Plasma Lithium Concentrations Research Articles

Calculating lithium doses in mental health

L is licensed for the acute and long-term management of mania in bipolar affective disorder (electronic Medicines Compendium, 2014). Lithium has a narrow therapeutic index, and the National Institute for Health and Care Excellence (NICE, 2014) recommends regular therapeutic drug monitoring and that health professionals should aim to achieve a lithium plasma concentration between 0.6 and 0.8 mmol/litre in patients initially treated with lithium. For those already on lithium and who have relapsed, a plasma concentration between 0.8–1.0 mmol/litre is recommended. If a patient’s lithium plasma concentration is suboptimal, they are at risk of relapsing with either a manic or depressive episode. Concentrations above the therapeutic range can result in lithium toxicity. Each preparation of lithium differs in its pharmacokinetic properties and the amount of lithium contained, therefore it is important that lithium is prescribed by brand name (Joint Formulary Committee (JFC), 2015). In addition, when substituting different preparations, it is important to ensure the conversion is done correctly. A patient is diagnosed with bipolar affective disorder and is currently prescribed Priadel (lithium carbonate) tablets 600 mg at night as prophylaxis of manic episodes. He has relapsed and is currently secreting his tablets, and the prescriber wishes to convert him to a liquid preparation. Priadel tablets contain 5.4 mmol of lithium per 200 mg tablet. Priadel liquid (lithium citrate) has a strength of 520 mg per 5 ml, and each 5 ml contains approximately 5.4 mmol (JFC, 2015). Priadel 200 mg tablets cost £2.30 per pack (containing 100 tablets), and 400 mg tablets cost £3.35 per pack (also containing 100 tablets). Priadel liquid costs £5.61 per 150 ml bottle (JFC, 2015).

Minor contribution of biliary excretion in lithium elimination in rats.

Lithium, which is often used for the treatment of bipolar disorders, is mainly recovered into urine after being orally administered. Due to the fact that it is completely absorbed via the gastrointestinal tract, it remains unknown whether biliary excretion is involved in the lithium disposition. In this study, we examined biliary excretion of lithium in rats and compared these with renal excretion. After the injection of lithium chloride to femoral vein, plasma levels and excretion into urine and bile of lithium were evaluated. After its intravenous administration as a bolus, the plasma concentration of lithium decreased time-dependently. Until 60 min, 6.47% and 0.694% of injected lithium were excreted into urine and bile, respectively. The biliary clearance of lithium was calculated to be 0.0779 mL/min/kg, and this was 11.3% of the renal clearance. These findings suggest the low ability of the liver to eliminate lithium from plasma in comparison with the kidney in rats.

All-Trans-Retinoic Acid (ATRA) Combined with Lithium As Treatment of Relapsed Non-Progranulocytic AML: Therapeutic Targeting Inhibition of the Glycogen Synthase Kinase 3-Beta (GSK3) Enzyme

Introduction: Targeting the maturation arrest in acute myeloid leukemia (AML) to induce differentiation instead of killing rapidly dividing cells can lead to more efficacious and less toxic therapies for AML. Inhibition of the GSK3 enzyme with lithium sensitizes AML cells to the differentiating effects of all-trans-retinoic acid (ATRA), resulting in differentiation and inhibition of proliferation (Gupta K, et al. and Wald DN. Leukemia. 2012;26:1277-85.). In vitroand animal studies suggest the combination of ATRA and lithium has therapeutic activity against AML. We are conducting a phase I study of ATRA and lithium for the treatment of relapsed, non-progranulocytic AML (NCT01820624).Methods: Eligible patients were older than 18 years of age and had relapsed /refractory non-progranulocytic AML. Lithium carbonate 300 mg by mouth thrice daily was started on day -3 and given continuously and was titrated to achieve a target plasma concentration of 0.6 – 1.0 mmol/l. ATRA, at a starting dose of 22.5 mg/m2by mouth daily in two divided doses, was given from day 1 through 7 and day 15 through 21 of a 28-day cycle. GSK3b activity was measured using flow cytometry-based assays with antibodies against its inhibited form: serine-9-phosphorylated GSK3β (pGSK3) in AML cells. phosphoGSK3α (pGSKα) and β-Catenin were also evaluated with flow cytometry. The AML blasts (CD34+CD38+) as well as AML stem cells (CD34+CD38-) were quantitated by flow cytometry and changes in surface markers (CD11b, CD14 and CD15) were followed after treatment.Results: Correlative data were available on the first 5 subjects. Median age was 67.5 (range 42-83) years; median number of prior therapies was 2.5 (range 1 - 6). Mean expression of pGSK3, compared to baseline, increased by 1.6-fold when the target lithium plasma concentration of 0.6 mmol/L was reached (95% CI 1.14- 2.07), whereas there was no increased expression at levels below 0.6 mmol/L (change in expression: 0.94; 95% CI 0.65-1.27). The difference between pGSK3 expression levels above and below the threshold was significant (p = 0.04). After 10 days of treatment, lithium plasma concentration and pGSK3b expression presented a positive correlation, with a Pearson correlation coefficient of 0.82 (p = 0.024, R20.67). The same cutoff value for lithium plasma concentration did not identify statistically significant differences in the expression of pGSK3α or β-catenin.The mean proportion of circulating blasts (CD34+) increased 4-fold after 4 weeks of treatment; correlating with the absence of clinical response in patients enrolled in this first cohort at low doses of ATRA. However, at the same time point, the proportion of leukemia stem cells (CD34+/CD38-) decreased to 38% of baseline (95% CI 21%-98%, p = 0.04). One subject presented evidence of differentiation after 1 week of treatment with the combination, with decreased blast expression of CD11b (from 20% to 3%) and CD15 (66 to 2%) and a concomitant 5-fold increase in CD14 expression in AML stem cells. An additional patient presented a 4-fold induction of CD15 expression in blasts, suggestive of partial AML differentiation.Conclusion: Lithium is capable of effecting GSK3β inhibition in vivo at plasma concentrations that are achievable in clinical settings. Study accrual continues and larger number of patients will allow for ROC analysis to determine the specific lithium concentration for optimal GSK3β inhibition. Treatment with the ATRA and lithium combination can decrease circulating AML stem cells and induce AML cell differentiation. DisclosuresNo relevant conflicts of interest to declare.

Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney

Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats. Their intravenous administration stimulated urinary excretion of phosphate or glucose. After the intravenous injection of lithium chloride as a bolus, plasma concentration of lithium decreased time-dependently. The renal clearance of lithium was calculated to be 0.740ml/min/kg in control rats, and this was 26.7% of creatinine clearance. Foscarnet and PTH significantly increased the renal clearance of lithium and its ratio to creatinine clearance, suggesting that they prevented the reabsorption of lithium. No effect of phlorizin on the renal handling of lithium was recognized. In control rats, the renal clearance of lithium showed a strong correlation with the renal excretion rate of phosphate, compared with creatinine clearance. These findings suggest that sodium-phosphate cotransporter reabsorbs lithium in the rat kidney. Furthermore, its contribution was estimated to be more than 65.9% in the lithium reabsorption. And, this study raised the possibility that therapeutic outcome of lithium is related with the functional expression of sodium-phosphate cotransporter in the kidney.

Lithium Protects Against Spinal Cord Injury in Rats: Role of Nitric Oxide

Lithium improves locomotor scores after spinal cord injury (SCI) in rats. However, the underlying mechanisms are unknown. Herein, we assess the role of nitric oxide (NO) in this action. The first set of experiments were performed to determine a dose of lithium that effectively improves locomotor scores in rats with SCI. Therefore, rats received different doses of lithium chloride (1, 4, 10, and 20 mg/kg intraperitoneally) or saline 1 hour before SCI. In the next step, the role of NO in the effect of lithium on SCI was investigated. For this purpose, rats were co-treated with an effective dose of lithium (20 mg/kg 1 hour before SCI) and a noneffective dose of Nω-nitro-L-arginine methyl ester (L-NAME, a nonselective NO synthase inhibitor; 15 mg/kg intraperitoneally 30 minutes before SCI). SCI was induced by compressing the T9 spinal segment with an aneurysmal clip for 60 seconds in anesthetized rats. Locomotor scores were determined at 1, 3, 5, 7, 14, 21, and 28 days after SCI. Plasma lithium levels were measured 12 hours after SCI. Spinal histopathologies were examined 30 days after SCI. Lithium (20 mg/kg) significantly improved locomotor scores and decreased histopathologic spinal damage. l-NAME (15 mg/kg) reversed the beneficial effects of lithium. The 20-mg/kg dose of lithium resulted in a 0.68 ± 0.02 mEq/L plasma lithium concentration, which is lower than the therapeutic level in humans (0.8-1.2 mEq/L). Lithium protects against SCI through an NO-dependent mechanism.

Aspirin for treatment of lithium‐associated sexual dysfunction in men: randomized double‐blind placebo‐controlled study

The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD). In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240mg/day) or placebo for six weeks. The International Index for Erectile Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist. Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time×treatment interaction were observed for total score [Greenhouse-Geisser: F(1.410,39.466)=6.084, p=0.010] and erectile function [Greenhouse-Geisser: F(1.629,45.602)=7.250, p=0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values=0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [χ(2) (1)=10.800, p=0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups. Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD.

Ramadan et trouble bipolaire : exemple de perturbation du rythme circadien et son impact sur la maladie

Fasting during the Ramadan month is a cornerstone of Islam. Several disorders of the chronobiological rhythms occur during this month and impact on mood. Through this paper the authors provide a literature review of the impact of fasting on patients with bipolar disorders. A literature review using Mesh keywords through Medline database. From 1970to 2011, articles in French and English were selected. Circadian rhythm refers to the approximately 24-hour cycles that are generated by an organism. Most physiological systems demonstrate circadian variations. Many hormones and other metabolisms, such as gastric pH, insulin, glucose, calcium and plasmatic gastrine, have been shown to exhibit circadian oscillation. The role of social rhythm in behaviors and its influence on circadian rhythms in humans is now obvious. It has been shown that the lack of concentration and irritability increased continuously during Ramadan month and reached its peak at the end of the month. Mood and vigilance are significantly decreased during the fasting month. Several authors have stated that the course of bipolar illness may be affected by the changes in social rhythm that occur during Ramadan (fasting month). Studies which have been devoted to this topic are sparse. Kadri et al., in 2000, studied 20bipolar patientsduring the fasting month of Ramadan of 1417 (Hegirian calendar, corresponding to January 1997). Diagnosis of bipolar disorder was made according to ICD-10criteria. Patients were assessed during the week before Ramadan, the second and the fourth weeks of the fasting month and the first week after its end, with the Hamilton Depression and Bech-Rafaelsen scales. The plasma concentration of lithium was also assessed. The main finding of the study was that 45% of the patients relapsed, 70% during the second week, and the remaining patients at the end of Ramadan. These relapses were not related to plasma concentration of lithium. Most of the relapses were manic (71,4%). Patients who did not relapse had more insomnia and anxiety during the second and third weeks of the study. The side effects of lithium increased and were seen in 48% of the sample, mostly dryness of the mouth with thirst and tremor. However, Farooq et al. in 2006studied 62bipolar patients during the fasting month of Ramadan 1427(from 25September to 24October 2006). Serum lithium, electrolytes, Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were assessed, one week before Ramadan, mid Ramadan and one week after Ramadan. The side effects and toxicity were measured by symptoms and signs checklist. There was no significant difference in mean serum lithium levels at three time points. The scores on HDRS and YMRS showed significant decrease during Ramadan (F=34,12, P=0,00, for HDRS and F=15,6, P=0,000for YMRS). Also the side effects and toxicity did not differ significantly at the three point's assessment. All physiologic parameters are influenced by the circadian rhythm, which is influenced in its turn by the food rhythm. So far, the results of these two main studies, with opposite results, do not help us advise bipolar patients to fast or not to fast. Other studies in this field are badly needed.

1840 – Pharmacokinetics of lithium during delivery and in the neonatal period. A preliminary data

Lithium has been used in the treatment of bipolar disorder in pregnant women. However, information on the pharmacokinetics of lithium during perinatal period is scarce. To study pharmacokinetics of lithium during delivery and in the neonatal period. A prospective, observational and naturalistic study was conducted at the PERINATAL PSYCHIATRY PROGRAM CLÍNIC-BARCELONA, from 2005 to 2012. We included all consecutive cases of pregnant women with bipolar disorder I or II (n = 22), and on maintenance treatment with lithium monotherapy (n = 13) or polytherapy (n = 9) during pregnancy who elected artificial feeding. Lithium plasma concentrations in maternal blood and umbilical cord were detected. Lithium plasma concentrations in infants (n = 16) at delivery and in the neonatal period were obtained to calculate elimination half-life, which was estimated by lineal regression. Technique: AVL 9180 electrolyte analyser using a lithium-selective electrode (detection limit =0.10 mEq/L). Women did not fulfil diabetes criteria pre-pregnancy and during pregnancy. Attending to neonatal outcomes, infants exposed to polytherapy had a higher weight at birth (percentils) than those exposed to lithium alone [53.38 (33.40) vs. 70.22 (26.25)]. No statistically significant differences were found in umbilical cord:maternal plasma concentration ratio between those treated with lithium monotherapy and women treated with polytherapy (1.05 vs. 1.08). The lithium mean elimination half-life (SD) in infants was 6.73 (9.12) days. Lithium crosses placental barrier almost completely. Elimination half-life in neonates exposed to lithium in utero was 6.73 days. Moreover, lithium treatment during pregnancy requires therapeutics monitoring in exposed dyads.

590 – Exposure to lithium during late pregnancy and neonatal outcomes

Introduction Lithium has been used in the treatment of pregnant women with bipolar disorder for many decades but information on the effects of its exposure on perinatal variables is scarce. Objectives To determine the effects of in-utero exposure to lithium on neonatal outcomes among infants born to women with treatment with lithium during pregnancy. Methods Prospective and observational study including all consecutive cases of pregnant women with bipolar disorder type I or II (N = 22) and maintenance treatment with lithium monotherapy (n=13) or polytherapy (n=9), attended at the PERINATAL PSYCHIATRY PROGRAM CLINIC-BARCELONA between 2005 and 2012. We evaluated sociodemographic data, lithium plasma concentrations in maternal blood and umbilical cord, obstetric and neonatal variables. Results No statistically significant differences were found regarding sociodemographic data between both groups. Rates for umbilical cord:maternal plasma lithium levels were higher in women treated with polytherapy than in women who received lithium alone (1.08 vs. 1.05). Neonates exposed to polytherapy had a higher weight percentile at birth (p70 vs p50) and greater gestational age (39.72 vs. 38.28 weeks), than those exposed to lithium alone. Acute neonatal complications were more frequently observed in infants that were exposed to lithium monotherapy (33.3% vs. 38.50), being all complications transitory and not severe. Conclusions The infants exposed to lithium polytherapy presented a higher weight at birth compared to those who received lithium monotherapy. However, no statistically significant differences were found between treatment groups. Further research is needed to better clarify safety of lithium and its effect on neonatal outcomes.

1816 – Prenatal exposure to lithium and fetal and neonatal growth

Insulin-dependent diabetes, obesity and gestational diabetes are factors associated with macrosomia. Some psychiatric medications have well established side effects of weight changes in exposed pregnants. However, very few studies have investigated about the effects of lithium in fetal and neonatal anthropometry. To investigate the effects of maternal use of lithium during pregnancy on fetal and neonatal growth. A case-control study was conducted at the PERINATAL PSYCHIATRY PROGRAM CLÍNIC-BARCELONA. Case group consisted of 18 pregnant women on maintenance treatment with lithium monotherapy (n=13) or polytherapy (n=5) during pregnancy; control group involves 49 healthy women selected from an initial sample of 309. We evaluated sociodemographic data, lithium plasma concentrations in maternal blood and umbilical cord, fetal and neonatal anthropometry. Women did not diabetes or obesity criteria pre-pregnancy and during pregnancy. Mean maternal age (SD) in lithium exposed cases was 33.5 (3.8) and 32.5 (4.1) in non-exposed pregnant. No statistically significant differences were found regarding sociodemographic variables and pre-pregnancy BMI. Caesarean section was required in 91.8% of lithium exposed mothers, whereas 8.2% of non-exposed women did not need it (p= 0.000). Fetuses exposed to lithium had greater abdominal circumference (p= 0.018) and femur length (p= 0.010) compared to non-exposed group. There were no differences in umbilical cord/maternal plasma lithium ratio between women treated with lithium monotherapy or polytherapy (1.11vs.1.03). The fetuses exposed to lithium had a greater abdominal circumference, greater femur length and more caesarean section in comparison to non-exposed group. Fetal growth surveillance is recommended in pregnant treated with lithium.

Effect of Carrageenan-Induced Acute Peripheral Inflammation on the Electrolyte Disposition to Cerebrospinal Fluid in Rats

To clarify whether peripheral inflammation has a remote effect on the central nervous system, the electrolyte disposition between the circulating blood and central nervous system was evaluated in rats with carrageenan-induced acute peripheral inflammation (API). λ-Carrageenan was subcutaneously injected in the hind paw of the rat, and lithium was utilized as a surrogate marker of sodium. When the plasma and cerebrospinal fluid (CSF) concentrations of lithium were examined following lithium being intravenously administered, it was revealed that the CSF concentration of lithium in API rats is reduced compared to that in normal rats, while the plasma concentration profile of lithium in API rats is indistinguishable from that in normal rats. The pharmacokinetic analysis showed that the lithium disposition from the plasma to CSF markedly decreased by 35.8% in API rats compared to that in normal rats. On the other hand, when lithium was immediately administered into the lateral ventricle, its elimination profiles in CSF were not different between normal and API rats. It is therefore probable that the lithium disposition from the plasma to CSF alters in API rats, reflecting the entry process of electrolytes from the circulating blood to brain tissue being suppressed in response to peripheral inflammation.

Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3β-positive epithelium

It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3β (pGSK-3β) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7-28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3β-immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β-, and pGSK-3β-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3β, proliferation, and microcysts.

From Lithium Intoxication to Lung Cancer

To the Editor: Sometimes, the suspicion of lithium intoxication may cause an “intoxication” in clinical diagnosis. Case report. Ms A, a 47-year-old woman with bipolar affective disorder (of multiple etiologies, including those conforming to ICD-10 and DSM-IV criteria) who had been treated with lithium, was admitted to our emergency department in December 2009 for myalgia, fever, and generalized weakness. Five years prior, she attempted suicide by jumping from the fifth floor. She had spinal decompression from T12–L3 as well as an instrumented reconstruction with platinum rods. Because of the spinal cord injury, she was using a catheter to empty the bladder. Her body temperature was 37.5°C. An x-ray study of the chest showed an infiltration into the left apex. Urinalysis revealed trace bacteria, 9–11 white blood cells per high power field. The plasma lithium concentration was 2 mmol/L, and the creatinine level was 0.8 mg/dL. The erythrocyte sedimentation rate was 80 mm/h. The 24-hour urine amount was 6000–7000 mL. In light of these findings, it is thought that lithium toxicity developed due to urinary or pulmonary infection. Lithium was stopped after the possibility of intoxication was identified. Olanzapine was started at the dose of 10 mg/d as a mood stabilizer. Because the patient's general condition was poor, the lithium could not be restarted and the diagnosis of intoxication could not be confirmed. The muscle strength in both of the upper extremities was normal. In the lower extremities, paraplegia with brisk deep tendon reflexes and Babinski's sign was detected bilaterally. These findings were considered sequelae of the prior spinal cord damage. Nerve conduction studies identified a serious decrease in the amplitudes in the lower extremities, suggesting smotor axonal damage. The cerebrospinal fluid (CSF) analysis showed 100 white cells/mm3, 315 mg/dL protein, and glucose level within normal limits. In light of these findings, an acute motor axonal neuropathy was diagnosed. Ms A received intravenous immunoglobulin (0.4 mg/kg/d) for 5 days. No clinical improvement was seen. The second CSF analysis showed 200 white cells/mm3, 823 mg/dL protein, and glucose level within normal limits. The spine was investigated with magnetic resonance imaging (MRI). Because thoracal epidural metastatic lesions were detected in spinal MRI, the cerebral MRI was established for research of spreading. It showed multiple metastatic lesions in brain parenchyma as well (Figure 1). Thoracic computed tomography (CT) showed a lung mass as the primary focus (Figure 2). Biopsy demonstrated lung adenocarcinoma. Figure 1 Cerebral Magnetic Resonance Imaging (MRI) Scans Showing Multiple Metastatic Lesionsa Figure 2 A Coronal Image From the Computed Tomography Scan Demonstrating a Left-Sided Apical Pulmonary Tumor In this patient, our first diagnosis was chronic lithium intoxication. Lithium is a mood-stabilizing agent commonly used for the treatment of bipolar disorder and it has a narrow therapeutic window from 0.6 to 1.5 mmol/L. Risk factors for lithium intoxication include drug interactions, infection, and dehydration.1 Our second diagnosis was acute motor axonal neuropathy. Acute motor axonal neuropathy is a known variant of Guillain-Barre syndrome with a clinical course that includes motor paralysis, hyporeflexia, albuminocytological dissociation in CSF, and finding of axonal involvement on nerve conduction study.2 Intravenous immunoglobulin and plasmapheresis have also been suggested for acute motor axonal neuropathy, as well as for Guillain-Barre syndrome.3 But our case did not show a response to intravenous immunoglobulin. Because of the failure to improve despite intravenous immunoglobulin treatment, the patient's prior spine surgery history, persistent abnormal CSF findings, and isolated lower extremity paresis suggestive of paraspinal lesion clued us that a spine MRI should be done immediately. We thought that lithium intoxication and sequelae findings of the former spinal injury were masking primary lung cancer, a metastatic cranial mass, and neoplastic polyradiculopathy. On the other hand, whole findings may have originated from the combination of these diseases.

Optimal Frequency of Lithium Administration in the Treatment of Bipolar Disorder

Bipolar disorder is a recurrent chronic illness distinguished by periods of mania and depression. Lithium has been used for about 60 years as a 'mood stabilizer' for bipolar disorder with proven efficacy in preventing relapse of both mania and depression. Despite its long history and ongoing use in current management of bipolar disorder, the optimal dosing of lithium is still the subject of ongoing debate. This article aims to evaluate different dosing schedules, in the light of the unique pharmacokinetic and pharmacodynamic properties of lithium, as well as its adverse-effect and toxicity profiles. This is all the more important given the narrow therapeutic index of lithium. Current recommendations mostly advocate that lithium be administered in multiple daily doses. However, single daily or alternate daily schedules may be viable options for administration. Multiple daily schedules are thought to be advantageous in maintaining more constant plasma lithium concentrations than single daily regimens, which are associated with significant fluctuations throughout the day. When comparing these two schedules with respect to plasma lithium concentrations, adverse-effect profiles and recurrence of symptoms, there are no significant differences between the two regimens. In fact, a single daily regimen may have added advantages in reducing the risk of long-term renal damage and increasing compliance. The evidence for alternate daily dosing is somewhat varied with regard to symptom recurrence; however, this schedule has been shown to be associated with decreased adverse effects, and further research into this issue is therefore warranted. Presently, therefore, clinicians should consider single daily administration of lithium to potentially minimize adverse effects and enhance compliance.

Push-pull osmotic pump for zero order delivery of lithium carbonate: Development and in vitro characterization

Lithium carbonate, a drug with narrow therapeutic index, needs therapeutic drug monitoring and dose adjustment to maintain lithium level within the therapeutic window. Conventional formulations of lithium carbonate exhibit immediate drug release causing swing/fluctuations in the plasma concentration of lithium, consequently leading to unfavorable side-effects and make dose adjustment difficult. The push-pull osmotic pump has been developed for zero order delivery of lithium carbonate for a period of 24 h. The effect of various formulation variables on bilayer core tablet and its semi permeable coating along with orifice diameter have been investigated and optimized for desired drug release profile. Drug release was found to be inversely proportional to the membrane thickness but directly related to the amount of pore formers in the semipermeable membrane. Images from a scanning electron microscope confirmed the presence of pores in the semipermeable membrane which facilitated the required water penetration. No distortion or change in orifice shape was noticed prior to and after the dissolution study. Drug release from the developed formulation was found to be independent of pH, agitation intensity and agitation mode but depended on osmotic pressure of dissolution media.

First-Dose Pharmacokinetics of Lithium Carbonate in Children and Adolescents

This study examines the pharmacokinetics of oral doses of lithium carbonate immediate-release capsules after administration of 600 or 900 mg in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar I disorder. Lithium plasma concentrations were followed over 48 to 72 hours in 39 subjects (20 male and 19 female subjects; ages, 7-17 years) with mixed or manic episodes enrolled at 7 clinical sites participating in the Collaborative Lithium Trials. Population pharmacokinetic modeling was performed using NONMEM, and influences of patient covariates on pharmacokinetics parameters were examined. The pharmacokinetics of lithium was best described using a 2-compartment model with a lag time and first-order absorption. There was considerable variability in lithium exposures. Lithium clearance related best to fat-free mass. Inclusion of fat-free mass as a covariate reduced the between-subject variability from 52% to 42%. Lithium clearances did not vary systematically with age group, dose, sex, or creatinine clearances. Allometrically scaled clearance and volume of distribution from the population analysis were within the range reported in adults. Single-dose profiles of lithium in young patients with BP-1 show marked variability. Therefore, ongoing serum monitoring is needed during continued therapy. The developed population pharmacokinetic model may be used to predict other dosage regimens, support scaling from adult to pediatric pharmacokinetics, and support the design of future clinical trials.

Effects of lithium carbonate on carboplatin-induced thrombocytopenia in dogs

To describe the effects of lithium carbonate on thrombopoiesis in clinically normal dogs and in dogs treated with carboplatin. 18 young adult sexually intact female Beagles. Dogs were assigned to each of 3 treatment groups (6 dogs/group). Group 1 received 150 mg of lithium carbonate (14 to 16 mg/kg), PO, every 12 hours on days 1 through 21. Group 2 received carboplatin (300 mg/m(2), IV) on day 0 and cephalexin (30 mg/kg, PO, q 12 h) on days 14 through 21. Group 3 received lithium, carboplatin, and cephalexin at the aforementioned doses and schedules. Plasma lithium and blood platelet concentrations were measured on days 0, 2, 4, 7, 9, 11, 14, 16, 18, and 21. Number of megakaryocytes in bone marrow specimens and the percentage of large unstained cells and CD34+ mononuclear cells in bone marrow aspirates were determined on days 0, 7, 14, and 21 by manual enumeration, automated hematologic analysis, and flow cytometric immunophenotyping, respectively. Plasma lithium concentrations ranged from 0.12 to 2.41 mmol/L. All dogs given lithium achieved a concentration within the target interval of 0.5 to 1.5 mmol/L by days 4 to 7. Thrombopoiesis was increased in dogs receiving lithium alone. All dogs given carboplatin developed mild thrombocytopenia. There were no differences between group 2 and group 3 throughout the study. Lithium stimulated thrombopoiesis in clinically normal dogs. Lithium administration at the doses and schedules used, with concurrent administration of cephalexin, did not prevent thrombocytopenia induced by carboplatin.

PW01-14 - Lithium placental passage and perinatal outcome: clinical management during late pregnancy

IntroductionDespite lithium has been used for the last 50 years as a maintenance treatment for bipolar disorder during pregnancy, there is limited information about perinatal clinical outcomes from fetal exposure to lithium.Objectives1.To quantify the rate of lithium placental passage2.To assess any association between plasma concentration of lithium at delivery and perinatal outcome.MethodsObservational and prospective study. Subjects: Women in maintenance treatment with lithium, being attended during pregnancy at the Perinatal Psychiatry Programme of Hospital Clínic (Barcelona, Spain) between 2007 and 2009. Procedure: We assessed sociodemographical data; dose/day of lithium carbonate; other drugs doses; plasmatic concentration of lithium carbonate in maternal blood intrapartum and in the umbilical cord; obstetrical maternal complications; gestational age at delivery; weight at delivery; Apgar scores; congenital malformations; hospital stays, infant serum concetrations of thyroid-stimulating hormone.ResultsEight mother-child diads. Mean age of the mother (SD): 32.1 (4,7); 100% caucasian and married. Mean dose of maternal lithium (SD): 675mg (237,5mg). Premature rupture of membranes (%):25. Gestational mean age (in weeks) (SD): 39,9 (1). Birth weight (SD) : 3625gr (451,2gr); Mean Apgar1min (SD): 8,38 (1,1); Mean Apgar5min (SD): 9,75 (0,4). Loss of fetal intrapartum wellness (%): 12,5. Days of hospitalization (mean) (SD):9,5(16,6). Lithium plasmatic concentration (mEq/L), mean (SD): maternal 0,45(0,1), umbilical cord 0,33(0,1), lithium ratio uc/m 0,93 (0,3); infant TSH μU/mL mean (SD): 4,9(4,6).ConclusionsLithium placental passsage was 0,93 (0,63-1,07). ≤At umbilical cord lithium levels ≤ 0.60 mEq/L, we didn't have any preterm deliveries, low birth weight newborns, nor neonatal complications.

Lithium poisoning: Is determination of the red blood cell lithium concentration useful?

Introduction. Despite a narrow therapeutic index, lithium remains a cornerstone for the treatment of bipolar disease. As lithium poisoning may result in life-threatening neurotoxicity, measurement of the lithium concentration is mandatory in drug monitoring as well as for the diagnosis and prognostic evaluation of lithium poisoning. However, toxic symptoms do not always correlate with plasma concentrations. Therefore, more reliable indicators have been proposed, including measurement of the red blood cell (RBC) lithium concentration and the RBC-to-plasma lithium ratio. Plasma and RBC lithium concentrations. Few studies have reviewed the relative utility of these measurements both in monitoring therapy and in poisoning, and they have involved only small numbers of subjects. Moreover, factors influencing plasma and RBC lithium concentrations are numerous, including gender, age, dosage, treatment duration, co-medications, and underlying diseases. In treated patients, investigated using in vivo magnetic resonance spectroscopy, there is a significant correlation between plasma and brain lithium concentrations in steady-state conditions. In contrast, lithium transport across erythrocytes markedly differs from its transport into the central nervous system, questioning the relevance of measuring the RBC lithium concentration. In poisoned patients, plasma and RBC lithium concentrations follow a parallel decline irrespective of the type of poisoning. Conclusions. Based on present evidence, measurement of the RBC lithium concentration and the calculation of the RBC-to-plasma lithium ratio offer no important clinical advantage over the measurement of the plasma lithium concentration, which remains the most important variable to monitor in lithium-treated or lithium-poisoned patients.

Lithium use in special populations

Byline: E. Mohandas, V. Rajmohan Lithium, a monovalent cation, was first used for the treatment of mania in the 1940s. Half a century into its use, the drug continues to be the preeminent choice for bipolar disorder with antimanic, antidepressant (modest) and antisuicidal property. Lithium is the "gold standard" mood stabilizer against which potential mood stabilizer agents are judged. The therapeutic uses of lithium also include use as an augmenting agent in depression, schizoaffective disorder, aggression, impulse control disorder, eating disorders, attention deficit disorder and in certain subsets of alcoholism. Lithium has been used in many medical disorders, especially cluster headache and dermatological disorders (seborrheic dermatitis, eczematoid dermatitis, genital herpes).[sup] [1] The drug is however associated with neurologic, endocrine, cardiovascular, renal, dermatologic and gastrointestinal adverse effects and possible teratogenicity. History Lithium was first discovered and defined by Johan August Arfvedson in 1817 when he did an analysis of the mineral petalite [LiAl(Si2O5)2]. Petalite was first found by Brazilian scientist Jose Bonifacio Andrade e Silva in 1800. Lepidolite, spodumene, petalite and amblygonite are the more important minerals containing lithium. It was Arfwedson's laboratory chief John Jacob Berzelius who named this alkali metal "lithion." Arfvedson was never able to fully isolate lithium, and it wasn't until 1855 that it was isolated by William Thomas Brande. Brande and Sir Humphrey Davy earlier had done electrolysis on lithium oxide in 1818. Lithium was first produced commercially in 1923 by Metallgesellschaft AG.[sup] [2] The use of lithium for medicinal purposes can be traced back 1,800 years to the Greek physician Galen, who treated patients with mania by having them bathe in alkaline springs and drink the water, which probably contained lithium. In 1843 Alexander Ure introduced lithium into modern medicine, and he showed the in vitro reduction of weight of a uric acid bladder stone in a lithium carbonate solution. Sir Alfred Garrod later discovered that gouty uric acid deposits also were soluble in lithium solution. The view in that time was that uric acid imbalances caused a wide range of diseases, and Armand Trousseau and Alexander Haig proposed that mania and depression also may result from this imbalance and lithium may be effective in these conditions. In the 1840s, lithium was mixed with carbonate or citrate to form a salt and was used to treat gout, epilepsy, diabetes, cancer and insomnia. In the 1870s, the then American Surgeon General William Hammond had provided anecdotal evidence for the use of lithium bromide in the treatment of acute mania. In the 1880s and 1890s the Lange brothers Carl and Fritz used lithium in depression, and Carl Lange was the first to systematically use lithium in the acute and prophylactic treatment of depression.[sup] [2] The introduction of lithium preparations and tablets in the 1900s brought to the fore the toxic effects of the drug; and there were reports of weakness, tremor, diarrhea, vomiting and deaths. The drug disappeared from the British Pharmacopoeia by 1932, but later in the 1940s it was used as a sodium substitute in low sodium diets; but the reports of severe intoxication led to its removal from American markets in 1949. [sup] [1] The appearance in 1949 in the Medical Journal of Australia of a paper entitled "Lithium salts in the treatment of psychotic excitement" by John F. J. Cade was an unspectacular entry into a new era of psychiatry. Manic patients showed improvement, with the patient becoming calmer after four to five days. There was no improvement in the excited schizophrenic patients, though there was a calming effect. There was no improvement or deepening of depression. The paper also gave details of initial dosage, maintenance doses, appearance of toxic symptoms and warning about lithium over-dosage. …