Pharmacokinetics Of Lithium Research Articles

Lithium management around delivery: a retrospective observational cohort study

IntroductionDuring the perinatal period lithium is proven effective as maintenance therapy and to prevent postpartum psychosis. Pregnancy affects all aspects of kidney physiology altering the pharmacokinetics of lithium. To minimize the risk of both maternal and neonatal complications around delivery, several authors have provided clinical advice on lithium dosing around delivery: decreasing dose by 30-50%, suspend lithium therapy 24-48 hours before scheduled cesarean section or induced delivery or even discontinuing lithium after first signs of labour.ObjectivesTo evaluate the validity of these recommendations by investigating 1) maternal lithium serum concentrations changes around delivery, 2) the lithium trasplacental passage at delivery and 3) the association between neonatal lithium serum concentration at delivery and neonatal outcomes.MethodsPsychopathologically stable women with a singleton pregnancy (n=66) who used lithium around delivery, were included in this retrospective observational cohort study (HCB/2020/1305). All women were advised to suspend lithium administration at the onset of labour in the event spontaneous deliveries. Study date: demographic, psychiatric, obstetric and neonatal outcomes for each mother-infant pair obtained from the hospital medical records.Lithium serum concentrations were determined by means of an AVL 9180 electrolyte analyzer based on the ion- selective electrode (ISE) measurement principle. Limit of quantification (LoQ) was 0.20 mEq/L.ResultsThe most common psychiatric diagnosis was a bipolar disorder type I (n=54, 90%). Forty mothers (61%) were on lithium monotherapy. Mean (SD) umbilical cord and intrapartum maternal lithium serum concentration was 0.59 (0.13) mEq/L and 0.55 (0.13) mEq/L respectively. There was a strong positive correlation between umbilical cord and maternal lithium serum concentrations (Pearson correlation coefficient 0.95 (95%IC: 0.91,0.97). In a subsample (N=22) a paired t test indicates that the maternal serum lithium concentrations at delivery were significantly lower (mean difference=0.19 mEq/L, 95%CI=0.13-0.25) than those during obtained the day before delivery hospitalization, after a mean (SD) of 31.29 (±11.92) hours (SD=11.92) have elapsed since the taking the last dose of lithium prior to delivery. Four women (6%) relapsed early postpartum.There were no significant differences between lithium monotherapy (N=18/40) and polytherapy (N=11/26) groups with regard to acute neonatal complications (p>0.05). The only acute neonatal complication associated to umbilical cord lithium serum concentration was hypotonia [0.712 (0.298) vs. 0.534 (0.214) (F=5.065; df=1,60; p=0.028)].ConclusionsWhen lithium is used around delivery, maternal and neonatal well-being can be maximized by maintaining maternal serum lithium concentrations at the minimal effective level and discontinuing briefly when presenting to hospital for delivery.Disclosure of InterestNone Declared

Lithium Pharmacokinetics in the Perinatal Patient With Bipolar Disorder.

The pharmacokinetics of lithium, the gold standard for the treatment of bipolar disorder, are well described in nonpregnant patients. Because lithium is commonly prescribed to women of childbearing age, more data are essential to characterize lithium pharmacokinetics during the perinatal period. Lithium is primarily eliminated by the kidney. As a result, shifts in lithium elimination clearance parallel pregnancy-related changes in glomerular filtration rate. Lithium's narrow therapeutic window increases the risk for therapeutic failure and toxicity when lithium elimination clearance is altered. To characterize the pharmacokinetics of lithium in pregnancy and postpartum, 3 women treated with lithium for bipolar disorder completed serial blood sampling protocols during each trimester of pregnancy and at least once postpartum. The trajectory of lithium elimination clearance, creatinine clearance, and serum lithium concentrations were determined. Manic, depressive, and anxiety symptoms were also assessed at each study visit. Compared to the nonpregnant state, lithium elimination clearance increased an average of 63.5% by the third trimester. Lithium elimination clearance was inversely related to changes in serum lithium concentration. Mood symptoms worsened with declines in serum lithium concentration. Lithium elimination clearance returned to baseline at 4 to 9 weeks postpartum. To maintain lithium effectiveness during pregnancy and prevent toxicity postpartum, lithium therapeutic drug monitoring and dose adjustments are warranted.

Population Pharmacokinetics and Dosing Regimen of Lithium in Chinese Patients With Bipolar Disorder.

Background: Lithium is an effective medication approved for the treatment of bipolar disorder (BD). It has a narrow therapeutic index (TI) and requires therapeutic drug monitoring. This study aimed to conduct a population pharmacokinetics (PPK) analysis of lithium and investigate the appropriateness of the dosing regimen according to different patient characteristics. Methods: A total of 476 lithium concentrations from 268 patients with bipolar disorder were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to investigate the influence of covariates, such as weight, creatinine clearance, and daily doses of lithium concentrations, and to determine the individualized dosing regimens for patients. Results: Lithium PK was described by a one-compartment model with first-order absorption and elimination processes. The typical estimated apparent clearance was 0.909 L/h−1 with 16.4% between-subject variability in the 62 kg patients with 116 ml/min creatinine clearance and 600 mg daily doses. To achieve a target trough concentration (0.4–0.8 mmol/L) in the maintenance phase, the regimen of 500 mg than 750 mg daily dose was recommended for patients with renal insufficiency and weighing 100 kg. Conclusion: A PPK model for lithium was developed to determine the influence of patient characteristics on lithium pharmacokinetics. Weight, creatinine clearance, and total daily dose of lithium can affect the drug’s clearance. These results demonstrate the nonlinear renal excretion of lithium; hence, dosage adjustments are recommended for patients with renal insufficiency.

Population Pharmacokinetics of Lithium in Young Pediatric Patients With Intellectual Disability.

Background: Lithium is a well-established treatment for bipolar disorders and has been shown to be neuroprotective, and thus low doses might be useful for the treatment of childhood brain injury and neurological sequelae. However, pharmacokinetic (PK) data in children are limited. This study was to investigate the PKs after oral administration of low-dose lithium carbonate in young children with intellectual disability. Methods: Fifty-two children with intellectual disability aged 4–10 years old were enrolled. A series of blood samples were collected after a single-dose administration of lithium carbonate. The serum lithium concentration was measured using a validated ion chromatography assay, and the PK concentration data were modeled using a nonlinear mixed effect model in the NONMEM program. Results: The lithium concentration over time was adequately described by a two-compartment disposition, with a transient absorption and first-order elimination process. The inclusion of body weight as an allometric factor significantly improved the model fit, but age and gender were not associated with the PKs of lithium. The clearance, central volume, inter-compartmental clearance, and peripheral volume estimates from the final population PK model were 0.98 L/h, 13.1 L, 0.84 L/h, and 8.2 L for children with a body weight of 20 kg. The model evaluation suggested that there is no obvious discrepancy between the observations and predictions in the proposed model. A visual predictive check demonstrated the good predictive performance of the final model. Conclusions: The lithium PK properties in young children were similar to those in older children and adults. The proposed model can be used for further PK/PD analysis to optimize the dosage regimen of lithium in children.

Estimation of lithium clearance in patients with bipolar disorder.

Lithium is an effective agent approved for the treatment of bipolar disorder. It has narrow therapeutic window and significant variability in its pharmacokinetic. The aim of this study is to determine the population pharmacokinetics of lithium in patients with bipolar disorder in Saudi Arabia and to identify the factors that explain variability. A retrospective chart review was performed on patients with bipolar disorder who received oral lithium. The population pharmacokinetic models were developed using Monolix 4.4. After the appropriate base model was established, five covariates were tested, namely age, sex, weight, serum creatinine, and creatinine clearance. The analysis included a total of 170 lithium plasma concentrations from 31 patients. The data were adequately described by a two-compartment open model with linear absorption and elimination. The average parameter estimates for lithium CL/F, V1/F, V2/F, and Q/F were estimated. The inter-individual variability (coefficients of variation) in CL was 42%. The most significant covariate on lithium CL was found to be creatinine clearance. The population pharmacokinetic model of lithium in patients with bipolar disorder in Saudi Arabia was established. Our findings showed that creatinine clearance is the most significant covariate on lithium clearance. Further studies are required to understand the factors that may influence the pharmacokinetics of lithium and assist in drug dosage decisions.

Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate.

Background and ObjectiveOlanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and, either as monotherapy or as an adjunct to lithium or valproate, for bipolar I disorder. Multiple daily doses of olanzapine do not affect the pharmacokinetics of lithium or valproate; therefore, concomitant olanzapine administration does not require dosage adjustment of lithium or valproate. ALKS 3831, a combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM), is currently under development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Olanzapine is recognized as one of the most efficacious antipsychotics; however, the benefits of olanzapine are offset by its propensity to cause significant weight gain, which may lead to long-term metabolic sequelae. This study evaluated the effects of multiple daily doses of OLZ/SAM on the pharmacokinetics of lithium or valproate in healthy subjects.MethodsThis was an open-label, single-sequence, two-cohort study (ALKS3831-B101) conducted at a single center in the USA. Thirty-four healthy adult subjects were assigned (1:1) to receive lithium carbonate 300-mg tablets (cohort 1) or divalproex sodium 500-mg tablets (cohort 2), once every 12 h on days 1–7. Once-daily oral doses of OLZ/SAM (olanzapine 10 mg/samidorphan 10 mg) bilayer tablets were administered on days 8–18. Subjects resumed every 12-h doses of lithium or valproate concomitantly with the once-daily oral doses of OLZ/SAM on days 12–18. Plasma concentrations of lithium and valproic acid (valproate) were quantified in blood samples collected prior to and up to 12 h after lithium or valproate dose administration on days 7 and 18. Pharmacokinetic parameters of lithium and valproate, including maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval, were calculated. The ratio of geometric means of maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval in the presence and absence of OLZ/SAM, and its two-sided 90% confidence intervals, were derived from a mixed-effects model. Adverse events were monitored throughout the study.ResultsThe 90% confidence intervals for the ratios of geometric means, in the presence vs. absence of OLZ/SAM, were within the equivalence interval of 80–125% for both maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval of lithium and of valproate. The safety profiles of lithium or valproate co-administered with OLZ/SAM were consistent with what has been previously reported for lithium or valproate. The safety profile of OLZ/SAM was consistent with that observed in previous clinical studies with OLZ/SAM.ConclusionsConsistent with previously reported findings on olanzapine, administration of multiple doses of OLZ/SAM did not have a clinically significant effect on the pharmacokinetics of lithium or valproate. Co-administration of OLZ/SAM and lithium or valproate was generally well tolerated; the safety profile of OLZ/SAM was consistent with that observed in previous clinical studies.

Factors influencing lithium pharmacokinetics in patients with acute mania: A population pharmacokinetic analysis.

The objective of this study was to conduct a population pharmacokinetic model of lithium in Thai patients with acute mania. Lithium concentrations from 222 acute manic patients were included in this study. The population pharmacokinetic model was developed using NONMEM 7.3 software. Influences of potential covariates including body size, age, renal function, and gender were evaluated through astepwise approach. Bootstrap analysis and an external validation approach were used to evaluate the robustness and predictability of the final model. A one-compartment model adequately described lithium pharmacokinetics. Body weight and age were significant predictors for lithium clearance, with the following relationship: CL/F (L/hr)=1.43*(WT/65)0.425 *(age/38)-0.242 . The population estimates of lithium clearance, volume of distribution, and absorption rate constant of the final model were 1.43L/hr, 54L (fixed), and 0.426hr-1 (fixed), respectively. Model evaluation showed that the final model was predictive and robust. A population pharmacokinetic model of lithium with good performance was developed in Thai patients with acute mania. This model can be used to assist clinicians in individualized lithium therapy.

Role of NHE3 and dietary phosphate in lithium pharmacokinetics

Lithium (Li+) is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, Li+ has been used to determine proximal tubule (PT) reabsorption based on the assumption that Li+ and Na+ transport go in parallel in the PT. However, the exact mechanism by which Li+ is reabsorbed remains elusive. The majority of PT Na+ reabsorption is directly or indirectly mediated by the Na+‐H+ exchanger 3 (NHE3). In addition, Na+‐phosphate cotransporters (Npt2a/c) have been implicated in renal Li+ reabsorption. We hypothesized that either NHE3 and/or Npt2a/c are mediating Li+ reabsorption. We studied Li+ pharmacokinetics in: i) tubule‐specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous (LiCl 5 mmol/kg, 2 μl/g BW) or oral administration (5 mmol/kg, 1% of BW via oral gavage) of LiCl did not result in differences in Li+ bioavailability (~80% in all groups), half‐life or urinary Li+/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, Li+ bioavailability was ~30% lower on low vs high dietary phosphate (64±4 vs 93±3%, P<0.05), possibly the consequence of a smaller area under the curve after oral administration (21±1 vs 25±1 mmol × L−1 × h, P<0.05). This was associated with lower urinary Li+/creatinine ratios on low vs high dietary phosphate (15±2 vs 47±7 mmol/mmol, P<0.05). Our data indicate that renal NHE3 does not play a role in Li+ pharmacokinetics; however, dietary phosphate has an indirect effect on Li+ bioavailability and Li+ disposition.Support or Funding InformationTR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK110621). JX was supported by an American Heart Association Predoctoral Fellowship (18PRE33990236) and LT by a Postdoctoral Fellowship (19POST34400026).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Contribution of NHE3 and dietary phosphate to lithium pharmacokinetics

Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium has been used as a measure to determine proximal tubule reabsorption based on the assumption that lithium and sodium transport go in parallel in the proximal tubule. However, the exact mechanism by which lithium is reabsorbed remains elusive. The majority of proximal tubule sodium reabsorption is directly or indirectly mediated by the sodium-hydrogen exchanger 3 (NHE3). In addition, sodium-phosphate cotransporters have been implicated in renal lithium reabsorption. In order to better understand the role of sodium-phosphate cotransporters involved in lithium (re)absorption, we studied lithium pharmacokinetics in: i) tubule-specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous or oral administration of lithium did not result in differences in lithium bioavailability, half-life, maximum plasma concentrations, area under the curve, lithium clearance, or urinary lithium/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, lithium bioavailability was ~30% lower on low versus high dietary phosphate, possibly the consequence of a smaller area under the curve after oral administration. This was associated with higher apparent lithium clearance after oral administration and lower urinary lithium/creatinine ratios on low versus high dietary phosphate. Collectively, renal NHE3 does not play a role in lithium pharmacokinetics; however, dietary phosphate could have an indirect effect on lithium bioavailability and lithium disposition.

Population Pharmacokinetic Analyses of Lithium: A Systematic Review.

Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic-pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic-pharmacodynamic study of lithium is recommended. Moreover, external validation of previously published models should be performed.

Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern

Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium-pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p<0.001) and vertical hypolocomotion (p<0.0001), increased anxiety-like behavior (p<0.05) and impaired memory (p<0.01) but no altered hedonic status. Horizontal (p<0.01) and vertical (p<0.001) hypolocomotion peaked more markedly 24h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal Emax model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation.

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats

Aims: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. Methods: Pharmacokinetic experiments with lithium were performed. Results: Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (C_cr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to C_cr was decreased by the (S)-enantiomer. Conclusion: This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats.

0863. Lithium pharmacokinetics in the rat according to the three different modalities of human poisoning

Lithium-related neurological toxicity may be severe resulting in seizures, myoclonic encephalopathy, and coma. Three different poisoning presentations exist in humans, including acute poisoning in non-previously treated patients (A), acute-on-chronic poisoning (A/C), and therapeutic overdose (T). The exact reasons why severity and features are different between these three presentations are unknown, although differences in brain lithium distribution have been suggested.

Risk factors for polyuria in a cross-section of community psychiatric lithium-treated patients.

Polyuria increases the risk of dehydration and lithium toxicity in lithium-treated patients. Risk factors have been inconsistently described and the variance of this adverse effect remains poorly understood. This study aimed to establish independent risk factors for polyuria in a community, secondary-level lithium-treated sample of patients. This was a cross-sectional study of the lithium-treated patients attending a general adult and an old age psychiatry service. Participants completed a 24-hour urine collection. Urine volume and the presence of polyuria were the outcomes of interest. The relationship between outcome and the participant's demographic and clinical characteristics was explored with univariable and multivariable analysis. A total of 122 participants were included in the analysis, with 38% being diagnosed with polyuria. Female gender and increased body weight independently predicted the presence of polyuria (standardized regression coefficient 1.01 and 0.94, respectively; p=0.002 and p=0.003, respectively). Female gender and increased body weight, lithium dose, and duration of lithium treatment independently predicted higher 24-hour urine volumes (standardized regression coefficients 0.693, p<0.0005; 0.791, p<0.0005; 0.276, p=0.043; 0.181, p=0.034, respectively). Of three different weight metrics, lean body weight was the most predictive. Female gender and increased body weight explain part of the variance of this adverse effect. Both risk factors offer fresh insights into the pathophysiology of this potentially reversible and dangerous adverse effect of lithium treatment. Future research should focus on understanding the differences between the genders and between different body compositions in terms of lithium pharmacokinetics and pharmacodynamics.

Traitement par lithium dans le trouble bipolaire du sujet jeune

Bipolar disorder in youths is a severe psychiatric disorder that potentially results in high-relapse rates and disrupts the normal psychosocial development. Many adults with bipolar disorder identify the onset of their symptoms in childhood and adolescence, indicating the importance of early accurate diagnosis and treatment. The lifetime prevalence is estimated in adolescence at 0.1% for bipolar I disorder and 1% for all bipolar spectrum disorders. “Classic” bipolar disorder with well-delineated episodes is rare among prepubertal children. The treatment of bipolar disorder in youths raises challenges and difficulties. Lithium is recommended as one of the first-line treatment options of bipolar disorder in children and adolescents with FDA approval as early as 12years. Lithium prescription is approved in France for bipolar disorder only for adolescents older than 16years old. This comprehensive literature review incorporates research studies evaluating the effectiveness of lithium in children and adolescents with pediatric bipolar disorder (randomized controlled trials, open-label studies and retrospective chart reviews). Lithium was evaluated as a monotherapy, as well as part of a combination treatment, in the acute and maintenance phases. The effectiveness of a lithium monotherapy is moderate with response rates of approximately 35 to 63%. Its efficacy is similar to valproate and carbamazepine; however, lithium appears to be superior in case of psychotic symptoms. A recent study reported the superiority of risperidone over lithium in bipolar mania with a comorbid attention-deficit/hyperactivity disorder. While it is ideal to use the lowest possible dose of monotherapy medication to decrease adverse side effects, most patients require adjunctive medication treatment for the stabilization of bipolar symptoms. Data suggest that a combined treatment with lithium (using valproate, carbamazepine or risperidone) may provide a better remission of symptoms, with response rates between up to 70 and 90%. The relapse rate in lithium monotherapy is high (37 to 56%); nevertheless, very few studies have measured the long-term effects of the medication in pediatric bipolar disorder. The data from the available pharmacological studies need to be interpreted cautiously because of the controversy surrounding the definition and diagnosis of bipolar disorder in youths. The continuity between childhood-onset bipolar disorder and the current adult-oriented DSM-IV criteria in adolescence is currently debated. The diagnostic framework has evolved to distinguish the diagnoses of “Severe Emotional Dysregulation” (or “Temper Dysregulation Disorder with Dysphoria” in DSM-V) in children from bipolar I disorder in adolescents. Research samples often include both of these clinical pictures. This heterogeneity in the patient population introduces a major caveat towards the interpretation of the available literature addressing treatment strategies. The distinction between these two forms is even more relevant given the fact that preliminary studies have shown various clinical courses, family psychiatric histories, different prognoses, as well as therapeutic responses. Even if the safety profile of lithium is reassuring, the reported side effects seem to be a more frequent in youths than in adults, especially if the child is young. The most commonly reported (>20%) adverse events were nausea/vomiting, diarrhea, abdominal pain, headache, dizziness, tremor and pollakiuria. Weight gain and acne are side effects that are perceived to be particularly shameful during adolescence. No data on long-term side effects are available. The limited studies examining the pharmacokinetics of lithium may indicate the need for vigilance in the variability induced by the weight in pediatric patients. Very few studies have examined predictors and moderators in the treatment of bipolar disorder in children and adolescents. Being younger or suffering from comorbid attention-deficit/hyperactivity disorder have been associated with a poorer response to lithium. The aims of future researches in bipolar disorder in youths may establish some evidence-based strategies for lithium especially: (i) by examining the acute efficacy in mania and also in bipolar depression with a particular attention to age-specific aspects and diagnosis at inclusion, (ii) by investigating the long-term effectiveness of lithium treatment, (iii) by characterizing the long-term safety of lithium, (iv) by identifying pretreatment variables associated with the effectiveness and tolerability of lithium, (v) by studying adherence concerns in adolescents.

Pharmacokinetics of Lithium in Egyptian Bipolar Patients: Dosage Adjustment Approach

Due to its proven clinical effectiveness, lithium has been considered as a corner stone for the long-term treatment of Bipolar Disorder (BPD) for more than half a century. The objective of this study was to evaluate the effect of patients’ different co-variables on lithium pharmacokinetics and the development of a pharmacokinetic model for the estimation of lithium clearance in Egyptian bipolar patients; this model can be used afterwards during dosage adjustment to achieve target’s steady-state plasma concentrations in similar settings. The study was conducted on 65 adult Egyptian bipolar patients of both genders, in both the in- and out-patient settings in the Institute of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Patients’ full profiles were prepared, containing all their data. Single daily dose regimen was followed by all patients and one blood sample was drawn 12 ± 0.5 hours post dose for steady-state lithium concentration, sodium level and serum creatinine determinations. Lithium trough levels were determined using Flame Emission Photometry technique. Data analysis and regression modeling revealed a significant correlation between total body weight (TBW), body surface area (BSA) and lithium clearance. Due to multicollinearity, BSA was excluded from the basic non-linear regression equation and TBW was found to be the only covariate affecting lithium clearance. Mean lithium clearance was found to be 0.243 ± 0.097 Lit/Kg/day, ranging from 0.091 to 0.71 Lit/Kg/day.

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.

Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole

The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co-administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects. Two similarly designed, open-label, single-sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1-7. Following Day 7 was a 2-day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post-lithium or valproate administration on Days 7 and 26. The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C(max) and AUC(τ) , respectively. Furthermore, the addition of aripiprazole did not change the median T(max) of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady-state pharmacokinetics of lithium or valproate. The majority of subjects (76·9% for aripiprazole plus lithium and 68·4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co-administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects.

Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial

Lithium has attracted much attention as a neuroregenerative agent for spinal cord injury in animal models. We hypothesized that the lithium can be beneficial to patients with spinal cord injury. The safety and pharmacokinetics of lithium has been studied in our earlier phase I clinical trial, indicating its safety. This is a phase II clinical trial to evaluate its efficacy on chronic spinal cord injury patients. The aim of this study was to investigate the efficacy of lithium on chronic spinal cord injury patients. A major spinal cord injury rehabilitation center in Beijing, China. Randomized, double-blind, placebo-controlled 6-week parallel treatment arms with lithium carbonate and with placebo. A total of 40 chronic spinal cord injury subjects were recruited. Oral lithium carbonate was titrated or placebo was simulated to maintain the serum lithium level of 0.6-1.2 mmol l(-1) for 6 weeks, followed by a 6-month follow-up. The functional outcomes and the neurological classifications, as well as the safety parameters, adverse events and pharmacokinetic data were carefully collected and monitored. No significant changes in the functional outcomes and the neurological classifications were found. The only significant differences were in the pain assessments using visual analog scale comparing the lithium and the placebo group. No severe adverse event was documented in the study. The lithium treatment did not change the neurological outcomes of patients with chronic spinal cord injury. It is worth to investigate whether lithium is effective in the treatment of neuropathic pain in chronic spinal cord injury. China Spinal Cord Injury Network Company Limited.

Hypomania Secondary to a Change in Altitude in an Adolescent Male

Introduction Altitude-associated changes in renal and endocrine function and lithium pharmacokinetics have not been applied to persons diagnosed with bipolar disorder. Development of a mood or affective syndrome secondary to a change in altitude has been a topic of some debate. Research is limited. This may represent an emerging area of concern for clinicians. Psychiatric and neurologic changes associated with altitude have been published. The potential for altitudemediated mood changes was evaluated both naturalistically and experimentally. Mood symptoms were evaluated as a function of rate of assent, climber experience, elevation, and duration of exposure. Adverse mood symptoms were found to be affected by altitude changes (1, 2). Acute changes secondary to altitude included new-onset anxiety disorders (3) and, rarely, cerebral edema (4). Additional altitude-associated neurological changes reported in the literature include headache, fatigue, and/or ataxia. Experimentally, researchers subjected experienced climbers to high-altitude conditions via a hypobaric chamber. They found a significant negative relationship with a personality measure for emotional stability (5). The designation of low versus high altitude may represent a valid point for discussion. Designations varied with the research design. When investigating the pharmacokinetics of lithium, one set of researchers defined low altitude as 600 meters, high altitude as 4,360 meters (6). High altitude for other researchers ranged from 3,000 to 8,848 meters (5). Changes in mood and cognitive and motor functions were reported with elevations above 3,000 meters (2). The treatment center in this Case Report was located at 1,088 meters. In persons diagnosed with bipolar disorder, changes in lithium pharmacokinetics may offer an alternate explanation for mood changes secondary to high-altitude exposure that may result in a number of physiological changes. One of these changes is an increase in circulating red blood cells (RBC) (7). This is an important consideration with lithium use. Intraand extra-cellular transport occurs via erythrocytes, where lithium is tightly bound (6). The question of whether mild-to-moderate cerebral hypoxia may constitute a hypoxic affective syndrome and contribute to physical illness was raised by some researchers. One theory focused on biogenic amine production: if hypoxia was a function of altitude, then a neurochemical process formed the basis for behavioral and physical changes (8). Changes in lithium pharmacokinetics were studied in healthy volunteers at high and low altitudes. Those at low altitude transitioned to high altitude. Findings were compared with a second group of volunteers exposed to long-term high altitude. Both the acuteand chronic-exposure groups demonstrated increases in hematocrit and RBC counts. Researchers concluded altered lithium pharmacokinetics were secondary to changes in altitude and may be important clinically (6). We report the first potential case of altitudeassociated hypomania, secondary to a change in lithium pharmacokinetics, in an adolescent patient following a change from a high-altitude residence to a return to low altitude.