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.

[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.

A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-(7) Li Magnetic Resonance Spectroscopy Study.

OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients. DISCUSSION: A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD. SUMMARY: Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.

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.

4-T 7Li 3D MR spectroscopy imaging in the brains of bipolar disorder subjects.

This work demonstrates the first whole brain "high spatial resolution" (7)Li MR spectroscopy imaging in bipolar disorder subjects. The in vivo quantification is validated by a phantom containing 5 mM lithium salt using the identical radiofrequency sequence and imaging protocol. This study is the first demonstration of the (7)Li distribution in the brain of bipolar disorder patients on lithium therapy using a 3D MR spectroscopy imaging approach. The results show that brain lithium level is strongly correlated with serum lithium concentration. The brain-to-serum lithium ratios for the average brain and the local maximum were 0.39 ± 0.08 (r = 0.93) and 0.92 ± 0.16 (r = 0.90), respectively. The lithium distribution is found to be nonuniform throughout the brain for all patients, which is somewhat unexpected and highly intriguing. This uneven distribution is more evident in subjects at a higher therapeutic serum lithium level. This finding may suggest that lithium targets specific brain tissues and/or certain enzymatic and macromolecular sites that are associated with therapeutic effect. Further investigations of bipolar disorder patients on lithium therapy using 3D (7)Li MR spectroscopy imaging are warranted.

The science and practice of lithium therapy.

INTRODUCTION: Despite more that 60 years of clinical experience, the effective use of lithium for the treatment of mood disorder, in particular bipolarity, is in danger of becoming obsolete. In part, this is because of exaggerated fears surrounding lithium toxicity, acute and long-term tolerability and the encumbrance of life-long plasma monitoring. Recent research has once again positioned lithium centre stage and amplified the importance of understanding its science and how this translates to clinical practice. OBJECTIVE: The aim of this paper is to provide a sound knowledge base as regards the science and practice of lithium therapy. METHOD: A comprehensive literature search using electronic databases was conducted along with a detailed review of articles known to the authors pertaining to the use of lithium. Studies were limited to English publications and those dealing with the management of psychiatric disorders in humans. The literature was synthesized and organized according to relevance to clinical practice and understanding. RESULTS: Lithium has simple pharmacokinetics that require regular dosing and monitoring. Its mechanisms of action are complex and its effects are multi-faceted, extending beyond mood stability to neuroprotective and anti-suicidal properties. Its use in bipolar disorder is under-appreciated, particularly as it has the best evidence for prophylaxis, qualifying it perhaps as the only true mood stabilizer currently available. In practice, its risks and tolerability are exaggerated and can be readily minimized with knowledge of its clinical profile and judicious application. CONCLUSION: Lithium is a safe and effective agent that should, whenever indicated, be used first-line for the treatment of bipolar disorder. A better understanding of its science alongside strategic management of its plasma levels will ensure both wider utility and improved outcomes.

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

WHAT IS KNOWN AND OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. WHAT IS NEW AND CONCLUSION: 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.

[Neurotoxicity in elderly patients being treated with lithium: is there a reason to adjust the dosage administered?]. / Neurotoxiciteit tijdens lithiumgebruik bij ouderen: reden om behandelbeleid aan te passen?

BACKGROUND: Neurotoxicity can occur in patients being treated with lithium. Features are cognitive dysfunctioning and motor symptoms. Some results of research performed on adults up to the age of 65 indicate that lithium can cause mild cognitive dysfunctioning. It is not clear, however, whether elderly patients are more susceptible than young adults to this form of neurotoxicity or, if this is the case, whether the dosage of lithium should be reduced. AIM: To determine whether elderly patients treated with lithium run an increased risk of neurotoxicity, and to discuss the pharmacodynamic aspects of lithium use in the elderly which may cause neurotoxicity. METHOD: Literature review in Cochrane (all EBM), Embase, PsycINFO, Medline and PubMed, with cross-checked references. RESULTS: Few studies described possible neurotoxic effects of lithium. We found no indications for cognitive dysfunctioning in elderly patients being treated with lithium. However, a lithiumassociated tremor was seen more often in elderly patients than in younger adults. Pharmacodynamic effects of aging, such as an increase in the lithium concentration in the brain with no change in the serum level, may give rise to side-effects. More research is needed into the relationship between the serum level and the neurotoxic effects of lithium in the elderly. CONCLUSION: There are no indications that lithium causes more neurotoxicity in the elderly than in younger adults. If the use of lithium is indicated, it can be safely prescribed for the elderly, provided age-related pharmacodynamics are taken into account.

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.

[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.

Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy.

Lithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and alpha-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrP(Sc)) in prion-infected neuronal and non-neuronal cultured cells by inducing autophagy. Treatment of prion-infected cells with 3-methyladenine, a potent inhibitor of autophagy, counteracted the anti-prion effect of lithium, demonstrating that induction of autophagy mediates degradation of PrP(Sc). Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrP(Sc) clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrP(Sc) and to induce autophagy is common for diverse lithium compounds, not only for the drug lithium chloride, usually administered in clinical therapy. Furthermore, we show here that besides reduction of PrP(Sc)-aggregates, lithium-induced autophagy also slightly reduces the levels of cellular prion protein. Limiting the substrate available for conversion of cellular prion protein into PrP(Sc) may provide an additional mechanism for reduction of PrP(Sc) by lithium-induced autophagy.

[Acute lithium intoxications, review of the literature and cases study]. / Intoxications aiguës au lithium : revue de la littérature et étude de cas cliniques.

The efficacy of lithium in the prevention of bipolar disorders is now well established. However, acute lithium intoxications still occur, often after suicide attempts. Symptoms are often different from one patient to the other, and long lasting neurologic sequelae may happen. Active treatments are available, notably haemodialysis, which increase lithium clearance dramatically. We report cases quoted in the department of intensive care of Tours University Hospital over the last three years and compared them with the literature. Lithium level and treatment of these intoxications were analysed. Although new medicines are available for the treatment of bipolar disorders, lithium is still an important drug in this disease, therefore, the prescribers have to be aware of the consequences of acute lithium intoxications.

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.