Lithium Treatment In Bipolar Disorder Research Articles

GSK3: The Shared Target of Circadian Rhythm and Lithium Treatment in Bipolar Disorder

GSK3: The Shared Target of Circadian Rhythm and Lithium Treatment in Bipolar Disorder

The Dilemma of Lithium Discontinuation in Bipolar Disorder During Pregnancy Planning: A Case Report and Literature Review

IntroductionLithium is considered the gold standard mood stabiliser for bipolar disorder, yet its use during pregnancy remains controversial, demanding careful consideration of potential risks and benefits. Classically, it has been associated with an increased risk in congenital heart defects, however, recent studies point towards a much lower absolute risk than was previously believed. Furthermore, discontinuation of lithium before or during pregnancy poses a high risk of destabilisation and lithium has been shown to reduce the risk of relapse both in pregnancy and in the postpartum period. Hence, treatment planning is of the upmost importance in this patient group and individual risk stratification should be undertaken for patients to make informed decisions about their treatment.ObjectivesTo describe the case of a patient with bipolar disorder who discontinued lithium treatment while attempting to conceive and subsequently presented with a manic episode and to expand the scientific knowledge on this topic.MethodsCase report and brief literature review.Results A 41-year-old patient with a diagnosis of bipolar disorder, previously on lithium 900mg/day, was admitted to the emergency department with symptoms suggestive of a manic episode. One month prior, the patient had discontinued treatment with lithium due to her desire to pursue pregnancy and interrupt treatment while trying to conceive. The patient had a history of postpartum psychosis followed by various depressive and manic episodes with psychotic symptoms, leading to a bipolar disorder diagnosis and commencing treatment with lithium. Her consultant psychiatrist had informed her of the individualised risks of interrupting treatment with lithium and had advised to continue treatment alongside frequent follow-up due to the high-risk of relapse. Despite her consultant’s recommendation, she decided to interrupt treatment and hence a personalised lithium tapering regime and advice to continue treatment with quetiapine 200mg/day was given. During the ED stay, treatment with olanzapine was introduced which helped to stabilise her symptoms. Lithium levels were subtherapeutic (lithium serum level 0.11 mmol/L). Inpatient psychiatric admission was avoided due to rapid symptom improvement, strong social support in the community and her preference for ambulatory care. Lithium was gradually reintroduced and antipsychotic treatment was adjusted at follow up appointments, which ultimately led to the resolution of symptoms and stabilisation.ConclusionsThis case highlights the significance of considering continuing lithium treatment in bipolar disorder during pregnancy planning. Decisions about medication in pregnancy are multifaceted, making appropriate risk stratification imperative in order to inform individualised care plans to minimise the risk of relapse in these patients.Disclosure of InterestNone Declared

Understanding Lithium intoxication in Bipolar Disorder: a comparative analysis and clinical implications

IntroductionLithium treatment is a proven method for bipolar disorder management, but its narrow therapeutic range and the risk of severe side effects, including lithium intoxication, pose significant clinical hurdles. Lithium intoxication, a potentially life-threatening complication, can occur during treatment, raising ongoing questions about its clinical factors, risk elements, and best practices for management.ObjectivesOur objective is a comparative analysis between patients who have experienced lithium intoxication and those who have not, aiming to identify influencing factors and enhance clinical care.MethodsWe collected demographic data, age at lithium treatment initiation, treatment duration, therapeutic adherence, Mental Health consultations, and lithium level monitoring from 14 individuals requiring clinical attention due to lithium intoxication and 14 patients with similar gender, age, and diagnosis with lithium treatment but without intoxication during four years of follow-up.ResultsRegarding the results, the age of onset of lithium treatment in patients with lithium intoxication was 30.2 years (SD=8), and the duration of lithium treatment averaged 11.1 years (SD=8.8), which did not significantly differ from the control group with ages of onset at 38.1 years (SD=15.1) and treatment duration of 9.27 years (SD=8.8), respectively. Lithium intoxication patients developed severe complications, including hospitalizations in medical-surgical units, the necessity for dialysis, and death, one fatal case. Although therapeutic adherence to lithium, measured through pharmaceutical dispensation, exceeded 90% and was comparable in both groups, patients affected by lithium intoxication exhibited a significantly higher treatment discontinuation rate (OR 32.5; 95% CI, 3.1 to 337.8) during the follow-up period. Patients who experienced lithium intoxication had an average of psychiatric consultations every 11.2 months (SD=13.4), with 35.7% not attending at least once a year, while the control group had an appointment every 5.31 months (SD=2.7) (p > 0.05). Lastly, despite both groups having a similar frequency of plasma lithium level monitoring, occurring approximately every 5.5 months (SD=2.6) and 7.8 months (SD=4.8), respectively, in 28.5% of those who suffered from lithium intoxication did not undergo any monitoring for periods exceeding 18 months (p < 0.05).ConclusionsOur research highlights the significance of delivering thorough clinical care and continuous monitoring to patients receiving lithium treatment for bipolar disorder. Ensuring effectiveness therapeutic adherence and maintaining strict monitoring of lithium levels are critical factors that significantly enhance treatment safety. Appropriate management has the potential to improve the quality and safety of care for people with bipolar disorder who are dependent on lithium therapy.Disclosure of InterestNone Declared

Methylomic signature of lithium response in bipolar disorder

Introduction Bipolar disorder (BD) is a chronic and severe psychiatric disorder, characterized by the alternance of episodes of (hypo)-mania and major depression. Lithium (Li) is the first-line treatment for BD but unfortunately response to Li is highly variable: after at least two consecutive years of treatment, only a fraction of patients receiving Li will display significant improvement in the frequency and/or severity of mood recurrences. This interindividual variability of treatment response is difficult to predict, in the bipolar disorder context. This could be determined by genetic factors still misidentified by available genetic studies. In addition, no clinical or biological markers are available to reliably define eligibility criteria for a lithium treatment in bipolar disorder. A consequence is a long process of therapeutic trials (18-24 months) to phenotype Li response, delaying the stabilization.ObjectivesTo identify objective biomarkers of the prophylactic response to lithium in order to improve patient care and propose therapeutic alternatives to patients who do not respond to lithium.Methods Using a genome-wide methylomic approach, and then logistic regressions incorporating as covariates the different types of treatments, we were able to identify differentially methylated regions (DMRs) whose methylation difference between responders and non-responders was not impacted by co-prescribed treatments. Then, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method than can be implemented in any medical laboratory at low cost and with minimal equipment, to estimate methylation proportion of 9 DMRs in 61 samples of bipolar patients.Results In the sample of 61 individuals with BD, the 9 MS-HRM-measured DMRs combined with clinical variables (age, sex, cigarette smoking status, lifetime number of hospitalizations, age at onset of BD, polarity at onset, psychotic symptoms at onset, family history of BD, lifetime alcohol/cannabis misuse, panic disorders, Li prescribed as the first mood stabilizer (vs 2nd or 3rd choice)) correctly classified 83,6% of individuals as good or non-responders (n=61, prophylactic response phenotype defined using the “Alda” scale). Excluding the partial responders, the percentage of correctly classified individuals is as high as 100% (n=43, 18 non responders and 25 responders). The AUC are respectively AUC=0.913 and AUC=1.0.ConclusionsThe MS-HMR method allow to identify the response status of individuals with BD with 9 DMR. These DMRs discriminate good from non-responders and can be used in combination with clinical variables.Disclosure of InterestNone Declared

Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons. We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling. In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not. Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices.

Invited commentary to Professor Belmaker's letter on lithium treatment for bipolar disorder.

Invited commentary to Professor Belmaker's letter on lithium treatment for bipolar disorder.

Exploring Calbindin-IMPase fusion proteins structure and activity

Calbindin-D28k is a calcium binding protein that is highly expressed in the mammalian central nervous system. It has been reported that calbindin-D28k binds to and increases the activity of inositol Monophosphatase (IMPase). This is an enzyme that is involved in the homeostasis of the Inositol trisphosphate signalling cascade by catalysing the final dephosphorylation of inositol and has been implicated in the therapeutic mechanism of lithium treatment of bipolar disorder. Previously studies have shown that calbindin-D28k can increase IMPase activity by up to 250 hundred-fold. A preliminary in silico model was proposed for the interaction.Here, we aimed at exploring the shape and properties of the calbindin-IMPase complex to gain new insights on this biologically important interaction. We created several fusion constructs of calbindin-D28k and IMPase, connected by flexible amino acid linkers of different lengths and orientations to fuse the termini of the two proteins together. The resulting fusion proteins have activities 200%–400% higher the isolated wild-type IMPase. The constructs were characterized by small angle X-ray scattering to gain information on the overall shape of the complexes and validate the previous model. The fusion proteins form a V-shaped, elongated and less compact complex as compared to the model. Our results shed new light into this protein-protein interaction.

Determinants of Kidney Function and Accuracy of Kidney Microcysts Detection in Patients Treated With Lithium Salts for Bipolar Disorder.

Objectives: Early kidney damage during lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection. Methods: In this cross-sectional cohort study, 217 consecutive lithium-treated patients underwent mGFR and kidney MRI with half-Fourier turbo spin-echo and Single-shot with long echo time sequences. Results: Median age was 51 [27–62] years, and median lithium treatment duration was 5 [2–14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration (β −0.8 [−1; −0.6] ml/min/1.73 m2 GFR decrease for each year of treatment), a higher age (β −0.4 [−0.6; −0.3] ml/min/1.73 m2 for each year of age, p < 0.001), albuminuria (β −3.97 [−6.6; −1.3], p = 0.003), hypertension (β −6.85 [−12.6; −1.1], p = 0.02) and hypothyroidism (β −7.1 [−11.7; −2.5], p = 0.003). Serum lithium concentration was not associated with mGFR. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as 1 year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r = −0.64, p < 0.001), but not in patients with no microcysts (r = −0.24, p = 0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73 m2 (AUC 0.893, p < 0.001, sensitivity 80%, specificity 81% for a cut-off value of five microcysts). Conclusion: Lithium treatment duration and hypothyroidism strongly impacted mGFR independently of age, especially in patients with microcysts. MRI might help detect early lithium-induced kidney damage and inform preventive strategies.

The Impact of Lithium on Brain Function in Bipolar Disorder: An Updated Review of Functional Magnetic Resonance Imaging Studies.

Lithium remains a gold standard treatment for bipolar disorder (BD), and functional magnetic resonance imaging (fMRI) studies have contributed to clarifying its impact on neural circuitries in affected individuals. However, the specific neurobiological mechanisms through which lithium exerts its effects on brain function are not fully understood. In this review, we aimed to summarize the results of recent fMRI studies evaluating the impact of lithium on brain functional activity and connectivity in patients diagnosed with BD. We performed a literature search of available sources found in the PubMed database reported in English since 2016, when the last available review on this topic was published. Five fMRI studies in resting-state condition and six studies performed during the execution of emotional tasks met the inclusion criteria. Overall, the available evidence supports normalizing effects of lithium on brain activity and connectivity. Most of these studies reported a normalization in prefrontal regions and interconnected areas involved in emotion regulation and processing, regardless of the task employed. Importantly, lithium treatment showed distinct patterns of activity/connectivity changes compared with other treatments. Finally, lithium modulation of neural circuitries was found to be associated with clinical improvement in BD. These results are consistent with the hypothesis that selective abnormalities in neural circuitries supporting emotion processing and regulation improve during lithium treatment in BD. However, the heterogeneity of the examined studies regarding study design, sample selection, and analysis methods might limit the generalizability of the findings and lead to difficulties in comparing the results. Therefore, in future studies, larger cohorts and homogeneous experimental tasks are needed to further corroborate these findings.

The Genetics of Response to and Side Effects of Lithium Treatment in Bipolar Disorder: Future Research Perspectives.

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and “multi-omics” approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.

MicroRNAs hsa-mir-34a and hsa-mir-124 as biomarkers for predicting and monitoring the lithium treatment in bipolar disorder: in silico analysis

MicroRNAs hsa-mir-34a and hsa-mir-124 as biomarkers for predicting and monitoring the lithium treatment in bipolar disorder: in silico analysis

Commentary: Lithium treatment for bipolar disorder.

Commentary: Lithium treatment for bipolar disorder.

Thyroid dysfunctions due to lithium treatment in bipolar disorder: changes in oxidative stress, trace elements, and hemorheological parameters

Thyroid dysfunctions due to lithium treatment in bipolar disorder: changes in oxidative stress, trace elements, and hemorheological parameters

Ethnicity as a Major Predictor of Lithium Response in Bipolar Disorder

Lithium response in Bipolar Disorder (BD) has shown to have a genetic basis. However, few studies have explored the effect of ethnicity in predicting lithium response. The aim of this study was to test the hypothesis whether ethnicity plays a role in defining the outcome of lithium treatment in BD.

Expression of telomerase reverse transcriptase positively correlates with duration of lithium treatment in bipolar disorder

Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. We determined TL and TERT expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. TERT expression was significantly increased in BD I patients currently on lithium treatment. TERT expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of TERT. We hypothesize that an increase in TERT expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.

Thyroid hormone levels and ultrasonographic changes in thyroid gland of patients on long-term lithium treatment for affective disorders: A controlled study

Background: Although lithium is known to cause thyroid dysfunction and increased thyroid gland volume, clinical examination and biochemical assessment are fundamental to thyroid workup of patients on lithium treatment. We aimed to determine the thyroid gland volume and the thyroid hormone levels of patients who have been receiving lithium treatment for affective disorders in comparison to voluntary healthy controls. Materials and Methods: This was a cross-sectional, hospital-based observational study, performed in 43 patients on long-term lithium treatment for bipolar disorder, major depressive disorder, and schizoaffective disorder. Patients with documented continuous and adequate serum lithium levels for more than or equal to 6 months recruited consecutively underwent ultrasonographic examination of the thyroid gland. Ultrasonographic examinations were also done in all gender- and age-matched healthy controls. All cases and controls underwent biochemical thyroid function tests. Results: There were no statistically significant differences in gender (P = 0.198; χ2 = 1.654) of cases and controls. Most of the cases were married; maximum number of them unemployed and belonged to the lower socioeconomic status. Total thyroid volume was significantly greater in the lithium-treated group than the control group (9.40 ± 1.41 vs. 4.79 ± 0.45). Clinical inspection and palpation only detected goiter in six (n = 6, 13.95%) of patients on lithium and none among controls. The mean triiodothyronine (T3), mean thyroxine (T4), and mean scores for thyroid-stimulating hormone were significantly increased in patients receiving lithium therapy as compared to controls. Conclusion: It would seem wise from a clinical point of view to include ultrasonographic examination of the thyroid gland as part of the standard thyroid workup before initiating lithium treatment.

Thyroid hormone levels and Thyroid Hormone Levels and Ultrasonographic Changes in the Thyroid Gland of Patients on Long-Term Lithium Treatment for Affective Disorders: A Controlled Study.

Background:Although lithium is known to cause thyroid dysfunction and increased thyroid gland volume, clinical examination and biochemical assessment are fundamental to thyroid workup of patients on lithium treatment. We aimed to determine thyroid gland volume and the Thyroid hormone levels of patients who have been receiving lithium treatment for affective disorders in comparison to voluntary healthy controls.Methods:This was a cross-sectional, hospital-based observational study which was performed in 43 patients on long-term lithium treatment for bipolar disorder, major depressive and schizoaffective disorders. Patients with documented continuous and adequate serum lithium levels for more than or equal to 6 months recruited consecutively underwent the ultrasonographic examination of the thyroid gland. Ultrasonographic examinations were also done in all gender- and age-matched healthy controls. All cases and controls underwent biochemical thyroid function tests.Results:There were no statistically significant differences in gender (P = 0.198; Chi-square = 1.654) of cases and controls. Most of the cases were married, maximum number of them unemployed and belonged to the lower socioeconomic status. Total thyroid volume was significantly greater in the lithium-treated group than the controls (9.40 ± 1.41 vs. 4.79 ± 0.45). Clinical inspection and palpation only detected goiter in six (n = 6, 13.95%) of patients on lithium and none among controls. The mean triiodothyronine, mean thyroxine, and mean scores for thyroid-stimulating hormone were significantly increased in patients receiving lithium therapy as compared to controls.Conclusion:It would seem wise from a clinical point of view to include ultrasonographic examination of the thyroid gland as part of the standard thyroid workup before initiating lithium treatment.

The Consortium On Lithium Genetics (Conligen): Genome-Wide Approaches To Bipolar Disorder Pharmacogenetics and A Testament To The Power of International Friendly Data Sharing

This presentation will give the audience an overview of current efforts to identify biomarkers of response to lithium treatment in bipolar disorder (BD). First, building on the experience of the Consortium on Lithium Genetics (www.conligen.org), I will underscore how our approach of “friendly data sharing”, honoring the invaluable efforts by all researchers involved, clinicians and basic scientists alike, has been pivotal to the success of the ConLiGen GWAS in more than 2,500 individuals, i.e. and how it will shape the next steps. Second, I will present in-depth analyses on a potential link between lithium response and genes involved in circadian rhythms, based on stringent gene-set analyses. Finally, I will talk about latest transcriptomic approaches that might help shed light on lithium’s mechanism of action.

Managing fertile women under lithium treatment: the challenge of a Teratology Information Service.

The objective of the present study is to review the literature regarding the management of fertile patients under lithium treatment for bipolar disorder and to report the experience of our Teratology Information Service over the past thirteen years in managing women treated with lithium during preconception, pregnancy and breastfeeding. This research focuses on a selective review of the literature and a retrospective survey has been carried out on fertile women under lithium treatment who called our service at A. Gemelli University Hospital in Rome from May 2002 to December 2015. A total of 140 women under lithium treatment called our TIS. A complete follow-up has been performed on 34 patients: 29 called during pregnancy and 5 called during preconception. None of the patients called during breastfeeding, while half of the patients were taking concomitant drugs during pregnancy. One major cardiac malformation (hypoplastic left heart syndrome) has been reported. No minor malformations have been detected. Twenty-one patients delivered a living child, with one premature neonate. Two patients underwent voluntary interruption of pregnancy and six patients had early spontaneous abortion. In one patient, intrauterine growth retardation occurred, but with no adverse neonatal outcomes. Four neonates experienced transient respiratory distress at birth. Two children developed mild to severe language delay, but normal motor development. Lithium treatment in fertile women is a very delicate topic, where risks and benefits of discontinuing therapy when women plan to become pregnant should be accurately evaluated. Thorough peri-conceptional counselling is crucial for the outcome of pregnancy and for maternal health status during preconception, gestation and breastfeeding.

Association between duration of lithium exposure and hippocampus/amygdala volumes in type I bipolar disorder

BackgroundPrior studies on the effects of lithium on limbic and subcortical gray matter volumes are mixed. It is possible that discrepant findings may be explained by the duration of lithium exposure. We investigated this issue in individuals with type I bipolar disorder (BP-I). MethodsLimbic and subcortical gray matter volume was measured using FreeSurfer in 60 subjects: 15 with BP-I without prior lithium exposure [no-exposure group (NE)]; 15 with BP-I and lithium exposure < 24 months [short-exposure group (SE)]; 15 with BP-I and lithium exposure > 24 months [long-exposure group (LE)]; and 15 healthy controls (HC). ResultsNo differences in limbic and subcortical gray matter volumes were found between LE and HC. Hippocampal and amygdalar volumes were larger bilaterally in both LE and HC when compared to NE. Amygdalar volumes were larger bilaterally in SE when compared to NE but did not differ from LE. Hippocampal volumes were smaller bilaterally in SE when compared to LE and HC but did not differ from NE. No between-group differences on subcortical gray matter or other limbic structure volumes were observed. LimitationsCross-sectional design and concurrent treatment with other medications limit attribution of between-group differences to lithium exposure alone. ConclusionsThe effect of lithium exposure on limbic and subcortical gray matter volumes appears to be time-dependent and relatively specific to the hippocampus and the amygdala, with short-term effects on the amygdala and long-term effects on both structures. These results support the clinical importance of long-term lithium treatment in BP-I.