Safety and efficacy of lithium in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: This study provides a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the safety and efficacy of lithium in amyotrophic lateral sclerosis (ALS) patients. METHODS: PubMed, Web of Science, Cochrane CENTRAL, Scopus, and Your Journals@Ovid were searched up to 9 December 2022. RCTs investigating lithium, either alone or with any supplement, in ALS patients were included. Meta-analysis was performed using RevMan and results are presented in forest plot. RESULTS: Four RCTs with 469 patients met the inclusion criteria and were included in our study. Lithium doses varied among the included studies and one study used a combined therapy of lithium with valproate. Meta-analysis showed no difference between lithium and placebo regarding severe adverse events (odds ratio = 1.13, 95% confidence interval: 0.73 to 1.75, P = 0.58). No significant differences were observed with regard to survival rate between the two groups (hazard ratio = 0.95, 95% confidence interval: 0.65 to 1.37, P = 0.77). There were also no significant differences between the two groups with regard to average changes of revised amyotrophic lateral sclerosis functional rating scale (P = 0.35) and forced vital capacity percentage predicted (P = 0.73). Subgroup analysis showed no significant differences regarding all investigated outcomes either for lithium alone or lithium with valproate. CONCLUSION: Current evidence suggests a safety profile with no benefit of lithium for ALS. However, given the limited number of RCTs and the safety findings, we recommend further well-designed RCTs to investigate lithium and valproate in ALS patients.

Time to perforation for button batteries lodged in the esophagus.

INTRODUCTION: New strategies recently proposed to mitigate injury caused by lithium coin cell batteries lodged in the esophagus include prehospital administration of honey to coat the battery and prevent local hydroxide generation and in-hospital administration of sucralfate suspension (or honey). This study was undertaken to define the safe interval for administering coating agents by identifying the timing of onset of esophageal perforations. METHODS: A retrospective study of 290 fatal or severe battery ingestions with esophageal lodgment was undertaken to identify cases with esophageal perforations. RESULTS: Esophageal perforations were identified in 189 cases (53 fatal, 136 severe; 95.2% in children ≤4 years). Implicated batteries were predominantly lithium (91.0%) and 92.0% were ≥20 mm diameter. Only 2% of perforations occurred in <24 h following ingestion, including 3 severe cases with perforations evident at 11-17 h, 12 h, and 18 h. Another 7.4% of perforations (11 cases) became evident 24 to 47 h post ingestion and 10.1% of perforations (15 cases) became evident 48 to 71 h post ingestion. By 3 days post ingestion, 26.8% of perforations were evident, 36.9% by 4 days, 46.3% by 5 days, and 66.4% by 9 days. CONCLUSION: Esophageal perforation is unlikely in the 12 h after battery ingestion, therefore the administration of honey or sucralfate carries a low risk of extravasation from the esophagus. This first 12 h includes the period of peak electrolysis activity and battery damage, thus the risk of honey or sucralfate is low while the benefit is likely high.

Electrolytes: Calcium Disorders.

A normal serum calcium level is 8 to 10 mg/dL. The diagnosis of hypercalcemia (ie, levels 10.5 mg/dL or greater) should be confirmed with an albumin-adjusted or ionized calcium level. The two most common causes of hypercalcemia are hyperparathyroidism and malignancy. Drugs, notably lithium and thiazide diuretics, also can cause hypercalcemia. Patients with severe or symptomatic hypercalcemia should be treated initially with hydration to decrease calcium levels. The evaluation should include a parathyroid hormone (PTH) level. If the PTH level is low, cancer is a likely cause, particularly multiple myeloma, breast cancer, or lymphoma. If the PTH level is normal or elevated, hyperparathyroidism is the likely cause. Symptomatic patients with hyperparathyroidism and patients with certain clinical markers should be considered for surgery. For patients with mild disease, monitoring is an option. Hypocalcemia often is caused by vitamin D deficiency. Symptomatic patients and patients with calcium levels less than 7.6 mg/dL should be treated with intravenous calcium gluconate; concomitant magnesium deficiency should be addressed. There is no evidence that routine calcium and vitamin D supplementation reduces the risk of fractures, but studies have shown that vitamin D supplementation does decrease the number of falls in older adults at risk.

Increased hippocampal, thalamus and amygdala volume in long-term lithium-treated bipolar I disorder patients compared with unmedicated patients and healthy subjects.

OBJECTIVE: Magnetic resonance imaging (MRI) studies in bipolar I disorder (BD-I) suggest that lithium is associated with increased volumes of cortico-limbic structures. However, more rigorous control of confounding factors is needed to obtain further support for this hypothesis. The aim of the present study was to assess differences in brain volumes among long-term lithium-treated BD-I patients, unmedicated BD-I patients, and healthy controls. METHODS: This was a cross-sectional study with 32 euthymic BD-I patients (16 on lithium monotherapy for a mean of 180 months, and 16 receiving no medication for at least the 2 months prior to the study) and 20 healthy controls. Patients were euthymic (Hamilton Depression Rating Scale [HDRS] <6 and Young Mania Rating Scale [YMRS] <7) and had not taken psychotropic medications other than lithium for at least 6 months. Brain images were acquired on a 1.5 Tesla MRI (Phillips, Amsterdam, The Netherlands) and segmented to generate volumetric measures of cortical and subcortical brain areas, ventricles and global brain. RESULTS: Significant differences were found in the volumes of the left amygdala (P=.0003), right amygdala (P=.030), left hippocampus (P=.022), left thalamus (P=.022), and right thalamus (P=.019) in long-term lithium-treated BD-I patients, compared to unmedicated patients and controls, after multivariable adjustment. No differences were observed in global brain volume or in ventricular size among the three groups. Likewise, there was no correlation between serum lithium levels and the increase in size in the described brain areas. CONCLUSIONS: The structural differences found among the three groups, and specifically those between long-term lithium-treated and unmedicated BD-I patients, indicate increased limbic structure volumes in lithium-treated patients.

A population-based study of the comparative effectiveness of second-generation antipsychotics vs older antimanic agents in bipolar disorder.

OBJECTIVES: Numerous antimanic treatments have been introduced over the past two decades, particularly second-generation antipsychotics (SGAs). However, it is not clear whether such newer agents provide any advantage over older treatments. METHODS: A historical cohort design investigated the nationwide population of outpatients with bipolar disorder treated in the Department of Veterans Affairs who were newly initiated on an antimanic agent between 2003 and 2010 (N=27 727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation, controlling for numerous demographic, clinical, and treatment characteristics. Potential correlates of effect were explored by investigating time to initiation of a second antimanic agent or antidepressant. RESULTS: After control for covariates, those initiated on lithium or valproate monotherapy, compared to those beginning SGA monotherapy, were significantly less likely to be hospitalized, had a longer time to hospitalization, and had fewer hospitalizations in the subsequent year. Those on combination treatment had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of an additional antimanic agent or antidepressant. CONCLUSIONS: The present analysis of a large and unselected nationwide population provides important complementary data to that from controlled trials. Although various mechanisms may be responsible for the results, the data support the utilization of lithium or valproate, rather than SGAs, as the initial antimanic treatment in bipolar disorder. A large-scale, prospective, randomized, pragmatic clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.

The investigation of the possible protective influence of selenium on antioxidant barrier in heart of rats exposed to lithium.

AIMS: Selenium is an essential element possessing antioxidant properties and the treatment with it has displayed protective effects against toxicity of different substances occurring in the environment and food as well as against the side effects of some drugs. Lithium is used in medicine although numerous side effects can occur during therapy, including disturbances of the heart. For these reasons studies to find protective adjuvants have been performed. In the current study the possibility of selenium (as sodium selenite) application as a protective adjuvant in lithium treatment was studied. MAIN METHODS: Male Wistar rats were treated: control - with saline; Li-group - with Li2CO3 (2.7 mg Li/kg b.w.); Se-group - with Na2SeO3 (0.5 mg Se/kg b.w.); Li+Se-group simultaneously with Li2CO3 and Na2SeO3 (2.7 mg Li/kg b.w. and 0.5 mg Se/kg b.w., respectively) by a stomach tube for a period of three weeks, once a day. In heart homogenate activities of antioxidant enzymes - catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), concentrations of low-molecular-weight antioxidants - ascorbic acid (AA) and reduced glutathione (GSH) as well as total antioxidant status (TAS) values were determined. GPx/SOD and CAT/SOD ratios were evaluated. KEY FINDINGS: In comparison with control selenium caused no significant changes of the studied parameters except for GPx, whereas lithium slightly disturbed TAS and markedly GPx, CAT and CAT/SOD ratio. In Li-treated rats co-administration of selenium displayed tendency towards restoring the impaired parameters. SIGNIFICANCE: The results suggest that research on selenium application as an adjuvant in lithium therapy is worthy to be continued.

Lithium and sexual dysfunction: an under-researched area.

OBJECTIVE: Lithium treatment remains an important part of the management of many patients with bipolar disorder, but the incidence of treatment-emergent sexual dysfunction with lithium is uncertain, and little is known about how it might be managed. METHOD: Systematic computerised literature search of preclinical and clinical studies. RESULTS: Thirteen relevant papers were identified. Preclinical studies suggest lithium can reduce testosterone levels and impair nitric oxide mediated relaxation of cavernosal tissue. Clinical reports suggest lithium may reduce sexual thoughts and desire, worsen erectile function and reduce sexual satisfaction. Concomitant benzodiazepine prescription with lithium is associated with an increased risk of sexual dysfunction. Sexual dysfunction during lithium treatment appears significantly associated with a lower level of overall functioning and may reduce compliance. CONCLUSION: The findings of this systematic review reveal the paucity of information about the incidence, associated factors and management of sexual dysfunction with lithium treatment and highlight the need for well-designed studies in this area.

Hyperthyroid rage: when bipolar disorder hides the real disorder.

Long-term lithium therapy has been associated with euthyroid goiter, hypothyroidism, and less commonly, hyperthyroidism. We report a case of a 19-year-old male patient with schizoaffective disorder who was hospitalized after trying to suffocate his mother. Severe psychomotor agitation persisted despite the high dose of antipsychotics. Initial laboratory tests showed elevated creatine kinase and free thyroxine. Lithium was replaced by sodium valproate, and new laboratory tests were obtained. After lithium discontinuation, the patient had a rapid improvement in agitation and tremors. Antithyroid drugs were not necessary, suggesting the diagnosis of lithium-associated thyrotoxicosis that progressed to spontaneous remission. There are only 2 other reports of lithium-associated thyrotoxicosis successfully treated with lithium withdrawal. Even patients on long-term use of lithium are not free from having acute thyroid dysfunction and may present with treatment-resistant symptoms.

Nephrogenic diabetes insipidus partially responsive to oral desmopressin in a subject with lithium-induced multiple endocrinopathy.

Lithium (Li) may cause multiple endocrinopathies, including hypercalcaemia, thyroid dysfunction and nephrogenic diabetes insipidus (NDI), but rarely in the same patient. The management of NDI remains a challenge. We report on a patient on long-term Li who had simultaneous NDI (paired serum and urine samples had abnormal osmolalities, typical of NDI, and treatment with parenteral desmopressin failed to affect urinary volume and serum osmolality), 'destructive' thyroiditis (hyperthyroidism, absent radioiodine uptake and absent thyrotrophin receptor antibodies) and primary hyperparathyroidism (compatible biochemistry, urine calcium excluding 'set point' anomalies and hypocalciuric hypercalcaemia, and normal parathyroid imaging). The thyroiditis resolved spontaneously and hypercalcaemia responded to reduction of Li dose. The NDI was unresponsive to amiloride, thiazides and ibuprofen in combination. However, urine output was reduced by 50% when a high dose of oral desmopressin was given. We conclude that Li-induced multiple endocrinopathy remains rare and, although NDI is difficult to manage, high dose oral desmopressin should be tried when other medications fail.

Rapamycin inhibition of mTORC1 reverses lithium-induced proliferation of renal collecting duct cells.

Nephrogenic diabetes insipidus (NDI) is the most common renal side effect in patients undergoing lithium therapy for bipolar affective disorders. Approximately 2 million US patients take lithium of whom ∼50% will have altered renal function and develop NDI (2, 37). Lithium-induced NDI is a defect in the urinary concentrating mechanism. Lithium therapy also leads to proliferation and abundant renal cysts (microcysts), commonly in the collecting ducts of the cortico-medullary region. The mTOR pathway integrates nutrient and mitogen signals to control cell proliferation and cell growth (size) via the mTOR Complex 1 (mTORC1). To address our hypothesis that mTOR activation may be responsible for lithium-induced proliferation of collecting ducts, we fed mice lithium chronically and assessed mTORC1 signaling in the renal medulla. We demonstrate that mTOR signaling is activated in the renal collecting ducts of lithium-treated mice; lithium increased the phosphorylation of rS6 (Ser240/Ser244), p-TSC2 (Thr1462), and p-mTOR (Ser2448). Consistent with our hypothesis, treatment with rapamycin, an allosteric inhibitor of mTOR, reversed lithium-induced proliferation of medullary collecting duct cells and reduced levels of p-rS6 and p-mTOR. Medullary levels of p-GSK3ß were increased in the renal medullas of lithium-treated mice and remained elevated following rapamycin treatment. However, mTOR inhibition did not improve lithium-induced NDI and did not restore the expression of collecting duct proteins aquaporin-2 or UT-A1.

Erythrocyte glutathione levels in lithium-induced hypothyroidism.

BACKGROUND AND OBJECTIVE: Lithium, widely used in the prophylaxis of psychiatric patients with bipolar affective disorders, is well known to induce thyroid alterations. However, a possible metabolic linkage between blood thyroxine levels and its regulatory function on erythrocyte glutathione concentration has not yet been evaluated in lithium-treated patients. The aim of this study was to assess the antioxidative capacity of erythrocytes in lithium-induced hypothyroidism before and after thyroxine replacement. PATIENTS AND METHODS: Thyroid ultrasound with clinical and laboratory evaluation of thyroid function and thyroid-stimulating hormone assay were performed prior to and at 6-month intervals during lithium prophylaxis in 76 patients with bipolar affective disorders. The daily lithium dosage was adjusted to 600-1200 mg and the mean duration of treatment was 2.2 +/- 0.4 years. Final assessment revealed that 12 patients had evidence of primary hypothyroidism, and these were assigned as the test group. Lithium prophylaxis was supplemented with thyroxine at a dosage of 100 mg/day within 6 months after thyroid dysfunction was diagnosed. Red blood cell superoxide dismutase activities and the glutathione contents were measured before and after thyroxine replacement. In order to assess the effect of long-term lithium administration on red blood cell glutathione and superoxide dismutase levels, 12 patients who had not developed hypothyroidism during the follow-up period were selected for the lithium-treated euthyroid group. Mann Whitney U-test and Wilcoxon rank sum W-test were used for comparison of data. RESULTS: A comparison of the lithium-treated test group with healthy volunteers and their own values after thyroxine replacement revealed a significant decrease in red blood cell glutathione concentrations (p = 0.000) in the hypothyroid state. However, no clinically significant changes were observed in red blood cell superoxide dismutase activities of the test group. A statistical survey also demonstrated that there was no significant difference in the thyroid-stimulating hormone values as well as the red blood cell glutathione contents or superoxide dismutase activities between healthy controls and lithium-treated euthyroid subjects. CONCLUSIONS: It is most likely that lithium primarily inhibited hormone production in the thyroid and that this led to a compensatory increase in thyroid-stimulating hormone secretion with a significant decrease in the red blood cell glutathione content. While the red blood cell glutathione content of hypothyroid patients was reduced to 40% of the post-thyroxine level, unchanged superoxide dismutase activity might render the erythrocytes vulnerable to oxidative stress and ultimately haemolysis. Thyroxine replacement during lithium prophylaxis of psychiatric patients is advisable in order to prevent subclinical hypothyroidism and related defects of erythrocyte antioxidant capacity.

[Adverse effects of lithium treatment and safety routines]. / Litiumbehandlingens biverkningar och säkerhetsrutiner.

Successful lithium treatment of manic disorders was reported in 1949 by John Cade. This marked the beginning of the pharmacological era in psychiatry. In spite of the emergence of alternative drugs with antimanic and moodstabilising properties, lithium remains the primary long-term treatment for preventing relapse of bipolar disorders. Among the adverse effects of lithium treatment are unintentional lithium intoxication, nephropathy, hypothyroidism, hypercalcemia, hyperparathyroidism, diarrhoea, tremor, weight gain, and effects on the fetus and the newborn child. Early detection or prevention of adverse effects, particularly lithium intoxication, is vital for safety. Therefore, P-lithium and P-creatinine are assessed every 4 months (and pre-lithium) while thyroid and parathyroid function, weight, 24 h consumption of liquids (or 24 h urinary output), B-glucose, and blood pressure are assessed annually (and pre-lithium). Urinary concentrating capacity and glomerular filtration rate are always measured after 5 years of lithium treatment, and always when clinically indicated. Patient education and annual reinforcement of his/her knowledge of pertinent aspects of the treatment and of risk factors for lithium intoxication are important aspects for ensuring safety.

Calcium channel blocker, nimodipine, for the treatment of bipolar disorder during pregnancy.

Bipolar disorder in pregnancy was treated with nimodipine, because of lithium-induced nephrogenic diabetes insipidus. A 33-year-old primigravida woman at approximately 22 weeks 6 days of gestation had increasing blood pressure since 16 weeks of gestation, despite methyldopa 500 mg twice daily. She also had hypothyroidism and bipolar disorder, which were treated with levothyroxine and lithium carbonate, respectively. Nephrogenic diabetes insipidus developed, presumably because of chronic lithium exposure in high doses. She did not tolerate carbamazepine (the other agent commonly used for bipolar disorder in pregnancy). Thus, nimodipine was tried and tolerated well; furthermore, it was very effective in controlling her bipolar disorder. Nimodipine successfully controlled the bipolar disorder of a woman during pregnancy, who was intolerant of more commonly used agents.

Treatment of bipolar I rapid cycling patients during dysphoric mania with olanzapine.

The simultaneous presentation of manic and depressive symptoms in the same patient is fairly common. The terms and have been used as equivalents to mixed states. Pharmacotherapy is less effective in this group of patients. The aim of this study is to determine the effectiveness and safety of olanzapine as an add-on therapy in patients with bipolar disorder with a rapid cycling course during a dysphoric mania episode. Thirteen patients treated with mood stabilizers for at least 1 year and diagnosed with a mixed episode were included in an open trial. All had at least 4 episodes in the last year. Patients with organic diseases, including altered thyroid function, were excluded from the research. Patients were evaluated at inclusion and at day 28. Response was defined as a decrease of 50% in the Young Mania Rating Scale and the Hamilton Rating Scale for Depression concomitant with a Clinical Global Impression improvement of 1 or 2. All patients completed the study. The doses of olanzapine were 16.15 +/- 5.82 mg/day. There was a reduction in the manic and depressive symptoms in all patients. Ten of the 13 patients were considered to have responded to the treatment according to the response definition. Adverse effects included somnolence (23.08%) and weight gain (0.81 +/- 1.96 kg in women, 2.20 +/- 2.28 kg in men). Our results suggest that olanzapine combined with mood stabilizers is safe and effective in the treatment of the manic and the depressive symptoms of dysphoric mania with a rapid cycling course.

Stereochemistry at phosphorus of the reaction catalyzed by myo-inositol monophosphatase.

myo-Inositol monophosphatase (IMPase), the proposed target for lithium therapy for manic depression, is an important enzyme in the biosynthesis of second messengers. Earlier studies have shown that the IMPase-catalyzed hydrolysis of myo-inositol monophosphates to inorganic phosphate and myo-inositol proceeds by direct attack of water at phosphorus. However, research groups have independently proposed either an in-line displacement (with inversion of stereochemistry at phosphorus) or an adjacent attack with a pseudorotation (with retention of stereochemistry at phosphorus). Here, the elucidation of the stereochemical pathway is presented. The IMPase-catalyzed hydrolysis of D-1-S(p)-myo-inositol [(17)O]-thiophosphate in the presence of H(2)(18)O gave inorganic R(p)-[(16)O,(17)O,(18)O]-thiophosphate, with inversion of configuration at phosphorus. This is only consistent with an in-line displacement, and it rules out the controversial adjacent/pseudorotation mechanism. This result will assist in the design of alternative inhibitors of IMPase.

Hair loss in psychopharmacology.

Medication-induced alopecia is an occasional side effect of many psychopharmaceuticals. Most of the mood stabilizer and antidepressant drugs can lead to this condition. Some antipsychotic and antianxiety agents induce alopecia. Hair loss is also related to hypothyroidism, which can be induced by lithium and other agents. Alopecia might not be reported by some people, but physicians should be aware of this potential problem which may contribute to noncompliance. Lithium causes hair loss in 12-19% of long-term users. Valproic acid and/ or divalproex precipitates alopecia in up to 12% of patients in a dose-dependent relationship. Incidences up to 28% are observed with high valproate concentration exposures. These pharmaceuticals also can change hair color and structure. The occurrence of carbamazepine-induced alopecia is at or below 6%. Hair loss is less common with other mood stabilizers. Tricyclic antidepressants, maprotilene, trazodone, and virtually all the new generation of antidepressants may on rare occasions lead to alopecia. The same applies to haloperidol, olanzepine, risperidone, clonazepam, and buspirone, but not to other neuroleptics, benzodiazepines, or barbiturates, selected antihistamines, and antiparkinsonians. Discontinuation of the medication or dose reduction almost always leads to complete hair regrowth. The therapeutic value of mineral supplements remains unclear.

Effect of lithium maintenance therapy on thyroid and parathyroid function.

OBJECTIVES: To assess changes induced by lithium maintenance therapy on the incidence of thyroid, parathyroid and ion alterations. These were evaluated with respect to the duration of lithium therapy, age, sex, and family history (whether or not the patient had a first-degree relative with thyroid disease). DESIGN: Prospective study. SETTING: Affective Disorders Clinic at St. Mary's Hospital, Montreal. PATIENTS: One hundred and one patients (28 men and 73 women) with bipolar disorder receiving lithium maintenance therapy ranging from 1 year's to 32 years' duration. The control group consisted of 82 patients with no psychiatric or endocrinological diagnoses from the hospital's out-patient clinics. OUTCOME MEASURES: Laboratory analyses of calcium, magnesium and thyroid-stimulating hormone levels performed before beginning lithium therapy and at biannual follow-up. RESULTS: Hypothyroidism developed in 40 patients, excluding 8 patients who were hypothyroid at baseline. All patients having first-degree relatives affected by thyroid illness had accelerated onset of hypothyroidism (3.7 years after onset of lithium therapy) compared with patients without a family history (8.6 years after onset of lithium therapy). Women over 60 years of age were more often affected by hypothyroidism than women under 60 years of age (34.6% versus 31.9%). Magnesium levels in patients on lithium treatment were unchanged from baseline levels. After lithium treatment, calcium levels were higher than either baseline levels or control levels. Thus, lithium treatment counteracted the decrease in plasma calcium levels associated with aging. CONCLUSIONS: Familial thyroid illness is a risk factor for hypothyroidism and hypercalcemia during lithium therapy.