these results suggest a possible role for the insulin-like growth factor system in lithium's mechanism of action.

Symptomatic Treatment of Graves Hyperthyroidism With Lithium in States of Thionamide Adverse Reactions

In this retrospective study, we evaluate the efficacy and safety of lithium as a second-line treatment of hyperthyroidism. The data were retrieved from the hospital recordings of 12 patients with a mean age of 42 years. All patients had Graves disease, and they had initially been treated with propylthiouracil. Indications for the change of treatment to lithium were elevation of transaminases (n = 5), agranulocytosis (n = 2), allergic reaction (n = 1), elevation of transaminases and allergy (n = 2), dyspepsia (n = 1), and resistance to propylthiouracil therapy (n = 1). A total of 900 mg lithium daily was given in 3 divided doses. One patient experienced an allergic reaction to lithium with a severe urticarial rash after the second dose. The mean follow up with lithium therapy in the remaining 11 patients was 36 days. Euthyroidism was achieved in 2 patients after 45 and 120 days of lithium treatment. In 9 patients who received lithium, the thyroid hormone levels tended to decline. Nine patients received radioactive iodine (RAI) therapy and 2 thyroid surgery as definitive treatment. The lithium therapy was generally well tolerated except in 1 patient with a high serum lithium level, nausea, and vomiting. Our results suggest that lithium has a weak antithyroid effect and can restore euthyroidism in a small number of patients. It can be tried as a second-line, symptomatic treatment when adverse reaction or resistance to thionamides occurs.

Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice

Glycogen synthase kinase-3 (GSK-3) is an intermediary enzyme in various cellular pathways, and has been implicated in the pathophysiology and treatment of numerous diseases, including Alzheimer’s disease, diabetes, and bipolar disorder. There is therefore in developing potent, selective GSK-3 inhibitors for the treatment of these devastating illnesses. A concern, however, is that the Wnt-signaling pathway—of which GSK-3 is an important intermediary molecule—has been implicated in many human cancers. It is thus of considerable importance to determine if GSK-3 inhibitors have tumorigenic potential in systems predisposed to developing tumors by virtue of mutations of the Wnt-signaling pathway. We therefore investigated the effects of a GSK-3 inhibitor, lithium, in a murine model predisposed to the formation of tumors due to activation of the Wnt pathway—the adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mouse. We found that 60 days of lithium treatment did not produce a significant increase in the number of tumors in these genetically predisposed mice. Lithium treatment resulted in a modest overall increase in the tumor size. The APC (min) mouse has previously been shown to be a robust indicator of tumorigenesis, with large increases in tumor number observed in response to a variety of agents; thus, our results suggest that lithium—and perhaps other inhibitors of GSK-3—pose a low risk for the development of cancers of the Wnt pathway. These results are consistent with the available epidemiological evidence that long-term lithium therapy does not increase cancer morbidity or mortality, but rather is associated with reduced overall mortality in bipolar disorder.

Immune parameters in rapid cycling bipolar patients before and after lithium treatment

This study investigates immune function in rapid cycling bipolar patients and normal volunteers before and after 30 days of lithium treatment. Previous small studies in symptomatic bipolar patients suggested that nonspecific immune activation might be present. While studies of the effects of lithium on immune function found that lithium increased serum SIL-2RS in normal volunteers and seemed to normalize immune function in bipolar patients. We hypothesized that the immune profile of rapid cycling bipolar patients would also manifest immune activation that lithium treatment might normalize. The more stable serum immune measures (SIL-2RS and SIL-6RS) were increased in symptomatic rapid cycling patients and did normalize with lithium treatment. Lithium treatment increased IL-2, SIL-2RS and SIL-6RS in normal volunteers. These data suggest that rapid cycling bipolar patients may have mild immune activation which seems to normalize with lithium treatment.

Lithium administration affects gene expression of thyroid hormone receptors in rat brain

Even though lithium has received wide attention in the treatment of manic depressive illness, the mechanisms underlying its mood stabilizing effects are not understood. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood stabilizing effects. Since lithium was recently reported to alter thyroid hormone metabolism in the rat brain, the present study investigated whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression. Adult male euthyroid rats were either given a diet containing 0.25% lithium or one without lithium for 14 days. Rats were sacrificed in the evening and RNA was isolated from different brain regions to quantitate the isoform specific mRNAs of THRs. Following 14 days of lithium treatment, THRα1 mRNA levels were increased in the cortex and decreased in hypothalamus; THRα2 mRNA levels were increased in the cortex and THRβ mRNA levels were decreased in the hypothalamus. No significant difference in the expression of these THR isoforms was observed in the hippocampus or cerebellum. Thus, chronic lithium treatment appeared to regulate THR gene expression in a subtype and region specific manner in the rat brain. It remains to be determined whether the observed effects of lithium on THR gene expression are related to its therapeutic efficacy in the treatment of bipolar disorder.

Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated 32P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder.

Effects of haloperidol, lithium, and valproate on phosphoinositide turnover in rat brain

The effects of acute, subacute, and chronic treatment with haloperidol, lithium, and valproate on inositol phosphate (IP) formation were examined. Acute treatment with haloperidol or the combination of haloperidol and lithium significantly reduced IP basal cortical levels. Subacute (three days) treatment with lithium decreased the IP basal level in the frontal cortex. Chronic treatment with haloperidol (14 and 28 days) caused a significant attenuation of carbachol-sensitive IP accumulation in the frontal cortex and striatum and a significant decrease in norepinephrine (NE)-induced IP formation in the frontal cortex (14 and 28 days) and striatum (28 days). Lithium treatment for 14 days produced a significant reduction in the IP basal cortical value, and a significant reduction in cortical carbachol- and NE-induced IP formation was found after 28 days of lithium treatment. The combination of haloperidol and lithium for 28 days decreased the striatal carbachol- and cortical NE-induced IP accumulation and caused a significant increase in NE-sensitive IP formation in the striatum at 14 days. Valproate treatment for 28 days was associated with a significant attenuation in striatal agonist-stimulated IP formation. Therefore, three drugs with different specificities for primary neurotransmitters may have common effects on second-messenger systems.

Lithium Treatment Increases Norepinephrine Turnover in the Plasma of Healthy Subjects

To the Editor.— Manji and associates 1 reported that 2 weeks of treatment with lithium enhanced norepinephrine (NE) levels in plasma and urinary NE and normetanephrine (NMN) excretion in normal subjects, while 1 week of treatment with lithium did not. These temporally specific effects of lithium treatment on NE turnover have been suggested to be connected to desensitization of presynaptic-2— adrenergic receptors in peripheral sympathetic nerves. We confirm these results and spec ify the temporal action of lithium salts on plasma NE turnover. Our study in healthy volunteers compared levels of dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of NE in the central nervous system, in plasma before, during, and after 20 days of lithium treatment. We administered lithium carbonate during 20 days to seven volunteers (five men and two women aged 30 to 40 years) in good health from whom informed consent was obtained. Lithium was administered at 9 AM

Lithium: Evidence for reduction in circulating testosterone levels in mice following chronic administration

Lithium, the widely-used antipsychotic drug, is known to exert adverse effects on a number of endocrine organs. In the present investigations, the effects of chronic lithium administration on circulating levels of testosterone and plasma and pituitary levels of luteinizing hormone (LH) were evaluated in order to examine whether or not the pituitary-gonadal axis is a probable target of lithium action. Adult male C57BL/6 mice, maintained on a fixed photoperiodism (LD 14:10), were administered lithium orally, by being fed on a specially prepared chow containing 0.4% lithium chloride for 15 or 30 days, while their matched controls were maintained on standard laboratory chow. At the termination of the respective experimental schedules, the animals were decapitated, their blood collected, and plasma was separated and stored frozen. Pituitaries were quickly removed, weighed, homogenized, centriguged and their supernatants were stored frozen. Testosterone in plasma and LH in pituitary and plasma were quantitated by standard RIA methods. Plasma Li concentration was determined by using flame photometric methods. A significant suppression in testosterone levels was noted after both 15 (p < .01) and 30 (p < .05) days of lithium treatment, but both pituitary and plasma LH levels remained unchanged at both the periods. It is, therefore, suggested that lithium exerts its effect directly at the level of the Leydig cells rather than through the pituitary-gonadal axis. Since the noted lithium-induced reduction of testosterone was manifested when the plasma lithium levels were within (or around) the therapeutic range, these results may have important clinical implications.

Lithium treatment of mania: Clinical characteristics, specify of symptom change, and outcome

The effects of lithium treatment and prediction of response in 18 manic patients were studied as part of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression. Patients were rated using the Mania Diagnostic and Severity Scale (MADS) and an additional battery of behavioral constructs developed for measurement of state and drug response in depressed patients. About 67% of the patients had good treatment outcome after 26 days of lithium treatment. Responders did not differ from nonresponders before treatment with respect to delusions, hallucinations, or irritable-paranoid symptoms. Nonresponders were rated as more anxious than responders before treatment and had higher scores on the Hamilton Rating Scale for Depression. Improvement on the MADS, however, did not correlate with pretreatment behavioral ratings. Patients with relatively high ratings for aspects of behavior not specific to mania tended to improve in these regardless of change in MADS score. Manic patients who were also depressed (44%) had higher mania ratings than manic patients who were not depressed. Patients with concomitant depression and mania had significantly worse overall treatment outcome, although their depression ratings improved during lithium treatment.

Lithium-induced changes in the plasma and pituitary levels of luteinizing hormone, follicle stimulating hormone and prolactin in rats

Adult male Sprague-Dawley rats, maintained under a controlled photoperiod of LD 14:10 (white lights on at 06:00 h, CST), were injected with lithium chloride and changes in the levels of plasma and pituitary homogenates of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were examined to evaluate the effects of this anti-manic drug on reproductive function. Two groups of rats were injected with lithium chloride intraperitoneally, twice daily at 09:00 and 16:00 h, for 2 and 7 days at a dosage of 2.5 meg/Kg body weight. Plasma and pituitary levels of LH, FSH and PRL were measured by radioimmunoassay. Plasma levels of LH were significantly (P<0.05) increased after 2 days of lithium treatment. In contrast, a significant (P<0.005) reduction in plasma levels of LH was evident when lithium injections were continued for 7 days. The plasma levels of FSH remained unaffected by lithium treatment by either time period. Lithium administered for 2 days did not bring about any significant alteration in the plasma levels of PRL, although there was a significant (P<0.002) reduction in plasma PRL levels after 7 days treatment. The concentrations of pituitary LH, FSH and PRL remained unchanged after 2 and 7 days of lithium treatment.

The effect of lithium on platelet monoamine oxidase activity in bipolar and schizoaffective disorders.

Platelet monoamine oxidase (MAO) activity was studied in 33 in-patients with bipolar and schizoaffective disorder who were treated with lithium. Platelet MAO activity was found to increase following 10-41 dys of lithium treatment compared to a prior drug free period, and the increase was positively correlated with the duration of lithium treatment. The increase in platelet MAO activity was not correlated wtih clinical improvement as measured by the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment Scale (GAS). The number of platelets per unit of blood was also significantly correlated with the number of days of lithium treatment. However, the increase in the number of platelets in lithium-treated patients was not correlated with the increase in MAO activity and thus appears not to account for it. These results indicate that studies relating platelet MAO activity to psychiatric diagnosis should be interpreted cautiously if patients are receiving lithium carbonate.

Weight gain and body composition in lithium treated rats.

Long-term lithium treated growing animals given 0.8-2.0 mmol/kg/day had a slightly but significantly faster weight gain than control animals. Greater doses did not give rise to significantly increased weight gain. Body composition, i.e., the percentage of water, fat, ash and "protein" was not affected in the faster growing lithium treated animals. The wet weight and the weight after drying of the stomach (with content) was increased shortly (hours) after the acute administration of lithium. The duration of the effect depended on the dose given. The weight of the large intestine was also increased after a dose of lithium, but only after some days of lithium pretreatment and mainly the wet weight. The effect was small but similar on the small intestine. In long-term lithium treated rats did the faecal weight and volume increase mainly due to increased water content, but only after some days of lithium treatment.

The effects of chronic lithium chloride administration on complex schedule performance, activity, and water intake in the albino rat

In an attempt to examine the behavioral effects of lithium, rats were trained on a multiple schedule consisting of fixed-ratio, fixed-interval, and time-out extinction requirements, and were subjected to lithium chloride in doses of 1.5, 2.5, and 3.0 meq/kg/day administered for 15 days at a time. The performance on the 5 days preceding the drug was compared to the performance on the last 5 days of lithium treatment. While there was a significant increase in water consumption in the two higher dose groups, there was little effect on the schedule performance of the 2.5 meq/kg dose group and no effect upon the activity of any group. The 3.0 meq/kg dose tended to result in prolongation of the postreinforcement pauses on the fixed-ratio portions of the schedule and to truncate the fixed-interval response curve.

Effects of lithium on adrenergic function in man.

Lithium is an effective agent in the treatment of mania. Since an abnormality of biogenic amines has been postulated to be a causative factor in mania and depression and since lithium has been found to alter biogenic amines in many animal systems, the effects of lithium on adrenergic function in man was investigated. The blood pressure response to infused norepinephrine (NE) and tyramine was investigated in 8 hypomanic patients who were studied during a control period and after 7 to 10 days of lithium treatment. Lithium decreased the pressor effect produced by NE by 22 ± 0.6 per cent. Lithium failed to alter the pressor effect to infused tyramine. Lithium failed to alter platelet serotonin content. Lithium decreased the pressor response to infused NE in man.