[Endocrinological Effects of Lithium: Pathophysiological Mechanisms and Clinical Implications]. / Efectos endocrinológicos del litio: Mecanismos fisiopatológicos e implicancias clínicas.

Lithium carbonate has a narrow therapeutic range capable of producing various adverse effects; despite this fact, it is used as first-line therapy in patients with bipolar disorder (BD) thanks to its high effectiveness. Among its adverse events are several conditions at the endocrine level, such as hypothyroidism, hyperthyroidism, hypercalcemia, hyperparathyroidism, and nephrogenic diabetes insipidus. The adherence to current guidelines for monitoring those events is low. The objective of this review is to provide insight into the pathophysiological mechanisms of the endocrine effects of lithium and give recommendations based on the current literature for the monitoring and treatment of these conditions.

Could effective iodine-131 half-life be extended by lithium carbonate in Graves' disease patients: Results from a retrospective analysis.

The effective iodine-131 (I-131) half-life (EHL) plays an important role in the evaluation of radioactive iodine therapy for Graves' disease (GD) patients. It has been observed that the EHL of GD patients varies after taking lithium carbonate. The purpose of this study is to investigate whether EHL can be extended and to identify the predictive factors associated with this outcome. The clinical data of 225 GD patients were retrospectively reviewed. Patients were divided into two groups based on whether the ΔEHL was ≥ 0.5 days. EHL tested after lithium carbonate was defined as Li-EHL. In the univariate analysis, age, sex, thyrotropin receptor antibody (TRAb), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and baseline-EHL exhibited significant differences between the two groups (P < 0.05). Cutoff values of age and baseline-EHL to predict significant EHL extension were 40.5 years and 4.85 days, respectively, as determined by receiver operating characteristic (ROC) curve analysis. Multiple linear regression analysis further revealed that the regression equation, which included age, sex, baseline-EHL, and the FT3, free triiodothyronine (FT4)/free thyroxine(FT3) ratio, was statistically significant (P < 0.05). Li-EHL positively correlated with baseline-EHL and the FT4/FT3 ratio, but negatively correlated with age. Li-EHL was also increased in female individuals. In conclusion, age, sex, baseline-EHL and the FT4/FT3 ratio were associated with Li-EHL in GD patients.

Effect of lithium on chemotherapy-induced neutropenia in Egyptian breast cancer patients; a prospective clinical study.

PURPOSE: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients. METHODS: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles. RESULTS: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups. CONCLUSION: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.

Lithium carbonate accelerates the healing of apical periodontitis.

Apical periodontitis is a disease caused by bacterial invasions through the root canals. Our previous study reported that lithium chloride (LiCl) had a healing effect on apical periodontitis. The aim of this report is to investigate the healing properties and mechanism of lithium ion (Li+) for apical periodontitis using rat root canal treatment model. 10-week-old male Wistar rat's mandibular first molars with experimentally induced apical periodontitis underwent root canal treatment and were applied lithium carbonate (Li2CO3) containing intracanal medicament. Base material of the medicament was used as a control. Subject teeth were scanned by micro-CT every week and the periapical lesion volume was evaluated. The lesion volume of Li2CO3 group was significantly smaller than that of the control group. Histological analysis showed that in Li2CO3 group, M2 macrophages and regulatory T cells were induced in the periapical lesion. In situ hybridization experiments revealed a greater expression of Col1a1 in Li2CO3 group compared with the control group. At 24 h after application of intracanal medicament, Axin2-positive cells were distributed in Li2CO3 group. In conclusion, Li2CO3 stimulates Wnt/ß-catenin signaling pathway and accelerate the healing process of apical periodontitis, modulating the immune system and the bone metabolism.

Valproate and lithium: Old drugs for new pharmacological approaches in brain tumors?

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Combination of strategies to initiate clozapine for refractory schizophrenia in a patient with low neutrophil levels.

Clozapine is the only drug with confirmed efficacy for refractory schizophrenia; however, its use is restricted due to the risk of potentially life-threatening side effects, such as agranulocytosis. Although this restriction ensures safety against haematological risks, some patients with refractory schizophrenia who have low neutrophil levels may miss the opportunity to receive clozapine treatment. We herein report the case of a patient with refractory schizophrenia and low neutrophil levels who was successfully initiated on clozapine treatment after the use of several methods for increasing neutrophil levels. These strategies consisted of discontinuation of antipsychotics, treatment with lithium carbonate and adenine, and light exercise before blood testing. Combining these procedures may be an effective option in the treatment of patients with refractory schizophrenia whose neutrophil levels are not sufficient to initiate clozapine.

Personality profile and therapeutic response to lithium carbonate and sodium valproate in mania with psychotic features.

Bipolar disorder is one of the major psychiatric disorders. Therefore, determining the factors that predict mood stabilizer response is important. This study aimed to investigate the relationship between personality profile and the response to lithium carbonate and sodium valproate in patients with psychotic mania. In this study, 50 patients with bipolar I disorder (manic episode with psychotic features) were randomly assigned to receive lithium carbonate (up to a serum level of 0.8-1.5 mEq/L) or sodium valproate (20 mg/kg). After stabilization of acute manic phase, Temperament and Character Inventory was completed by the patients themselves. Fifty subjects completed this study. The mean age ± SD of participants in the sodium valproate group and lithium carbonate group was 32.99 ± 9.94 and 30.73±7.94 years, respectively. The responders to sodium valproate had significantly higher scores in novelty seeking, harm avoidance (P = 0.003 and 0.004, respectively) and lower scores in persistence (P = 0.006) than the non-responders, but the responders to lithium carbonate did not have significantly different personality profiles. The results of the present study revealed that the personality profiles in the inpatients with psychotic mania are related to the responses to sodium valproate, but are irrelevant to the responses to lithium carbonate.

The development and validation of a prediction model of lithium carbonate blood concentration by artificial neural network: a retrospective study.

BACKGROUND: Bipolar disorder (BD) is common in clinical practice. Lithium (Li) carbonate is often used in the treatment of BD. However, the therapeutic dose of Li carbonate is close to the toxic dose, and Li poisoning is prone to occur. Precise prediction of Li concentration will help clinician to identify patients at high risk of toxic dose of Li carbonate. The purpose of this study was to establish a model for predicting the blood concentration of Li carbonate through an artificial neural network (ANN), and to provide a basis for the clinical rapid and effective formulation of individualized dosing regimens. METHODS: Patients with BD who were diagnosed and treated in our hospital from October 2016 to April 2021 were enrolled as the research participants. We collected patient demographic data, including age and gender; physical examination information, including height and weight; laboratory test results, including liver and renal function, and Li concentrations; medication information, including Li carbonate usage, concomitant medications, and dose; and information on comorbidities and adverse reactions. The Li concentration data of 236 patients were randomly divided into 2 groups: 195 cases in the training group and 41 cases in the test group. The ANN fitting module of SPSS 26.0 was used for modeling and prediction. RESULTS: A total of 236 patients with BD were included in this study. Daily dose (before testing Li concentration), age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), and creatinine (Cr), and co-administered zopiclone, quinine, tipine, lorazepam, olanzapine, valproate, metoprolol, and statins were used as model input variables for training. The test results of the model in the testing group showed that the correlation coefficient between the predicted value of Li concentration and the actual value was r=0.9883, r2=0.9767, P<0.001, the prediction error range was -0.05 to 0.07 mmol/L, and the deviation range was -18.52 to 13.04%; the mean absolute error was 0.03, and the mean prediction error deviation was between -10% and 10% in 33 cases (80.5%). CONCLUSIONS: The correlation, accuracy, and precision of ANN prediction are worthy to be further investigated to predict the blood concentration of Li carbonate.

Preventive Effects of Lithium Carbonate on Antidepressant-Induced Switch During Depressive Episodes: Chinese Data Analysis.

CONTEXT: Some patients experiencing depressive episodes can switch to mania or become mania during treatment with antidepressants. Avoiding a switch is an important part of any therapeutic plan, whether a patient suffers from unipolar or bipolar depression. One method of avoiding switching is use of a mood stabilizer, such as lithium carbonate. DESIGN: The research team performed a narrative review by searching Chinese electronic databases: the Chinese Biomedical Database (CBM), the China National Knowledge Infrastructure (CNKI), WANFANG, and the Chinese Social Sciences Citation Index (VIP). The search used the keywords depression-bipolar depression and depressive episode-and lithium carbonate. Results such as comments, letters, reviews, and case reports were excluded. SETTING: The study took place at Jinhua Second Hospital, China. RESULTS: A random effect model was used to account for the data, using Revman 5.2. The switch rate for the intervention groups was 8.28% or 29 out of 351 participants and of the control groups was 25.29% or 87 out of 344 participants (OR = 0.25, 95% CI: 0.16 to 0.39). Lithium carbonate reduced the switch rate by 67.25% [(25.29%-8.28%) /25.29%]. In the bipolar depression group, lithium carbonate reduced the switch rate by 68.11% [(25.84%-8.24%) /25.84%]. In the depression and unipolar depression groups, lithium carbonate reduced the switch rate by 67.07% [(25.29%-8.26%) /25.29%]. In the group of patients treated with selective serotonin reuptake inhibitors (SSRIs), lithium reduced the switch rate by 60.3% [(29.85%-11.85%) /29.85%]. In group of patients treated by tricyclic antidepressants (TCAs), lithium carbonate reduced the switch rate by 73.14% [(22.28%-6.01%) /22.28%]. CONCLUSIONS: As typical mood stabilizer, lithium carbonate can reduce the antidepressant-induced switch rates in patients with depressive episodes regardless of the type of antidepressant and the type of depressive episode. Further research should compare the effectiveness of lithium carbonate to that of other mood stabilizers in preventing switching associated with antidepressants.

Lithium carbonate alleviates colon inflammation through modulating gut microbiota and Treg cells in a GPR43-dependent manner.

BACKGROUND: Recent evidence suggests that neuropsychiatric stabilizers have a place in resolving gastrointestinal disorders. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder clinically. Here, we estimate the therapeutic function of LC against colitis and investigate the mechanism of intestinal flora and metabolism modulation. METHODS: A colitis model was constructed by continuously administering 2.5% dextran sodium sulfate (DSS) solution daily for 7 days. Analysis of gut microbiota was carried out by 16S rRNA gene high-throughput sequencing. Spectrum antibiotic cocktail (ABX) and faecal microbiota transplantation (FMT) were employed to evaluate the protective effect of intestinal flora. Colonic Treg cells and related immune responses were detected by flow cytometry. RESULTS: LC treatment significantly alleviated colon inflammation by regulating gut microbial diversity and altering flora composition. Notably, LC treatment upregulated short-chain fatty acid (SCFA)-producing bacteria, especially Akkermansia muciniphila (A. muciniphila), and transformed metabolite SCFA profiles. LC activated anti-inflammatory Treg cell responses in colonic lamina propria (LP) in a G-protein coupled receptor 43 (GPR43)-dependent mechanism. ABX, FMT and single bacteria gavage experiments were conducted to confirm the above mechanism. CONCLUSIONS: As an intestinal microbiome and metabolite modulator, LC alleviates colon inflammation in a GPR43-dependent manner through activating Treg cell responses. Therefore, the therapeutic strategy of the microbiome-metabolite-immune axis, as observed in the A. muciniphila-SCFA-Treg cell axis in our study, might provide a new direction for the treatment of IBD.

The entropy of chaotic transitions of EEG phase growth in bipolar disorder with lithium carbonate.

The application of chaos measures the association of EEG signals which allows for differentiating pre and post-medicated epochs for bipolar patients. We propose a new approach on chaos necessary for proof of EEG metastability. Shannon entropies of concealed patterns of Schwarzian derivatives from absolute instantaneous frequency transformations of EEG signals after Hilbert transform are compared and found significantly statistically different between pre and post-medication periods when fitted to von Bertalanffy's functions. Schwarzian dynamics measures was compared at first baseline and then at the end of the first hour of one dose 300 mg lithium carbonate intake for the same subject in depressive patients. With an application of Schwarzian derivative on the prediction of von Bertalanffy's models, integration and segregation of phase growth orbits of neural oscillations can be understood as an influence of chaos on the mixing of frequencies. A phase growth constant parameter was performed to determine the bifurcation parameter of von Bertalanffy's model at each given non-overlapped EEG segment. Schwarzian derivative was sometimes very close positive near the origin but stayed negative for most of the number of segments. Lithium carbonate changed the chaotic invariants of the EEG Schwarzian dynamics and removed sharp boundaries in the bipolar spectrum.

Lithium treatment in the era of personalized medicine.

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

Investigation of the impact of an ADCY2 polymorphism as a predictive biomarker in bipolar disorder, suicide tendency and response to lithium carbonate therapy: the first report from Iran.

High rates of mortality due to both suicide and medical comorbidities in bipolar patients can be decreased through the administration of lithium, which affects the cerebral endothelium as well as neurons. To investigate the role of ADCY2 in risk of bipolar disorder, we genotyped the ADCY2 rs2290910 in bipolar patients and healthy controls using amplification refractory mutation system PCR. This polymorphism was associated with risk of bipolar disorder (odds ratio [OR]: 0.430; 95% CI: 0.296-0.624; p = 0.001). The C allele was more frequent in suicide ideation group compared other groups (OR: 2.7; 95% CI: 1.386-5.302; p = 0.004). The T allele was more frequent in suicide attempt group compared with suicide ideation group (OR: 0.238; 95% CI: 0.111-0.509; p = 0.001).