In-silico functional analyses identify TMPRSS15-mediated intestinal absorption of lithium as a modulator of lithium response in bipolar disorder.

BACKGROUND: The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi+Gen). METHODS: We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg. RESULTS: The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi+Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium. LIMITATIONS: Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi+Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies. CONCLUSIONS: The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.

A reappraisal of the role of fever in the occurrence of neurological sequelae following lithium intoxication: a systematic review.

INTRODUCTION: We aimed to review cases of Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological sequelae following acute lithium toxicity and to explore whether cerebellar sequelae are more frequent in cases presenting with fever and/or infection. AREAS COVERED: Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. EXPERT OPINION: We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). SILENT may occur at any time during lithium treatment. This complication is most frequently observed during routine lithium treatment, with fewer than 10% of cases occurring after accidental or intentional overdoses. SILENT may occur even when lithium plasma levels are within the therapeutic range: 63% of cases had lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever and/or infection were reported in nearly half of the patients (48%). The likelihood of presenting with cerebellar vs. other neurological sequelae was independently increased by elevated plasma lithium level (≥ 2.5 mEq/l) and by a history of fever and/or infection. Lithium users should be warned of the need to consult in case of fever to adjust their lithium dosage.

The role of brain barriers in the neurokinetics and pharmacodynamics of lithium.

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response.

[Extracorporeal renal replacement therapies in lithium intoxication].

Drug poisoning is a significant source of morbidity, mortality and health care expenditure worldwide. Lithium, methanol, ethylene glycol and salicylates are the most important ones, included in the list of poisons, that may require extracorporeal depuration. Lithium is the cornerstone of treatment for bipolar disorders, but it has a narrow therapeutic window. The therapeutic range is 0.6-1.2 mEq/L and toxicity manifestations begin to appear as soon as serum levels exceed 1.5 mEq/L. Severe toxicity can be observed when plasma levels are more than 3.5 mEq/L. Lithium poisoning can be life threatening and extracorporeal renal replacement therapies can reverse toxic symptoms. Currently, conventional intermittent hemodialysis (IHD) is the preferred extracorporeal treatment modality. Preliminary data with prolonged intermittent renal replacement (PIRRT) therapies - hybrid forms of renal replacement therapy (RRT) such as sustained low efficiency dialysis (SLED) - seem to justify their role as potential alternative to conventional IHD. Indeed, SLED allows rapid and effective lithium removal with resolution of symptoms, also minimizing rebound phenomenon.

Pharmacotherapy for depression and bipolar disorder during lactation: A framework to aid decision making.

OBJECTIVE: Breastmilk is recommended as the exclusive source of nutrition for infants younger than 6 months due to the numerous health benefits for both infants and mothers. Although many women are prescribed medications during pregnancy and postpartum, limited data are available to assist women in weighing the benefits compared to the risks of peripartum medication use. The goals of this paper are to discuss the importance of breastmilk for the health of both the mother and infant, evaluate the impact of medication use on women's infant feeding choice, describe the transfer of drugs to breastmilk and infants, and provide a framework for clinicians to support evidence-based counseling for women treated for mood disorders. RECOMMENDATIONS: We recommend early pregnancy counseling to discuss the benefits and risks of medications during breastfeeding. The Surgeon General's Call to Action (2011) highlights the short and long-term negative health effects of not providing breastmilk. Integrating recommendations from the pediatric and obstetric teams allows patients to make decisions based on evidence and reach their infant feeding goals. Databases containing summaries of research findings and pharmacologic properties of the drug of interest are an essential resource for clinicians.

Psychotropic drug use in perinatal women with bipolar disorder.

Optimal dose management of psychotropic drugs during the perinatal period reduces the risk for recurrence of mood episodes in women with Bipolar Disorder. Physiological changes during pregnancy are associated with decreases in the plasma concentrations of the majority of mood stabilizing medications. Regular symptom and drug concentration monitoring for lithium and anticonvulsants with reflexive dose adjustment improves the probability of sustained symptom remission across pregnancy. The elimination clearance trajectory across pregnancy for psychotropics dictates the frequency of laboratory monitoring and dose adjustment. The literature on the pharmacokinetics of lithium, lamotrigine, carbamazepine and atypical antipsychotics during pregnancy and postpartum are reviewed, recommendations for symptom and laboratory monitoring are proposed and recommendations for dose adjustments are presented.

A Review for Lithium: Pharmacokinetics, Drug Design, and Toxicity.

Lithium as a mood stabilizer has been used as the standard pharmacological treatment for Bipolar Disorder (BD) for more than 60 years. Recent studies have also shown that it has the potential for the treatment of many other neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's disease, through its neurotrophic, neuroprotective, antioxidant and anti-inflammatory actions. Therefore, exploring its pharmacokinetic features and designing better lithium preparations are becoming important research topics. We reviewed many studies on the pharmacokinetics, drug design and toxicity of lithium based on recent relevant research from PubMed, Web of Science, Elsevier and Springer databases. Keywords used for searching references were lithium, pharmacology, pharmacokinetics, drug design and toxicity. Lithium is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Its level is initially highest in serum and then is evidently redistributed to various tissue compartments. It is not metabolized and over 95% of lithium is excreted unchanged through the kidney, but different lithium preparations may have different pharmacokinetic features. Lithium has a narrow therapeutic window limited by various adverse effects, but some novel drugs of lithium may overcome these problems. Various formulations of lithium have the potential for treating neurodegenerative brain diseases but further study on their pharmacokinetics will be required in order to determine the optimal formulation, dosage and route of administration.

Lithium-related medication problems on nonpsychiatric inpatient medical units.

PURPOSE: Results of a study of medication-related problems (MRPs) associated with lithium use on nonpsychiatric inpatient medical units are reported. METHODS: In a single-center, retrospective study, the records of all patients hospitalized over a 21-month period who received lithium or had a documented serum lithium concentration during hospitalization were evaluated. The primary objective was to identify patient-specific factors associated with lithium MRPs on nonpsychiatric inpatient medical units. Secondary objectives included characterization of lithium MRPs. Identified MRP occurrences were further evaluated to determine if an intervention was necessary to resolve the MRP and whether or not an intervention was made. RESULTS: A total of 150 patients were included in the study sample. One or more lithium MRPs were identified in 85% of the patients, with a total of 255 lithium MRPs identified. None of the patient-specific factors analyzed were significantly associated with MRP occurrence. Of the 128 patients in whom a lithium MRP occurred, 92.2% (n = 118) were judged to be appropriate candidates for interventions as defined per the study definitions; among those 118 patients, such interventions were documented for only 40.7% (n = 48). CONCLUSION: Lithium MRPs were found to have occurred frequently on nonpsychiatric inpatient medical units at 1 hospital. Laboratory test- related MRPs and drug-drug interactions were the most commonly identified types of MRPs. Interventions to address MRPs were not made in the majority of patients; however, interventions were more frequently made when psychiatry consultation was involved.

Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder. METHODS: Here we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response. RESULTS: While no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia. CONCLUSIONS: Evidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review.

BACKGROUND: Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications. OBJECTIVES: To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data. METHODS: Clinical trials in pediatric samples with at least one standardized measure of efficacy/ effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients. RESULTS: Different and non-alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe. CONCLUSIONS: Lithium seems an effective and well-tolerated medication in pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications.

Compliance with the safety guidelines for long-term lithium treatment in Sweden.

BACKGROUND: Lithium has been used for more than 50 years and guidelines for treatment monitoring have been documented in Sweden since the beginning of the 1980s. AIMS: The aim of this study was to describe compliance over time with the Swedish guidelines for long-term lithium treatment. METHODS: The study material was obtained from Sahlgrenska University Hospital's laboratory database. We analysed data (serum lithium and serum creatinine) of adult patients treated with lithium between 1981 and 2010, and determined compliance with guidelines and serum lithium levels over time. RESULTS: Our study material included 2841 patients and 25,300 treatment-years. The compliance with guidelines' recommendations regarding lithium and creatinine monitoring increased from 36% in 1981 to 68% in 2010. Women were on average 2% more compliant than men ( p < 0.01). Most lithium samples (87-94%) were within recommended intervals throughout the study period. The average lithium level decreased from 0.70 mmol/L in 1981 to 0.58 mmol/L in 2001, and remained stable thereafter. CONCLUSIONS: Compliance with lithium monitoring guidelines improved slowly but steadily over time. It took three decades to reach a compliance rate of just below 70%. Gender differences were small, but with a significantly better compliance rate for women. Serum lithium was kept within the recommended target interval to a large extent, throughout the study period.

[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral therapy: analysis from a randomized placebo-controlled trial.

BACKGROUND: The prevalence of bipolar disorder in HIV-infected patients is higher than the general population. Lithium is the most effective mood stabiliser, while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy (ART). Both TDF and lithium are associated with renal tubular toxicity, which could be additive, or a pharmacokinetic interaction may occur at renal transporters with a decrease in TDF elimination. OBJECTIVE: We report on the change in estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease formula in participants who received ART including TDF and were enrolled in a 24 week randomised trial of lithium versus placebo in patients with HIV-associated neurocognitive impairment. METHODS: We included HIV-infected adults with cognitive impairment established on ART for at least 6 months with a suppressed viral load attending public sector ART clinics in Cape Town, South Africa. We excluded participants with an eGFR <60 mL/min and treated with medications predisposing to lithium toxicity. We reviewed participants weekly for the first month for adverse events followed by 4 weekly visits for renal function assessment, adverse event monitoring and adherence. Lithium dose was titrated to achieve the maintenance target plasma concentration of between 0.6 and 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. RESULTS: We included 23 participants allocated to the lithium arm and 30 participants allocated to the placebo arm. Baseline characteristics were not statistically different with a mean age of 37.7 and 40.8 years, a median time on ART of 33 and 40 months and an eGFR of 139.3 and 131.0 mL/min in the lithium and placebo arms respectively. There was no statistical significant difference in the reduction in eGFR or increase in potassium between the two arms during the 24 weeks. CONCLUSIONS: We found that 24-week treatment of HIV-infected patients with lithium and TDF did not result in increased nephrotoxicity. Trial registration The study was registered on the Pan African Clinical Trials Registry (PACTR) with the identifier number PACTR201310000635418. Registered 11 October 2013 before the first participant was enrolled.

Lithium Toxicity in a Pregnant Woman.

Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women. A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr after admission mandating an emergent haemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on haemodialysis. Caesarean section was carried out, but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities. Although the foetus had the signs/symptoms of distress, continuation of haemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue haemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency haemodialysis instead of immediate caesarean section should be considered.

Lithium-Responsive Seizure-Like Hyperexcitability Is Caused by a Mutation in the Drosophila Voltage-Gated Sodium Channel Gene paralytic.

Shudderer (Shu) is an X-linked dominant mutation in Drosophila melanogaster identified more than 40 years ago. A previous study showed that Shu caused spontaneous tremors and defects in reactive climbing behavior, and that these phenotypes were significantly suppressed when mutants were fed food containing lithium, a mood stabilizer used in the treatment of bipolar disorder (Williamson, 1982). This unique observation suggested that the Shu mutation affects genes involved in lithium-responsive neurobiological processes. In the present study, we identified Shu as a novel mutant allele of the voltage-gated sodium (Nav) channel gene paralytic (para). Given that hypomorphic para alleles and RNA interference-mediated para knockdown reduced the severity of Shu phenotypes, Shu was classified as a para hypermorphic allele. We also demonstrated that lithium could improve the behavioral abnormalities displayed by other Nav mutants, including a fly model of the human generalized epilepsy with febrile seizures plus. Our electrophysiological analysis of Shu showed that lithium treatment did not acutely suppress Nav channel activity, indicating that the rescue effect of lithium resulted from chronic physiological adjustments to this drug. Microarray analysis revealed that lithium significantly alters the expression of various genes in Shu, including those involved in innate immune responses, amino acid metabolism, and oxidation-reduction processes, raising the interesting possibility that lithium-induced modulation of these biological pathways may contribute to such adjustments. Overall, our findings demonstrate that Nav channel mutants in Drosophila are valuable genetic tools for elucidating the effects of lithium on the nervous system in the context of neurophysiology and behavior.

Population pharmacokinetic model of lithium and drug compliance assessment.

Population pharmacokinetic analysis of lithium during therapeutic drug monitoring and drug compliance assessment was performed in 54 patients and 246 plasma concentrations levels were included in this study. Patients received several treatment cycles (1-9) and one plasma concentration measurement for each patient was obtained always before starting next cycle (pre-dose) at steady state. Data were analysed using the population approach with NONMEM version 7.2. Lithium measurements were described using a two-compartment model (CL/F=0.41Lh-1, V1/F=15.3L, Q/F=0.61Lh-1, and V2/F = 15.8L) and the most significant covariate on lithium CL was found to be creatinine clearance (reference model). Lithium compliance was analysed using inter-occasion variability or Markovian features (previous lithium measurement as ordered categorical covariate) on bioavailability parameter. Markov-type model predicted the lithium compliance in the next cycle with higher success rate (79.8%) compared to IOV model (65.2%) and reference model (43.2%). This model becomes an efficient tool, not only being able to adequately describe the observed outcome, but also to predict the individual drug compliance in the next cycle. Therefore, Bipolar disorder patients can be classified regarding their probability to become extensive or poor compliers in the next cycle and then, individual probabilities lower than 0.5 highlight the need of intensive monitoring, as well as other pharmaceutical care measurements that might be applied to enhance drug compliance for a better and safer lithium treatment.

Moderate to severe HIV-associated neurocognitive impairment: A randomized placebo-controlled trial of lithium.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains highly prevalent despite effective anti-retroviral therapy (ART). A number of adjunctive pharmacotherapies for HAND have been studied with disappointing results, but preliminary data suggest that lithium may provide clinical benefit. In addition, the low cost of lithium would facilitate access in low- and middle-income countries which carry the greatest burden of HIV. METHODS: Our objective was to evaluate the 24-week efficacy and safety of lithium in patients with moderate to severe HAND. Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, whereas our secondary endpoint was the change in proton magnetic resonance spectroscopy (H-MRS) brain metabolite concentrations. We conducted a 24-week randomized placebo-controlled trial of lithium as adjunctive pharmacotherapy. We enrolled participants with moderate to severe HAND, on ART for at least 6 months, with suppressed viral loads and attending public sector primary care clinics in Cape Town, South Africa. We randomized 66 participants to lithium (n = 32) or placebo (n = 34). Lithium or placebo was dosed 12-hourly and titrated to achieve the maintenance target plasma concentration of 0.6 to 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. RESULTS: Totally 61 participants completed the study (lithium arm = 30; placebo arm = 31). Participants at enrolment had a mean age of 40 years and a median CD4+ T-cell count of 500 cells/µL. The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); P = 0.716. The improvement remained similar when analyzed according to age, severity of impairment, CD4+ count, time on ART, and ART regimen. Standard H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. Six serious adverse events occurred, but none were considered related to the study drug. CONCLUSION: Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment.