Effects of Plasmapheresis on Serum Lithium Levels in an ICU Patient with Bipolar Disorder: A Case Study.

ABSTRACT: This is a case description of a patient with bipolar disorder undergoing lithium therapy who received plasmapheresis for neuromyelitis optica spectrum disorder. Plasmapheresis resulted in lower and subtherapeutic serum lithium levels. Using therapeutic drug monitoring, a dose escalation of 80% was necessary to maintain therapeutic serum lithium levels. This underscores the importance of individualized therapy through therapeutic drug monitoring.

Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics.

BACKGROUND: This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. METHODS: In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. RESULTS: The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). CONCLUSIONS: This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

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.

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.

The effects of the atypical antipsychotic asenapine in a strain-specific battery of tests for mania-like behaviors.

Asenapine is indicated for the treatment of schizophrenia and manic episodes in bipolar disorder (BPD). There is a paucity of information on the effects of asenapine in animal models of BPD, but such work is essential to discover its scope of effects and its mechanisms of therapeutic action. This study evaluated the effects of asenapine in a validated test battery for manic-like behaviors in Black Swiss mice. Male Black Swiss mice received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7 days and were tested for spontaneous activity, sweet solution preference, forced-swim test, social interaction, and amphetamine-induced hyperactivity. Asenapine treatment resulted in dose-dependent, clinically relevant plasma levels. Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity, with the 0.3 mg/kg dose also resulting in increased time in the center of an open field, increased immobility in the forced-swim test, and reduced amphetamine-induced hyperactivity. Asenapine exerted no effects in the social interaction or sweet solution preference tests. The results suggest that asenapine exerts antimanic-like effects in some of the behavioral tests performed in Black Swiss mice. These data support the utilization of asenapine in the treatment of BPD.

Lithium for post-electroconvulsive therapy depressive relapse prevention: a consideration of the evidence.

Lithium has been used for several decades as a prophylactic against depressive relapse after successful index electroconvulsive therapy (ECT). The literature on this topic is reviewed, and it is concluded that, in the main, there is strong evidence that lithium can help prevent relapses in the first 6 months after index ECT. However, there are several unanswered questions about its use post-ECT, including optimal target blood level, duration of use, and concomitant antidepressant choice. In this report, the author provides a review of the evidence for using lithium in this setting, outlines the pertinent unanswered questions, and proposes future research directions and guidelines for current clinical care.

Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study.

BACKGROUND: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. METHODS: Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. RESULTS: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (≥ 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. CONCLUSIONS: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.

Temporal association as a prerequisite factor of valsartan-induced lithium toxicity.

OBJECTIVES: Lithium is often the mood stabilizer of choice for the treatment of type I bipolar disorder. However, side effects as well as the narrow therapeutic dosing range often complicate its use. Lithium toxicity can be fatal and its serum level needs to be closely monitored, especially at the time of introduction and titration, or whenever combined with potentially interacting drugs, such as inhibitors of angiotensin-converting enzyme (ACE-I) or angiotensin receptor 1 (AT1 ) blockers. ACE-I and AT1 blockers can increase serum lithium levels, leading to acute lithium toxicity upon their introduction or titration. METHODS: Here, we report a case of lithium toxicity during concomitant treatment with valsartan, an AT1 blocker, in a patient who previously displayed a stable serum lithium level. The patient was observed for a few weeks and the serum lithium concentration was measured regularly. RESULTS: In contrast to previous reports, the toxicity in our patient occurred not upon introduction or titration of lithium or valsartan but after subtle modifications in daily dosing schedule for lithium. Just before the onset of toxicity, lithium had been split into two doses, whereby half of the lithium daily dose was administrated concomitantly with valsartan. We presumed that this combination had led to simultaneous concentration peaks of valsartan and lithium, promoting lithium retention within a sharp time window. CONCLUSIONS: Our observation points to the need for caution not only during the introduction and titration of ACE-I/AT1 blockers in lithium-treated patients, but also whenever the temporal pattern of drug administration is modified.

Lithium tremor revisited: pathophysiology and treatment.

OBJECTIVE: Tremor occurs frequently as a side-effect of lithium, and it is, however, easily overlooked in the clinical setting. In this article, we attempt to review the pathophysiology and the clinical approach of lithium tremor. METHOD: We searched the Pubmed and Cochrane Library for relevant articles up to the year 2012. Sixty-four articles including 10 review papers, 3 clinical trials, and 12 case reports were reviewed. RESULTS: Lithium tremor is classified as a postural tremor and subcategorized as an exaggerated physiologic tremor. Differential diagnosis includes metabolic abnormalities, benign essential tremor, Parkinson's disease, and lithium toxicity. Various methods of evaluating lithium tremor and treatment options are discussed. CONCLUSION: When lithium tremor has developed, thorough history taking, physical examination, and blood examination including serum lithium level are needed. Pharmacotherapy is indicated only in patients with disabling tremor.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

Oral loading of sodium valproate compared to intravenous loading and oral maintenance in acutely manic bipolar patients.

BACKGROUND: In patients suffering from bipolar disorders (BPD), we explored to what extent oral loading of sodium valproate (SV) leads to more rapid symptom improvement compared to intravenous loading and oral maintenance administration. METHODS: Ninety patients (mean age: 35.00 years) with BPD and currently in an acute manic state were randomly assigned to one of three study conditions: oral loading (20 mg/kg oral single-dose SV on the first day, then 10-15 mg/kg SV daily, divided dose), intravenous loading (20 mg/kg SV intravenous injection on the first day, then 10-15 mg/kg orally, divided dose), or oral maintenance administration (15-20 mg/kg SV daily from the beginning) over the first 7 days of treatment. SV plasma levels, side effects and symptoms were evaluated at baseline and on days 1, 3, and 7 after commencing treatment. RESULTS: There were significant Time-by-Group interactions for symptom improvements, symptom severity, and SV plasma levels, with positive values in the oral and intravenous loading conditions, compared to the oral maintenance condition. Post hoc analyses showed that oral and intravenous conditions led to similar improvements. CONCLUSIONS: Both oral and intravenous loading of SV led to quicker and more efficient improvement and SV plasma levels as compared to an oral maintenance regimen.

The toxic trio: valproic acid, lithium, and carbamazepine.

Patients with altered mental status and seizure or psychiatric disease often present with an unclear medication history. Commonly prescribed medications include valproic acid (VPA), lithium (Li), or carbamazepine (CZN) of which the regional poison center (RPC) often recommends obtaining these serum concentrations. Regularly ruling out supratherapeutic concentrations without a known history of ingestion may help direct care. Cases from the RPC coded as VPA, Li, and CZN, from January 1, 2006 to December 31, 2008, were searched. All patients with supratherapeutic concentrations (VPA >100 µg/mL, Li >1.2 mEq/L, and CZN >12 µg/mL) were evaluated for the following criteria: (1) those with altered mental status and an unclear history of seizure or psychiatric disorder and (2) a mediation profile not including VPA, Li, or CZN. Twenty-six patients met the inclusion criteria: 8 patients in the VPA group (113-247 µg/mL; mean, 158), 9 patients in the Li group (1.9-5.2 mEq/L; mean, 2.9), and 9 patients in the CZN group (13.4-38.8 µg/mL; mean, 23.2). All patients survived and were treated with supportive care; however, 1 patient had a Li level of 5.2 mEq/L and received hemodialysis. In altered patients potentially being treated for seizure or psychiatric disorders and unknown ingestions or medication lists, obtaining concentrations of VPA, Li, and CZN may help direct care and provide clinically relevant information. The RPC detected 26 patients with supratherapeutic VPA, Li, or CZN concentrations in patients with potential indications for the agent but no available history of drug ingested or medication list. A prospective study is warranted to evaluate the usefulness of obtaining these concentrations in this patient population.

Lithium dosing equations: are they accurate?

BACKGROUND: Several equations are used to predict lithium doses necessary to attain therapeutic serum concentrations. A number of studies have evaluated these equations; however, few equations were compared simultaneously. OBJECTIVE: To assess the accuracy and precision of published dosing equations in predicting daily lithium doses and to evaluate if pertinent laboratory tests were performed prior to initiation. METHODS: A retrospective analysis was performed of patients who received lithium at the Medical University of South Carolina Institute of Psychiatry between July 2010 and July 2012. Using dosing equations, expected lithium doses were calculated based on corresponding serum concentrations identified in patient charts. Expected doses were then compared with actual lithium doses. The primary end point was to assess the accuracy and precision of dosing equations using mean differences in daily lithium doses and standard deviations. Secondary end points included presence of pertinent laboratory tests and use of concomitant interacting drugs . RESULTS: Of 155 patients identified, 59 were eligible for analysis. Equations developed by Abou-Auda et al and Pepin et al did not predict doses that were significantly different from actual doses. Conversely, equations by Jermain et al, Terao et al, and Zetinet al did predict statistically different doses. CONCLUSIONS: Abou-Auda et al developed a predictive lithium dosing equation that was more accurate than equations developed by Jermain et al, Terao et al, and Zetin et al and more precise than the Pepin et al equation. Further study evaluating the influence of equations on clinical outcomes is warranted.

Microarray analysis of global gene expression in leukocytes following lithium treatment.

OBJECTIVES: To elucidate the molecular effects of lithium, we studied global gene expression changes induced by lithium in leukocytes from healthy subjects. METHODS: Eight healthy male subjects participated in this study. Lithium was prescribed for weeks to reach a therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), after 1 and 2 weeks of medication and at 2 weeks after stopping medication. Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays (The Agilent Technologies, Santa Clara, CA, USA). Expression of some candidate genes was also assessed by real-time polymerase chain reaction (PCR). RESULTS: Gene ontology analysis revealed that the cellular and immune responses to stimulus and stress indeed played a major role in the cellular response to lithium treatment. Pathway analysis revealed that the interleukin 6 pathway, the inhibitor of differentiation pathway, and the methane metabolism pathway were regulated by lithium. Using real-time PCR, we also confirmed that five candidate genes in these pathways were significantly changed, including suppressor of cytokine signaling 3 and myeloperoxidase. CONCLUSIONS: Our investigation suggests that the molecular action of lithium is mediated in part by its effects on the cellular and immune response to stimulus and stress followed by the interleukin 6, inhibitor of differentiation, and methane metabolism pathways.

Can valproic acid be an inducer of clozapine metabolism?

INTRODUCTION: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. METHODS: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. RESULTS: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). DISCUSSION: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

The effect of lithium variation coefficient on the risk of attack in patients with bipolar disorder: A pilot study.

BACKGROUND: This study examines the association between the coefficient of variation (%CV) of lithium levels and episode risk and frequency in bipolar patients maintaining serum lithium levels within the therapeutic range. METHODS: We retrospectively reviewed patients with bipolar disorder under care from 2018 to 2022. Inclusion criteria were at least 2 years of follow-up, a minimum of three annual lithium level measurements within the therapeutic range. Patients were categorized based on seizure status. We calculated mean lithium levels, standard deviation (SD), and %CV. RESULTS: The study included 75 patients (patients with-without episodes, 39-36). Demographic data revealed no significant differences. While mean lithium levels showed no significant disparity between groups, SD and %CV were notably higher in patients with episodes (P < .05). ROC analysis demonstrated AUC values of 0.722 (95% CI: 0.607-0.836 P = .001) for %CV and 0.709 (95% CI: 0.593-0.826; P = .002) for SD. The optimal %CV cutoff was 17.39, with 67% sensitivity and 69% specificity. A weak correlation was found between %CV and the number of episodes (P = .001, r = 0.376). The post-hoc power analysis for this study was 0.78. CONCLUSIONS: Despite acceptable lithium levels, patients with recent episodes exhibited significant lithium level fluctuations. Integrating %CV with real-time lithium measurements during bipolar disorder follow-up may enhance clinical monitoring and seizure prediction.

Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

RATIONALE: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. OBJECTIVES: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. METHODS: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. RESULTS: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (ß = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (ß = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. CONCLUSIONS: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.

The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144).

OBJECTIVES: There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2 mEq/L and below 0.6 mEq/L with that of placebo. METHODS: We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18 years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104 weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2 mEq/L, and 137 obtained median lithium levels <0.6 mEq/L. Their outcomes were compared with those of patients receiving placebo (n = 404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event. RESULTS: Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2 mEq/L group versus placebo and versus lithium <0.6 mEq/L, with no differences between lithium <0.6 mEq/L and placebo. CONCLUSIONS: The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6 mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization.