Lithium administered to pregnant, lactating and neonatal rats: entry into developing brain.

BACKGROUND: Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. METHODS: Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15-18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0-P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. RESULTS: Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups' blood was consistently below that in maternal blood (30-35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. CONCLUSIONS: Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

Association of Lithium Use and a Higher Serum Concentration of Lithium With the Risk of Declining Renal Function in Older Adults: A Population-Based Cohort Study.

OBJECTIVE: Lithium is an important mood disorder treatment; however, the renal risks of its use in older adults are unclear. We wished to determine in older adults (1) whether lithium is associated with increased risk of renal decline compared to valproate and (2) whether this association differs with higher vs lower baseline serum lithium concentrations. METHOD: We conducted a population-based cohort study using linked health care databases (Ontario, Canada). The cohort consisted of older adults (mean age 71 years) accrued 2007-2015; 3,113 lithium users were propensity-score matched 1:1 to 3,113 valproate users. Users with higher (> 0.7 mmol/L) or lower concentration of serum lithium were further examined. The primary outcome was ≥ 30% loss in estimated glomerular filtration rate from baseline. RESULTS: Matched lithium users and valproate users demonstrated similar indicators of baseline health over a median (maximum) follow-up of 3.1 (8.3) years. Lithium was associated with increased risk of renal function loss compared to valproate (674/3,113 [21.7%] vs 584/3,113 [18.8%]; 6.5 vs 5.7 events per 100 person years; hazard ratio = 1.14 [95% CI = 1.02-1.27]). When baseline serum lithium concentrations were > 0.7 mmol/L, the risk of renal decline compared to valproate use was 1.26 (95% CI = 1.06-1.49); when baseline lithium concentrations were ≤ 0.7 mmol/L, the risk was 1.06 (95% CI = 0.92-1.22). CONCLUSION: In older adults, lithium use is associated with a statistically significant increased risk of renal decline compared to valproate use, although the decline is less than previously reported. Further studies should confirm whether this effect is primarily in patients with higher serum lithium concentrations.

Electronic health record nested pragmatic randomized controlled trial of a reminder system for serum lithium level monitoring in patients with mood disorder: KONOTORI study protocol.

BACKGROUND: The weaknesses of classical explanatory randomized controlled trials (RCTs) include limited generalizability, high cost, and time burden. Pragmatic RCTs nested within electronic health records (EHRs) can be useful to overcome such limitations. Serum lithium monitoring has often been underutilized in real-world practice in Japan. This trial aims to evaluate the effectiveness of the EHR-nested reminder system for serum lithium level monitoring in the maintenance of therapeutic lithium concentration and in the improvement of the quality of care for patients on lithium maintenance therapy. METHODS: The Kyoto Toyooka nested controlled trial of reminders (KONOTORI trial) is an EHR-nested, parallel-group, superiority, stratified, permuted block-randomized controlled trial. Screening, random allocation, reminder output, and outcome collection will be conducted automatically by the EHR-nested trial program. Patients with a mood disorder taking lithium carbonate for maintenance therapy will be randomly allocated to the two-step reminder system for serum lithium monitoring or to usual care. The primary outcome is the achievement of therapeutic serum lithium concentration between 0.4 and 1.0 mEq/L at 18 months after informed consent. DISCUSSION: The KONOTORI trial uses EHRs to enable the efficient conduct of a pragmatic trial of the reminder system for lithium monitoring. This may contribute to improved quality of care for patients on lithium maintenance therapy. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000033633. Registered on 3 July 2018.

[Symptoms of lithium toxicity at therapeutic levels]. / Klachten van lithiumintoxicatie bij een therapeutische spiegel.

A 60-year-old woman was admitted to the medical psychiatric unit with neurological and psychiatric symptoms. She was being treated with a maintenance dose of lithium for bipolar I disorder. Lithium toxicity and manic state were both considered. However, serum lithium levels appeared to be non-toxic. During hospital admission, her symptoms worsened and many diagnostic tests were performed. Lithium toxicity was considered again and lithium was discontinued, despite therapeutic blood levels. The neuro-psychiatric symptoms subsequently disappeared and the patient improved without residual symptoms. When neuro-psychiatric symptoms occur without elevated lithium levels, the possibility of chronic lithium toxicity should still be considered. More caution is required when risk factors are present, such as: old age, interacting medication, reduced renal function, dehydration and fever. Finally, electroencephalography can contribute to the diagnosis of chronic lithium toxicity.

A Method for Rapid, Reliable, and Low-Volume Measurement of Lithium in Blood for Use in Bipolar Disorder Treatment Management.

GOAL: Lithium preparations are considered the most reliable mood stabilizers for patients with Bipolar Disorder (BD), and are the most effective at reducing the risk of suicide. However, maintaining blood lithium concentration within the narrow therapeutic range of 0.4-1.2 mEq is crucial but extremely difficult. The aim of this work is to develop a personal lithium blood level analyzer using a novel method of combined optical and electrical impedance spectroscopy to test micro volumes of spiked samples of human blood. RESULTS: Impedance measurements alone showed a limit of detection of less than 0.1 mEq within the therapeutic range, whereas optical measurements could verify the presence of lithium and provide a degree of lithium content. Optical specificity to lithium was further verified in qualitative assessment of lithium spiked blood samples with varying concentrations of sodium. Moreover, analysis of multiple linear regression yielded a prediction model of R2 = 0.322716 and RMSEP = 0.223602 for optical measurements only using feature wavelengths, which were found to appear at minima 560 and 605 nm. Combined with impedance measurements, prediction of lithium concentration in samples with unknown lithium content was significantly increased to R2 = 0.876438 and RMSEP = 0.513554. CONCLUSION: The combination of optical and impedance modalities for determinations of blood lithium resulted in significant improvement to the sensitivity and accuracy of measurement. SIGNIFICANCE: Results are complementary of the proposed opto-impedance method, and future work will now focus on the technical development of an integrated and miniaturized system for measurement of lithium levels in blood with a high level of accuracy and sensitivity.

Lithium Toxicity with Severe Bradycardia Post Sleeve Gastrectomy: a Case Report and Review of the Literature.

Lithium is one of the major treatment options in bipolar disorder. Bariatric surgery can significantly modify the oral bioavailability of drugs, and lithium is no exception; although in most cases drug absorption seems to decrease, in the case of lithium, toxicity is the risk. In this article, we describe a 61-year-old male patient presented with lithium toxicity, including newly diagnosed severe bradycardia requiring a permanent pacemaker, after undergoing sleeve gastrectomy. We discuss the mechanisms behind this case, provide potential solutions for clinicians treating bariatric patients with lithium, and review previous reports of lithium toxicity post bariatric surgery. Awareness of changes in drug absorption, particularly lithium, following bariatric surgery, is prudent and essential for optimal patient care. Close clinical and drug levels monitoring is strongly advised.

Methodology for rapid assessment of blood lithium levels in ultramicro volumes of blood plasma for applications in personal monitoring of patients with bipolar mood disorder.

Bipolar disorder (BD) is a common mental health condition, characterized by extreme changes in mood, energy, and behavior. BD is often managed through mood-stabilizing medications, of which lithium formulations remain the most reliable and effective at reducing the risk of suicide. To achieve adequate and consistent efficacy, lithium concentrations need to be maintained within a narrow therapeutic range (0.4 to 1.2 mmol / L). Because of its narrow therapeutic index, long-term lithium therapy is associated with serious side effects and risks of toxicity. It is believed that the availability of a personal blood lithium analyzer would benefit patients who are on lithium treatment. We detail the results of a spectrophotometric method performed on ultramicro volumes to determine blood plasma lithium concentrations as compared with reference measurements of flame photometry, and validated in samples of unknown lithium content. Applying multiple linear regression, lithium concentrations could be determined in a rapid manner using full-range spectra or triwavelength data. Both techniques highly correlated with reference standards and could predict lithium levels accurately (R2 = 0.794214 and RMSEP = 0.209584, and R2 = 0.863921 and RMSEP = 0.167524, respectively). Therefore, this method can be a useful for rapid assessment of blood lithium in nonlaboratory settings i.e., general practices, hospital clinics, and community health centers by healthcare professionals and/or by patients. Future work will now focus on completion of a miniaturized and integrated system that will deliver a portable and personal lithium-monitoring device.

Chronic lithium intoxication: Varying electrocardiogram manifestations.

Lithium is a commonly used drug in psychiatric practice. It is used in the treatment of depression and bipolar disorder. It has a narrow therapeutic index with documented adverse effects even near therapeutic levels. It has myriad of manifestations at toxic levels. The cardiovascular effects range from relatively benign ST-T wave changes to fatal arrhythmias. We describe a case of lithium toxicity which presented as a junctional rhythm and later showed a variety of manifestations such as complete heart block, atrial fibrillation, sinus bradycardia, and finally reverted to sinus rhythm at par with serum lithium levels.

Changes in drug disposition of lithium during pregnancy: a retrospective observational study of patient data from two routine therapeutic drug monitoring services in Norway.

OBJECTIVES: Pregnancy may cause changes in drug disposition, dose requirements and clinical response. For lithium, changes in disposition during pregnancy have so far been explored in a single-dose study on 4 participants only. The aim of this study was to determine the effect of pregnancy on serum levels of lithium in a larger patient material in a naturalistic setting. DESIGN: A retrospective observational study of patient data from 2 routine therapeutic drug monitoring services in Norway, linked to the Medical Birth Registry of Norway. SETTING: Norway, October 1999 to December 2011. MEASUREMENTS: Dose-adjusted drug concentrations of lithium during pregnancy were compared with the women's own baseline (non-pregnant) values, using a linear mixed model. RESULTS: Overall, coupling 196 726 serum concentration measurements from 54 393 women to the national birth registry identified 25 serum lithium concentration analyses obtained from a total of 14 pregnancies in 13 women, and 63 baseline analyses from the same women. Dose-adjusted serum concentrations in the third trimester were significantly lower than baseline (-34%; CI -44% to -23%, p<0.001). CONCLUSIONS: Pregnancy causes a clinically relevant decline in maternal lithium serum concentrations. In order to maintain stable lithium concentrations during the third trimester of pregnancy, doses generally need to be increased by 50%. Individual variability in decline implies that lithium levels should be even more closely monitored throughout pregnancy and in the puerperium than in non-pregnant women to ensure adequate dosing.

Severe chronic lithium intoxication in patient treated for bipolar disorder.

OBJECTIVE: Lithium has been long used in psychiatry as an adjuvant treatment for bipolar disorder. Chronic lithium intoxication is very rare. DESIGN: We present the case of a 72-year-old female, treated with lithium for more than 10 years for bipolar disorder, who was admitted for gait impairment with weakness of limbs, myoclonus, speech impairment and memory disturbances. RESULTS: Diagnosis of lithium intoxication was based on clinical picture and determination of serum lithium levels. EEG showed severe encephalopathy with triphasic wave complexes. Sensory and motor axonal neuropathy was observed by EMG. Discontinuation of the drug leads to clinical improvement, although not to a fully neurological recovery. CONCLUSION: Lithium is still very effective drug, but requires regular monitoring of serum levels to prevent overdose and symptoms of intoxication. Neurophysiological methods, including EEG and EMG, are strongly recommended to determine the level of peripheral and/or central nervous system impairment.

How long does the pharmacokinetic interaction between carbamazepine and quetiapine last after carbamazepine withdrawal?

OBJECTIVES: Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. METHODS: In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. RESULTS: No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. CONCLUSION: We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.

Lurasidone adjunctive with lithium or valproate for bipolar depression: A placebo-controlled trial utilizing prospective and retrospective enrolment cohorts.

In this study, designed to evaluate the efficacy of lurasidone as adjunctive therapy with lithium or valproate, patients with bipolar I depression were randomized to 6 weeks of double-blind treatment with lurasidone (N = 180) or placebo (N = 176), added to background treatment with lithium or valproate. All patients were treated with lithium or valproate for a minimum of 4 weeks prior to screening. This was confirmed either by prospective treatment after study enrolment (run-in cohort), or retrospectively, with blood levels of lithium and valproate at screening (non-run-in cohort). Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP-S), respectively. Treatment with lurasidone was associated with non-significant improvement at week 6 vs. placebo for the MADRS total score (-11.8 vs -10.4; P = 0.176), and the CGI-BP-S score (-1.36 vs -1.13; P = 0.095). Significant separation from placebo was observed from weeks 2-5 for the MADRS and weeks 3-5 for the CGI-BP-S. Improvement in the placebo-subtracted MADRS total score was notably larger at week 6 for the non-run-in cohort compared to the run-in cohort (LS mean difference in endpoint change scores, -4.6; P = 0.009). Adverse events most frequently reported for lurasidone were akathisia, somnolence, and extrapyramidal side effects. In conclusion, lurasidone adjunctive with lithium or valproate demonstrated significant improvement in depressive symptoms based on the MADRS from weeks 2-5 but not at the primary week 6 endpoint.