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PubMed1999

Lithium-associated clinical hypothyroidism. Prevalence and risk factors.

BACKGROUND: Rates of, and risk factors for, lithium-associated clinical hypothyroidism are uncertain. AIMS: To determine prevalence of and risk factors for clinical hypothyroidism in patients treated with lithium carbonate. METHOD: Retrospective case-note review of 718 patients who had undergone serum lithium estimation during a 15-month period. Patients on thyroxine had a more detailed review. RESULTS: The prevalence of clinical hypothyroidism during lithium treatment was 10.4%. The main risk factor was female gender (women 14% v. men 4.5%). Women were at highest risk during the first two years of lithium treatment, and women starting lithium aged 40-59 years had the greatest prevalence (> 20%). No equivalent risk factors emerged in men, although, like women, their prevalence of hypothyroidism was substantially higher than community rates. CONCLUSIONS: The high rates of clinical hypothyroidism identified may call for a review of the drug information given to women, particularly to those starting lithium in middle age. Consideration should be given to screening for thyroid antibodies before treatment in high-risk cases. Monitoring of thyroid function should take into account gender, age and stage of lithium treatment.

Adult↗
PubMed1999

Lithium as a potential adjuvant to 131I therapy of metastatic, well differentiated thyroid carcinoma.

As lithium inhibits the release of iodine from the thyroid but does not change iodine uptake, it may potentiate 131I therapy of thyroid cancer. The effects of lithium on the accumulation and retention of 131I in metastatic lesions and thyroid remnants were evaluated in 15 patients with differentiated thyroid carcinoma. Two 131I turnover studies were performed while the patients were hypothyroid. One was performed while the patient received lithium; the second served as a control study. From a series of gamma-camera images, it was found that lithium increased 131I retention in 24 of 31 metastatic lesions and in 6 of 7 thyroid remnants. A comparison of 131I retention during lithium with that during the control period showed that the mean increase in the biological or retention half-life was 50% in tumors and 90% in remnants. This increase occurred in at least 1 lesion in each patient and was proportionally greater in lesions with poor 131I retention. When the control biological half life was less than 3 days, lithium prolonged the effective half-life, which combines both biological turnover and isotope decay, in responding metastases by more than 50%. More 131I also accumulated during lithium therapy, probably as a consequence of its effect on iodine release. The increase in the accumulated 131I and the lengthening of the effective half-life combined to increase the estimated 131I radiation dose in metastatic tumor by 2.29 +/- 0.58 (mean +/- SEM) times. These studies suggest that lithium may be a useful adjuvant for 131I therapy of thyroid cancer, augmenting both the accumulation and retention of 131I in lesions.

Adult↗
PubMed2000

Effects of lithium on the pharmacokinetics of valproate in rats.

Combined treatment with lithium and valproate has been used for bipolar disorder. However, the studied interaction between these two drugs has not been fully investigated. We therefore examined the effects of lithium on the pharmacokinetics (plasma disappearance, metabolism and urinary excretion) of valproate in rats. Lithium (2 mEq kg(-1)) was administered intraperitoneally twice a day for ten days. Plasma disappearance curves of valproate (50 mg kg(-1), i.v.), valproate-metabolizing activities of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) in liver microsomes and urinary excretion of free valproate and valproate-glucuronide were examined. The metabolizing activity of UGT and CYP were determined by enzyme assays and a fluorescence polarization immunoassay system. Urinary valproate-glucuronide was obtained using this system by subtracting the free level from total level, which was determined after deconjugating the sample with heat and NaOH. The half-life of plasma disappearance of valproate was 25% reduced by lithium pretreatment (0.428 +/- 0.031 h with repeated lithium pretreatment vs 0.578 +/- 0.062 h for controls). The valproate-metabolizing activity of UGT and CYP were not altered by lithium although lithium increased the urinary excretion of valproate-glucuronide. In conclusion, lithium pretreatment causes a decrease in plasma valproate levels and an increase in urinary excretion of valproate-glucuronide in rats.

Animals↗
PubMed1985

Evidence for in vivo effect of lithium on p-aminohippurate transport in rat kidney, preliminary study.

We examined the effect of lithium on rat renal handling of p-aminohippurate (PAH) and accumulation of organic ions by rat kidney cortical slices. When infused intravenously with lithium at the rate of 0.13 mmoles/kg/min, decreased renal clearance of PAH as well as no significant changes in glomerular filtration rate and plasma PAH level was observed at the first clearance period during lithium infusion. As we expected, tubular secretion of PAH also was decreased significantly by the infusion of lithium. Therefore, it is suggested that the decrease in the clearance of PAH was due to the decrease in the tubular secretion of PAH. After four days of injections with lithium (4 mmoles/kg, i.p., once a day), a significant decrease in PAH accumulation in the slices was detected. No inhibition of tetraethylammonium accumulation was observed. Lithium pretreatment did not alter water content and extracellular space of the slices. The results suggest that lithium selectively inhibits the organic anion transport system in kidney with the in vivo treatment and follows our previous work in which we showed the in vitro effect of lithium on organic anion accumulation in the slices.

Aminohippuric Acids↗
PubMed1991

Effects of lithium on the beta-adrenergic receptor-adenylate cyclase system in rat cerebral cortical membranes.

The effects of lithium on the beta-adrenoceptor-adenylate cyclase system in cerebral cortical membranes of rats were investigated. Lithium chloride inhibited adenylate cyclase activity in a concentration-dependent manner in vitro. However, relatively high concentrations of lithium were needed for this inhibition; and at 1 mM, no significant reduction in adenylate cyclase activity was seen under any condition. Administration of lithium carbonate for 21 days decreased the maximum number of [3H]dihydroalprenolol binding sites without changing the apparent dissociation constant. Activation of adenylate cyclase by (-)-isoproterenol in the presence of 1 microM guanyl-5'-ylimidodiphosphate (Gpp(NH)p) was significantly attenuated in lithium-treated rats compared with the controls. Lithium treatment reduced the Gpp(NH)p-stimulated adenylate cyclase activity in the presence of 10 microM (-)-isoproterenol, but not in the absence of this beta-adrenergic receptor agonist. Basal activity or adenylate cyclase activity stimulated by forskolin or manganese was not affected, whereas the activity stimulated by sodium fluoride was significantly attenuated by long-term lithium treatment. These results indicate that chronic lithium treatment induces subsensitivity in the beta-adrenoceptor-adenylate cyclase system, for which down-regulation of beta-adrenergic receptors is chiefly responsible.

Adenylyl Cyclase Inhibitors↗
PubMed2003

Influence of lithium on cell function in two different cell systems.

Lithium is widely used in the treatment and prophylaxis of bipolar psychiatric disorders. It accumulates in the thyroid gland and can cause goitre or thyroid dysfunction. The mechanisms of various effects of the lithium ion on thyroid cells have not been completely clarified. The aim of our work was to establish whether lithium, in the presence or absence of TSH, stimulates the synthesis of cAMP; as model systems we used a strain of rat thyroid follicular cells FRTL-5 and a line of Chinese hamster ovary fibroblasts with the human TSH receptor (CHO-R). Lithium at concentrations of 0.35 mM, 1 mM, 1.4 mM, 1.7 mM and 2 mM without TSH and at selected concentrations with TSH stimulation significantly increased cAMP synthesis in FRTL-5 and in CHO-R cells when compared with controls without lithium. These results are different from the published data, which have been unable to confirm the influence of lithium on cAMP synthesis or have even reported the inhibition of cAMP synthesis. However, in most published investigations only lithium in combination with TSH was tested. In conclusion, lithium was found to stimulate cAMP synthesis in FRTL-5 cells and in CHO-R cells.

Animals↗
PubMed2002

Thyroid and pituitary thyroxine-5'-deiodinase activity and thyrotrophin secretion in lithium-treated rats.

Some authors have reported increased serum thyrotrophin (TSH) in animals chronically treated with lithium, suggesting that lithium might decrease pituitary thyroxine (T(4))-5'-deiodinase activity. On the other hand, the effect of lithium treatment on thyroidal T(4)-5'-deiodinase activity is also unknown. The present study was undertaken to evaluate the effects of lithium treatment on pituitary and thyroid T(4)-5'-deiodinase activity. Serum and pituitary TSH levels and thyroidal and pituitary T(4)-5'-deiodinase activities were determined in 3-month-old isogenic male Dutch-Miranda rats treated with lithium for 8 weeks. Chronic lithium treatment produced a slight increase in pituitary TSH content, but no change in serum TSH, and a significant increase in the thyroidal T(4)-5'-deiodinase activity. However, the pituitary T(4)-5'-deiodinase activity was unaffected by lithium administration. As far as we know, the present data show for the first time that chronic lithium treatment can increase the thyroxine to tri-iodothyronine conversion in the murine thyroid gland, be it directly or indirectly.

Analysis of Variance↗
PubMed2006

Teratogenic and developmental effects of lithium.

A review is presented on the effects of lithium in therapeutic doses on the outcome of human pregnancy. The results of various studies including cohort, prospective, retrospective and small number case reports indicate that lithium is a "weak" teratogen in humans. The main effects attributable to lithium are, cardiac malformations and babies with increased birth weight. There is a possibility that, in particular, lithium may be associated with the Ebstein anomaly but present evidence cannot definitely affirm or deny this association. Animal studies with lithium using doses comparable to human therapeutic serum levels have not reported any abnormalities. However, higher doses have produced exencephaly, skeletal and craniofacial defects and abnormalities of blood vessel development. Experiments with other vertebrates have shown that lithium affects dorsoventral specification and inhibition of vasculogenesis. Both these effects can be prevented by pretreatment with myo-inositol indicating that lithium interferes with the phosphatidyl inositol cycle. More recent findings have shown that the effects of lithium on invertebrates may be mediated through inhibition of GSK-3beta in the Wnt-GSK-3 pathway.

Animals↗
PubMed2001

Lithium-related genetics of bipolar disorder.

Lithium is a potent prophylactic medication and mood stabilizer in bipolar disorder. However, clinical outcome is variable, and its therapeutic effect manifests after a period of chronic treatment, implying a progressive and complex biological response process. Signal transduction systems known to be perturbed by lithium involve phosphoinositide (PI) turnover, activation of the Wnt pathway via inhibition of glycogen synthase kinase-3beta (GSK-3beta), and a growth factor-induced, Akt-mediated signalling that promotes cell survival. These pathways, acting in synergy, probably prompt the amplification of lithium signal causing such immense impact on the neuronal network. The sequencing of the human genome presents an unparallelled opportunity to uncover the full molecular repertoire involved in lithium action. Interrogation of high-resolution expression microarrays and protein profiles represents a strategy that should help accomplish this goal. A recent microarray analysis on lithium-treated versus untreated PC12 cells identified multiple differentially altered transcripts. Lithium-perturbed genes, particularly those that map to susceptibility regions, could be candidate risk-conferring factors for mood disorders. Transcript and protein profiling in patients could reveal a lithium fingerprint for responsiveness or nonresponsiveness, and a signature motif that may be diagnostic of a specific phenotype. Similarly, lithium-sensitive gene products could provide a new generation of pharmacological targets.

Bipolar Disorder↗
PubMed1999

Efficacy of lithium vs. valproate in the treatment of mania in the elderly: a retrospective study.

BACKGROUND: This retrospective study was conducted to assess the efficacy of lithium and valproate and associated serum levels in the treatment of mania in elderly patients. METHOD: Records of 59 patients aged 55 years and older with minimal or no neurologic impairment, hospitalized for mania, and discharged on lithium (N = 30) or valproate (N = 29) therapy were reviewed. Data on mood stabilizer choice, serum levels, and type of mania were recorded. A clinician blinded to medications rated improvement in each case with Clinical Global Impressions (CGI) scores based on abstracted notes. RESULTS: Overall, the percentage of patients improved was significantly greater in the lithium group than in the valproate group (67% vs. 38%, chi2 = 4.88, p = .027). Patients taking lithium with serum levels > or =0.8 mmol/L were more improved at discharge than those outside this range (> or =0.8, CGI 2.0+/-0.6 vs. <0.8, CGI 2.6+/-0.8, t = 2.15, p = .043). Patients taking valproate with serum levels between 65-90 microg/mL were more improved at discharge than those outside this range (65-90, CGI 2.1+/-0.6 vs. <65, >90, CGI 3.3+/-0.8, t = 3.73, p = .002). When response rates among only patients with these "therapeutic" levels were assessed, they were similar for lithium (82%) and valproate (75%). The difference in efficacy between drugs was maintained in classic mania, but the 2 drug groups were similar when only mixed mania was analyzed (lithium 63% vs. valproate 67% improved). CONCLUSION: Results suggest that lithium may be more efficacious than valproate overall, but response rates for the 2 drugs were similar when "therapeutic" serum levels were achieved. For lithium, levels similar to those reported for younger adults were associated with response. For valproate, a "therapeutic window" different from that in younger adults was found. While the retrospective and naturalistic design of this study has limitations, these data may help direct further studies and treatment of mania in the elderly.

Age Factors↗
PubMed2003

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder.

BACKGROUND: The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. METHOD: During an 8- to 16-week open-label phase, lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. The primary outcome measure was time from randomization to intervention (addition of pharmacotherapy) for any mood episode (depressive, manic, hypomanic, or mixed). Data were gathered from September 1997 to August 2001. RESULTS: Time to intervention for any mood episode was statistically superior (p = .029) for both lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode (p = .047). The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77%, lithium 86%, and placebo 72%. Headache was the most frequent adverse event for all 3 treatment groups. CONCLUSION: Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with lamotrigine predominantly effective against depression and lithium predominantly effective against mania.

Adult↗
PubMedDate not supplied

Lithium-associated thyroiditis.

OBJECTIVE: To report an unusual case of thyrotoxicosis caused by "silent thyroiditis" in a lithium-treated patient and to summarize all prior case reports of lithium-associated thyroiditis and compare them with our current case. METHODS: In addition to reporting our case, we undertook a MEDLINE search of all case reports of lithium-associated thyroiditis from 1978 until the present. All reported cases of lithium-associated thyroiditis must have had documented low thyroid radioiodine uptake to be included. RESULTS: A 52-year-old man with a history of bipolar disorder, who had been treated with lithium carbonate for 15 years, was admitted because of delusional mania. Although he had discontinued his lithium therapy 3 months before admission, he had noted symptoms of hyperthyroidism at least 1 month before admission. He was diagnosed with thyrotoxicosis due to silent thyroiditis on the basis of a high free thyroxine level, suppressed thyrotropin level, and low thyroid radioiodine uptake. We found only 10 other case reports of lithium-associated thyrotoxicosis due to silent thyroiditis. CONCLUSION: Thyrotoxicosis caused by silent thyroiditis may be associated with lithium therapy and is likely to be underreported. The pathogenic mechanism for such cases of thyroiditis is still unclear.

Bipolar Disorder↗
PubMed1999

Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report.

A combination of clozapine and lithium can be used in the treatment of refractory schizophrenia, schizoaffective disorder and bipolar disorder with rapid cycling. We report a patient with refractory bipolar disorder who developed side-effects after combination therapy with clozapine and lithium at usual therapeutic dosages. Reversible neurotoxicity developed twice during the therapeutic course, once with the restarting of lithium, the other with increasing the dose of lithium, despite the lithium concentrations being less than 0.5 mEq/l. Neurotoxicity manifested as ataxia, coarse tremor, myoclonus, facial spasm and increased deep tendon reflex. While the mechanism causing toxicity is not clear, interaction between the serotonergic effect of clozapine and lithium may be the cause. This report is evidence that a combination of clozapine and lithium may increase the risk of neurotoxicity. We suggest the need to keep clozapine and lithium at lower dosages and closely monitor their side-effects as necessary when these drugs are used concomitantly.

Adult↗
PubMed1999

Lithium dosage and leukocyte counts in psychiatric patients.

OBJECTIVE: To evaluate differences in leukocyte counts among patients treated with either lithium alone, antipsychotic medications alone, or a combination of both. DESIGN: Retrospective study. SETTING: Long-stay psychiatric hospital. PATIENTS: Patients admitted between 1990 and 1993, and treated with lithium for at least 1 week and/or with antipsychotic medication for at least 2 weeks. Excluded from the study were those patients for whom complete blood counts at baseline and during therapy were not available, and those patients whose blood picture could primarily be accounted for by extraneous factors. Included in the study were 38 patients treated with lithium alone, 207 patients receiving antipsychotic medications alone, and 71 patients receiving both. OUTCOME MEASURES: Leukocyte, lymphocyte and granulocyte counts. RESULTS: Patients treated with lithium alone had significantly higher mean leukocyte and granulocyte counts than those treated with antipsychotic medication alone (analysis of variance, p < 0.05). None of the patients receiving lithium alone showed leukopenia. The dosage of lithium was significantly correlated with leukocyte count (r = 0.25, 95% confidence interval [CI] 0.14 to 0.35, p < 0.001,) and granulocyte count (r = 0.27, 95% CI 0.16 to 0.38, p < 0.001), but not with lymphocyte count (r = 0.06, p = 0.286, 95% CI -0.05 to 0.17). CONCLUSIONS: Lithium therapy is associated with higher leukocyte and granulocyte levels in psychiatric patients. This leukocytotic effect of lithium may be dose dependent.

Adult↗
PubMed1999

Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.

BACKGROUND: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. RESULTS: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. CONCLUSION: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

Ambulatory Care↗
PubMed2000

Enhancement of hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by repeated lithium treatment in rats.

Hippocampal cholinergic neuronal activity is reported to be regulated, at least partly, through serotonin1A (5-HT1A) receptors. Chronic lithium treatment has been shown to alter both behavioral and neurochemical responses mediated by postsynaptic 5-HT1A receptors. We investigated whether long-term lithium treatment affects central cholinergic neurotransmission through 5-HT1A receptor-mediated pathways. Changes in acetylcholine (ACh) release induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, in the rat hippocampus were measured using a microdialysis technique and a radioimmunoassay for ACh. Administration of lithium for 21 days resulted in a serum lithium concentration of 1.03 mM and caused little change in density or affinity of [3H]8-OH-DPAT binding sites in the hippocampus. The local application of 8-OH-DPAT into the hippocampus of lithium treated rats increased the ACh efflux in both the absence and the presence of physostigmine, a cholinesterase (ChE) inhibitor, in the perfusion fluid. The basal ACh efflux of lithium treated rats was not different from that of the control rats under normal conditions, but was significantly higher than that of the controls when ChE was inhibited. These results demonstrate that chronic lithium treatment increases spontaneous ACh release in the hippocampus under conditions of ChE inhibition, but not under normal conditions, and enhances cholinergic neurotransmission through 5-HT1A receptor-mediated pathways, and suggest that activation of 5-HT1A receptor function by lithium is related to the enhancement of hippocampal cholinergic neurotransmission.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

[Myasthenic syndrome induced by lithium].

BACKGROUND: Lithium salts can induce a dysfunction of the neuromuscular junction. CASE REPORT: A patient given lithium for bipolar psychosis developed a state of major fatigue revealing a myasthenia syndrome which resolved progressively after lithium withdrawal. DISCUSSION: In the literature, we found 4 cases of neuromuscular junction disorders in patients treated with lithium. A myasthenia syndrome was induced by lithium in 3 cases and underlying myasthenia was disclosed by lithium in the last one. The long-term course in our patient was in favor of an induced syndrome rather than underlying myasthenia. We discuss the pathophysiological mechanisms. Lithium is a commonly prescribed drug. Clinicians should be aware of the possibility of neuromuscular junction disorder in patients taking lithium who develop muscle fatigue.

Anti-Anxiety Agents↗
PubMed2001

Preventing lithium intoxication. Guide for physicians.

OBJECTIVE: To raise awareness of risk factors for, and symptoms of, lithium intoxication. QUALITY OF EVIDENCE: The literature was searched via MEDLINE from January 1970 to December 1999 using the MeSH headings Lithium, Lithium Carbonate, Drug Toxicity, and Aging. Articles were selected based on clinical relevance and design. Most were case reports, case series, or reviews. MAIN MESSAGE: A case study illustrates both risk factors predisposing patients to lithium intoxication and the symptoms of lithium intoxication. Lithium intoxication can be avoided by conservative dosing, care in combining drug therapies, regular clinical observation, monitoring drug plasma concentrations, and educating patients and caregivers to recognize early signs of intoxication. CONCLUSION: Knowing about lithium intoxication and how to avoid it is most important for family physicians who regularly treat patients receiving lithium.

Aged↗