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Delgado JM, Klein PS, Varma S. ATP-Ion Complexation and Lithium's Bioactive Form in Cellular Solutions. J Am Chem Soc 2025. [PMID: 40405352 DOI: 10.1021/jacs.5c04061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Lithium (Li+) is a first-line therapy for millions of people with bipolar disorder. However, the molecular mechanism underlying Li+'s action remains unclear. Here we resolve a key issue concerning its bioactive form that is central to all hypotheses proposed to explain its therapeutic action─under cellular conditions, it is unclear as to what fraction of Li+ is free vs bound to ATP. We address this using molecular dynamics (MD) simulations and kinetic modeling. The polarizable force field (AMOEBA-HFC) employed in MD is benchmarked against quantum mechanical and experimental data, including local ion-ligand interactions, aqueous phase ion properties, and ion-ATP binding free energies. The kinetic model is built using observations from MD and parametrized using MD and experimental data. We discover that Mg2+-bound ATP (ATP·Mg) has two binding sites for monovalent cations, and both sites can be loaded simultaneously. In Li+'s absence, ATP·Mg predominantly exists as a ternary or quaternary complex with Na+ and/or K+ ions. Li+ also competes for these two sites. Although its standard affinity is stronger than Na+ and K+, its loading its limited by its low therapeutic concentration. Nevertheless, the extent of Li+ loading increases with ATP levels, and 50% of Li+ can be sequestered by ATP·Mg at physiological extremes. This means that both Li+ forms can be present in high fractions, providing a basis to investigate molecular modes of Li+ action. Overall, our work provides new structural, thermodynamic, and kinetic insights into how ATP binds ions in cellular solutions, also revealing Li's bioactive form.
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Affiliation(s)
- Julian M Delgado
- Department of Molecular Biosciences, University of South Florida, 4202 E. Fowler Ave., Tampa FL-33620, United States
| | - Peter S Klein
- Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Sameer Varma
- Department of Molecular Biosciences, University of South Florida, 4202 E. Fowler Ave., Tampa FL-33620, United States
- Department of Physics, University of South Florida, 4202 E. Fowler Ave., Tampa FL-33620, United States
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Li Y, Peng X, Liu N, Guo H, Jia Y, Liang Y, Song M, Hu L, Jiang G. Lithium Levels in Umbilical Cord Blood from Two Cities in China: Indicating Unidentified Sources of Human Exposure. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:4344-4351. [PMID: 39993142 DOI: 10.1021/acs.est.4c12959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
As lithium demand continues to grow, increasing environmental lithium concentrations pose potential health risks to sensitive populations, particularly pregnant women and fetuses. However, data on fetal lithium exposure and umbilical cord blood lithium concentrations in nonpolluted regions remain scarce. To address this gap, we monitored lithium concentrations in maternal and umbilical cord blood in Beijing and Changsha, and analyzed exposure sources using a one-compartment model. Significant regional differences were observed: in 2019 and 2021, the mean (±SD) of lithium concentrations in umbilical cord blood in Beijing were 13.05 ± 7.34 and 11.23 ± 2.56 μg/L, respectively, while in Changsha, a significantly lower level of 0.61 ± 0.64 μg/L was found. Model estimates indicated that umbilical cord blood lithium in Changsha primarily originated from cereal, vegetables, and drinking water. However, most of the lithium in Beijing's cord blood came from unidentified sources, likely anthropogenic. This study highlights significant regional differences in umbilical cord blood lithium exposure and underscores the existence of unidentified exposure sources in Beijing except natural resource. As lithium usage increases in the future, ongoing monitoring and evaluation of potential health risks to fetuses will be critical.
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Affiliation(s)
- Yu Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xianglian Peng
- Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410000, China
| | - Nian Liu
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China
| | - Hua Guo
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China
| | - Yurong Jia
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yong Liang
- School of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Maoyong Song
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ligang Hu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China
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Tondo L, Baldessarini RJ. History of Suicide Prevention with Lithium Treatment. Pharmaceuticals (Basel) 2025; 18:258. [PMID: 40006071 PMCID: PMC11858927 DOI: 10.3390/ph18020258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/19/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Suicidal behavior is prevalent among individuals with psychiatric illnesses, especially mood, substance abuse, and psychotic disorders. Over the past several decades, lithium treatment in patients with mood disorders has been increasingly used to lower the risk of suicidal behavior. This overview considers that lithium treatment has the most abundant evidence of reducing suicidal behavior. It also examines the hypothesis that higher natural lithium levels in drinking water correlate with reduced suicide rates. We report findings from trials comparing lithium treatment with its absence, placebos, or alternative treatments for suicide prevention and address substantial challenges in such studies. The mechanisms behind lithium's potentially protective effects against suicidal behavior remain uncertain. However, it is believed that lithium may produce anti-aggressive/anti-impulsive effects that directly contribute to anti-suicidal outcomes and mood-stabilizing effects that indirectly lead to the same results. Anti-aggressive/anti-impulsive effects may be obtained at the very low levels of lithium present in drinking water, whereas recurrence prevention may be attained at therapeutic levels.
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Affiliation(s)
- Leonardo Tondo
- Department of Psychiatry, Harvard Medical School, 116 Mill Street, Boston, MA 02478, USA;
- International Consortium for Mood & Psychotic Disorder Research, McLean Hospital, Belmont, MA 02478, USA
- Lucio Bini Mood Disorder Centers, 42 Via Crescenzio, 00,193 Rome, Italy
- Lucio Bini Mood Disorder Centers, 28 Via Cavalcanti, 09,128 Cagliari, Italy
| | - Ross J. Baldessarini
- Department of Psychiatry, Harvard Medical School, 116 Mill Street, Boston, MA 02478, USA;
- International Consortium for Mood & Psychotic Disorder Research, McLean Hospital, Belmont, MA 02478, USA
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Noguera L, Benito D, Briaudeau T, Ruiz P, Izagirre U. Integration of responses to lithium in mussels at different levels of biological complexity. CHEMOSPHERE 2025; 371:144021. [PMID: 39733952 DOI: 10.1016/j.chemosphere.2024.144021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/04/2024] [Accepted: 12/22/2024] [Indexed: 12/31/2024]
Abstract
The increasing use of lithium (Li) in modern technology and medicine has raised up concerns in the scientific community due to the potential impact of this metal on the aquatic environment. Although several effects have been reported in different organisms, there is still scarce information concerning the mechanisms and chronic effects of Li toxicity in marine life. Our main objective is to determine biological effects of sub-lethal concentrations in Mytilus galloprovincialis at different biological organization levels using the biomarker approach. Mussels were exposed to environmental Li concentrations: 0.1, 1 and 10 mg/L. Samples of gills, muscle and digestive gland were taken at days 1, 7 and 21 for the assessment of biochemical, histochemical and histological endpoints. Results showed that exposure to Li caused greater impacts in a dose and time-dependent manner at different biological organization levels. Changes in acetylcholinesterase (AChE) activity were detected at day 1 (induction) and day 21 (inhibition) in accordance with increasing Li levels, indicating possible neurotoxic effects, while catalase (CAT) inhibition, and subsequent induction, was detected at day 1 in proportion to Li concentrations. Lysosomal biomarkers demonstrated a decreasing lysosomal membrane stability with higher Li doses after 21 days of exposure, whereas 10 mg Li/L provoked lysosomal size reduction from day 1. Finally, the integration of these biological responses into an IBR index indicated a clear effect of exposure after 21 days in a dose-dependent way, leading to cellular and tissue damage as consequence. Moreover, a time-course response was observed with an enhanced oxidative stress at day 1, and a neurotoxic effect, lysosomal membrane destabilization and histopathological alterations after 7 and 21 days of exposure to medium and high Li concentrations. Consequently, these findings provide valuable insights into Li's effects on marine life, emphasizing the need for further long-term studies across different biological organization levels.
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Affiliation(s)
- Laura Noguera
- CBET + Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology, Research Centre for Experimental Marine Biology and Biotechnology PiE-UPV/EHU, University of the Basque Country UPV/EHU, Areatza z/g, 48620, Plentzia, Bizkaia, Spain.
| | - Denis Benito
- CBET + Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology, Research Centre for Experimental Marine Biology and Biotechnology PiE-UPV/EHU, University of the Basque Country UPV/EHU, Areatza z/g, 48620, Plentzia, Bizkaia, Spain.
| | - Tifanie Briaudeau
- CBET + Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology, Research Centre for Experimental Marine Biology and Biotechnology PiE-UPV/EHU, University of the Basque Country UPV/EHU, Areatza z/g, 48620, Plentzia, Bizkaia, Spain.
| | - Pamela Ruiz
- CBET + Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology, Research Centre for Experimental Marine Biology and Biotechnology PiE-UPV/EHU, University of the Basque Country UPV/EHU, Areatza z/g, 48620, Plentzia, Bizkaia, Spain.
| | - Urtzi Izagirre
- CBET + Research Group, Department of Zoology and Animal Cell Biology, Faculty of Science and Technology, Research Centre for Experimental Marine Biology and Biotechnology PiE-UPV/EHU, University of the Basque Country UPV/EHU, Areatza z/g, 48620, Plentzia, Bizkaia, Spain.
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Rybakowski JK. Lithium: Fifteen Years Later. Neuropsychobiology 2024; 83:205-213. [PMID: 39510063 DOI: 10.1159/000542490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 11/02/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND The 75th anniversary of introducing lithium into modern psychiatry is recognized, attested by the 1949 paper of John Cade. About this event, my editorial in the special 2010 issue of Neuropsychobiology was titled "Lithium: Sixty Years Thereafter." Since then, fifteen more years have brought further information about lithium. This paper makes a narrative review of the most important articles published in this period. SUMMARY The selected key literature of 2010-2024 addressed lithium prophylactic efficacy in bipolar disorder (BD), including pediatric, recurrent depression, and lithium augmentation of antidepressants in treatment-resistant depression (TRD). Novel data have been obtained for lithium adverse effects (kidney, thyroid) and beneficial outcomes of long-term lithium administration (anti-suicidal, neuroprotective, antiviral, and others). The results on the mechanisms of lithium action covered genetic investigations of the Consortium of Lithium Genetics (ConLiGen) and in vitro studies with induced pluripotent stem cells and lymphoblastoid cell lines. The underutilization of lithium nowadays was emphasized, and the ways to overcome it were considered. KEY MESSAGES Lithium remains the choice drug for recurrence prevention in BD, also in adolescents, and a significant option for augmentation of antidepressants in TRD. The adverse side effects should be carefully followed and managed according to current guidelines. There are also beneficial lithium impacts, of which anti-suicidal and anti-dementia seem the most important. Most of the results of neurobiological studies on lithium mechanisms may be related to lithium response and some (e.g., immunomodulatory) to the pathogenesis of BD. Better education about lithium could make more patients the beneficiary of this drug.
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Affiliation(s)
- Janusz K Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
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Terao T, Hirakawa H, Muronaga M, Izumi T, Kohno K. Trace Lithium for Suicide Prevention and Dementia Prevention: A Qualitative Review. Pharmaceuticals (Basel) 2024; 17:1486. [PMID: 39598397 PMCID: PMC11597136 DOI: 10.3390/ph17111486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Anti-manic effects of lithium and the nature of trace element in lithium were first observed in 1949. In this review, we explore the potential effects of trace lithium in the prevention of suicide and dementia. Methods: This is a qualitative and non-systematic review. Results: While most studies to date have been cross-sectional, limiting the establishment of causal relationships, the potential benefits of trace lithium for suicide prevention and dementia prevention are notable, especially in the absence of radical treatments for suicide and dementia. Furthermore, trace lithium appears to lack many of the adverse effects associated with so-called therapeutic lithium levels. Conclusions: The present findings suggest that trace lithium may be associated with lower suicide rates and reduced dementia rates. Probably, trace lithium may inhibit testosterone and thereby mitigate aggression and impulsivity and decrease suicide. Also, trace lithium may inhibit GSK-3β and thereby lower amyloid β and tau hyperphosphorylation and inhibit pro-inflammatory cytokines such as IL 6 and IL 8 and thereby mitigate inflammation, whereas trace lithium may promote BDNF and neurogenesis in the general population.
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Affiliation(s)
- Takeshi Terao
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Daigaoka 1-1, Hasama-machi, Yufu 879-5593, Oita, Japan; (H.H.); (M.M.); (T.I.); (K.K.)
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Eugene AR. Country-specific psychopharmacological risk of reporting suicidality comparing 38 antidepressants and lithium from the FDA Adverse Event Reporting System, 2017-2023. Front Psychiatry 2024; 15:1442490. [PMID: 39575192 PMCID: PMC11580034 DOI: 10.3389/fpsyt.2024.1442490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 10/10/2024] [Indexed: 11/24/2024] Open
Abstract
Background The United States Food and Drug Administration (FDA) maintains a black-box warning for antidepressants warning of an increased risk of suicidality in children and young adults that is based on proprietary clinical trial data from study sponsors that were submitted for regulatory approval. This article aimed to assess whether the black-box warning for antidepressants is still valid today using recent drug safety data. Methods Post-marketing adverse drug event data were obtained from the US FDA's Adverse Event Reporting System (FAERS) for the years 2017 through 2023. Logistic regression analysis was conducted using the case versus non-case methodology and adjusted for gender, age group, drug role (primary drug, secondary drug, interacting drug, and concomitant drug), initial FDA reporting year, reporter country, and a drug*gene*age group interaction. Results In the multivariate analysis, compared to fluoxetine and patients aged 25 to 64 years, children [adjusted reporting odds ratio (aROR) = 7.38, 95% CI, 6.02-9.05] and young adults (aROR = 3.49, 95% CI, 2.65-4.59) were associated with an increased risk of reporting suicidality, but not for the elderly (aROR = 0.76, 95% CI, 0.53-1.09). Relative to fluoxetine, esketamine was associated with the highest rate of reporting suicidality in children (aROR = 3.20, 95% CI, 2.25-4.54); however, esketamine was associated with a lower risk of reporting suicidality in young adults (aROR = 0.59, 95% CI, 0.41-0.84), but not significantly in the elderly (aROR = 0.77, 95% CI, 0.48-1.23). For country-specific findings, relative to the USA, the Slovak Republic, India, and Canada had the lowest risk of reporting suicidality. For the overall study population, desvenlafaxine (aROR = 0.61, 95% CI, 0.46-0.81) and vilazodone (aROR = 0.56, 95% CI, 0.32-0.99) were the only two antidepressants associated with a reduced risk of reporting suicidality. Conclusion This study shows that with recent antidepressant drug safety data, the US FDA's black-box warning for prescribing antidepressants to children and young adults is valid today in the USA. However, relative to the USA, 15 countries had a significantly lower risk of reporting suicidality, while 16 countries had a higher risk of reporting suicidality from 38 antidepressants and lithium.
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Harandi H, Ahmadinia H, Ghaffarian-Bahraman A, Alimoradi H, Nasab ZB, Rezaeian M. Correlation between lithium concentrations in drinking water and suicide attempt in the southeast of Iran. ENVIRONMENTAL MONITORING AND ASSESSMENT 2024; 196:1144. [PMID: 39480571 DOI: 10.1007/s10661-024-13325-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/25/2024] [Indexed: 11/02/2024]
Abstract
Suicide, as an avoidable cause of death in public health systems, currently lacks effective global strategies to prevent it. However, several epidemiological studies found a correlation between the concentration of lithium (Li) in drinking water and lower suicide rates in the general population. Our ecological study investigated this hypothesis in the Rafsanjan district of Iran. Samples from the public water supply in 16 areas in the district were analyzed using the graphite furnace atomic absorption. The resulting data were examined in relation to the suicide attempt from March 2019 to March 2020 obtained from Iran's Ministry of Health's registration system. During that period, 239 suicide attempts were recorded, resulting in an average of 69 individuals (85 women and 54 men) per 100,000 residents of the area. The average Li concentration in the drinking water was 47.30 µg/L (ranging from 9.4 to 141 µg/L). A negative significant correlation (r = -0.551, p = 0.027) between Li concentration in water and the rate of suicide attempt were observed in the studied population. Notably, these findings indicate an inverse significant relationship between Li levels and suicide attempt rate in women (r = -0.725, p = 0.001). This is the first study in Iran that examines the relationship between Li levels in drinking water and suicide attempt rate. The findings of this study support an inverse relationship between the level of Li in public drinking water and the rate of women suicide attempt.
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Affiliation(s)
- Hamidreza Harandi
- Department of Biochemistry Rafsanjan Branch, Islamic Azad University, Rafsanjan, Iran
| | - Hassan Ahmadinia
- Department of Epidemiology and Biostatistics, Occupational Environment Research Center, Medical School, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Ghaffarian-Bahraman
- Occupational Environment Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Houman Alimoradi
- BioMatter Unit-Biomass Transformation Lab (BTL), École Interfacultaire de Bioingénieurs (EIB), Université Libre de Bruxelles, Brussels, Belgium
| | - Zoheira Bagheri Nasab
- Department of Biochemistry Rafsanjan Branch, Islamic Azad University, Rafsanjan, Iran
| | - Mohsen Rezaeian
- Department of Epidemiology and Biostatistics, Occupational Environment Research Center, Medical School, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Iordache AM, Voica C, Roba C, Nechita C. Evaluation of potential human health risks associated with Li and their relationship with Na, K, Mg, and Ca in Romania's nationwide drinking water. Front Public Health 2024; 12:1456640. [PMID: 39377005 PMCID: PMC11456539 DOI: 10.3389/fpubh.2024.1456640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/09/2024] [Indexed: 10/09/2024] Open
Abstract
Background Increasing lithium (Li) demand worldwide due to its properties and role in renewable energy will raise water reservoir pollution and side effects on human health. Divergent results regarding Li concentration in water and affective disorders are found in the literature, which is why regional reports are expected. Objective The present study evaluated the occurrence and human health risks resulting from oral exposure, respectively, and the relationship between alkali metals (Li, Na, and K) and minerals (Mg, Ca) in balanced purified water (bottled) and spring water. Methods The ICP-MS technique was used to measure a national database with 53 bottled and 42 spring water samples randomly selected. One-way ANOVA, Pearson correlation, and HCA analysis were applied to assess the possible relationship between metals in water. The possible side effects of Li poisoning of water resources on human health have been evaluated using the Estimated Daily Intake Index (EDI) and Total Hazard Quotient (THQ). Results The toxic metals (As, Hg, and Pb) were measured, and the results indicate values above the detection limit of 22.3% of samples in the case of lead but not exceeding the safety limits. Depending on the water sources, such as bottled and spring water, the Li concentration varied between 0.06-1,557 and 0.09-984% μg/L. We found a strong positive correlation between Li and Na and Mg, varying between bottled and spring waters (p% <%0.001). Li exceeded the limit set by the Health-Based Screening Level (HBSL) in 41.37 and 19% of bottled and spring water samples. The oral reference doses (p-RfDs) for the noncancer assessment of daily oral exposure effects for a human lifetime exceeded threshold values. The THQ index shows potential adverse health effects, requiring further investigations and remedial actions in 27.58% of approved bottled waters and 2.38% of spring waters. Conclusion We can conclude that water is safe based on the Li concentration found in drinking water and supported by a gap in strict regulations regarding human Li ingestion. The present study can serve decision-makers and represent a starting database with metals of interest for further clinical studies. Decision-makers can also use it to find solutions for sustainable management of clean and safe drinking water.
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Affiliation(s)
- Andreea Maria Iordache
- National Research and Development Institute for Cryogenics and Isotopic Technologies—ICSI, Râmnicu Vâlcea, Romania
| | - Cezara Voica
- National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania
| | - Carmen Roba
- Faculty of Environmental Science and Engineering, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Constantin Nechita
- Department of Biometry, National Research Institute in Forestry Marin Dracea – ICAS, Bucharest, Voluntari, Romania
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García-Acosta JC, Castillo-Montoya AI, Rostro-Alonso GO, Villegas-Vázquez EY, Quintas-Granados LI, Sánchez-Sánchez L, López-Muñóz H, Cariño-Calvo L, López-Reyes I, Bustamante-Montes LP, Leyva-Gómez G, Cortés H, Jacobo-Herrera NJ, García-Aguilar R, Reyes-Hernández OD, Figueroa-González G. Unrevealing Lithium Repositioning in the Hallmarks of Cancer: Effects of Lithium Salts (LiCl and Li 2CO 3) in an In Vitro Cervical Cancer Model. Molecules 2024; 29:4476. [PMID: 39339471 PMCID: PMC11434384 DOI: 10.3390/molecules29184476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/07/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Lithium, a natural element, has been employed as a mental stabilizer in psychiatric treatments; however, some reports indicate it has an anticancer effect, prompting the consideration of repurposing lithium for cancer treatment. The potential anticancer use of lithium may depend on its form (salt type) and the type of cancer cells targeted. Little is known about the effects of Li2CO3 or LiCl on cancer cells, so we focused on exploring their effects on proliferation, apoptosis, migration, and cell cycle as part of the hallmarks of cancer. Firstly, we established the IC50 values on HeLa, SiHa, and HaCaT cells with LiCl and Li2CO3 and determined by crystal violet that cell proliferation was time-dependent in the three cell lines (IC50 values for LiCl were 23.43 mM for SiHa, 23.14 mM for HeLa, and 15.10 mM for HaCaT cells, while the IC50 values for Li2CO3 were 20.57 mM for SiHa, 11.52 mM for HeLa, and 10.52 mM for HaCaT cells.) Our findings indicate that Li2CO3 and LiCl induce DNA fragmentation and caspase-independent apoptosis, as shown by TUNEL, Western Blot, and Annexin V/IP assay by flow cytometry. Also, cell cycle analysis showed that LiCl and Li2CO3 arrested the cervical cancer cells at the G1 phase. Moreover, lithium salts displayed an anti-migratory effect on the three cell lines observed by the wound-healing assay. All these findings imply the viable anticancer effect of lithium salts by targeting several of the hallmarks of cancer.
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Affiliation(s)
- Juan Carlos García-Acosta
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
| | - Alejando Israel Castillo-Montoya
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
| | - Gareth Omar Rostro-Alonso
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
| | - Edgar Yebrán Villegas-Vázquez
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
| | - Laura Itzel Quintas-Granados
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Ciudad de México 07160, Mexico; (L.I.Q.-G.); (I.L.-R.)
| | - Luis Sánchez-Sánchez
- Laboratorio de Biología Molecular del Cáncer, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.S.-S.); (H.L.-M.)
| | - Hugo López-Muñóz
- Laboratorio de Biología Molecular del Cáncer, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.S.-S.); (H.L.-M.)
| | | | - Israel López-Reyes
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Ciudad de México 07160, Mexico; (L.I.Q.-G.); (I.L.-R.)
| | | | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Zacatenco, Ciudad de México 07360, Mexico
| | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra, Ciudad de México 14389, Mexico;
| | - Nadia Judith Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Ciudad de México 14080, Mexico;
| | - Rosario García-Aguilar
- Laboratorio de Citometría de Flujo y Hematología, Diagnóstico Molecular de Leucemias y Terapia Celular (DILETEC), Ciudad de México 07800, Mexico;
| | - Octavio Daniel Reyes-Hernández
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (J.C.G.-A.); (A.I.C.-M.); (G.O.R.-A.); (E.Y.V.-V.); (O.D.R.-H.)
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11
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Callovini T, Montanari S, Bardi F, Barbonetti S, Rossi S, Caso R, Mandracchia G, Margoni S, Brugnami A, Paolini M, Manfredi G, Giudice LL, Segatori D, Zanzarri A, Onori L, Calderoni C, Benini E, Marano G, Massetti M, Fiaschè F, Di Segni F, Janiri D, Simonetti A, Moccia L, Grisoni F, Ruggiero S, Bartolucci G, Biscosi M, Ferrara OM, Bernardi E, Monacelli L, Giannico AM, De Berardis D, Battisti G, Ciliberto M, Brisi C, Lisci FM, D’Onofrio AM, Restaino A, Di Benedetto L, Anesini MB, Boggio G, Specogna E, Crupi A, De Chiara E, Caroppo E, Ieritano V, Monti L, Chieffo DPR, Rinaldi L, Camardese G, Cuomo I, Brugnoli R, Kotzalidis GD, Sani G, Mazza M. Obstetric Outcomes in Women on Lithium: A Systematic Review and Meta-Analysis. J Clin Med 2024; 13:4872. [PMID: 39201016 PMCID: PMC11355283 DOI: 10.3390/jcm13164872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/02/2024] Open
Abstract
Background/Objectives: Lithium taken during pregnancy was linked in the past with increased risk for foetal/newborn malformations, but clinicians believe that it is worse for newborn children not to treat the mothers' underlying psychiatric illness. We set to review the available evidence of adverse foetal outcomes in women who received lithium treatment for some time during their pregnancy. Methods: We searched four databases and a register to seek papers reporting neonatal outcomes of women who took lithium during their pregnancy by using the appropriate terms. We adopted the PRISMA statement and used Delphi rounds among all the authors to assess eligibility and the Cochrane Risk-of-Bias tool to evaluate the RoB of the included studies. Results: We found 28 eligible studies, 10 of which met the criteria for inclusion in the meta-analysis. The studies regarded 1402 newborn babies and 2595 women exposed to lithium. Overall, the systematic review found slightly increased adverse pregnancy outcomes for women taking lithium for both the first trimester only and any time during pregnancy, while the meta-analysis found increased odds for cardiac or other malformations, preterm birth, and a large size for gestational age with lithium at any time during pregnancy. Conclusions: Women with BD planning a pregnancy should consider discontinuing lithium when euthymic; lithium use during the first trimester and at any time during pregnancy increases the odds for some adverse pregnancy outcomes. Once the pregnancy has started, there is no reason for discontinuing lithium; close foetal monitoring and regular blood lithium levels may obviate some disadvantages of lithium administration during pregnancy.
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Affiliation(s)
- Tommaso Callovini
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Silvia Montanari
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Francesca Bardi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara Barbonetti
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara Rossi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Romina Caso
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giuseppe Mandracchia
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Stella Margoni
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Andrea Brugnami
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Marco Paolini
- Department of Psychiatry, Università Vita-Salute San Raffaele, 20132 Milan, Italy;
| | - Giovanni Manfredi
- UOC Psichiatria, Sant’Andrea University Hospital, Università La Sapienza of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy;
| | - Luca Lo Giudice
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Daniele Segatori
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Andrea Zanzarri
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Luca Onori
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Claudia Calderoni
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Elisabetta Benini
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giuseppe Marano
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Marco Massetti
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Federica Fiaschè
- ASL RM1, Presidio Ospedaliero San Filippo Neri, Servizio Psichiatrico di Diagnosi e Cura, Via Giovanni Martinotti, 20, 00135 Rome, Italy;
| | - Federica Di Segni
- ASL Roma 2, Dipartimento di Salute Mentale, Servizio Per Le Dipendenze Patologiche Distretto 7, Via dei Sestili 7, 00174 Rome, Italy;
| | - Delfina Janiri
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Alessio Simonetti
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Lorenzo Moccia
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Flavia Grisoni
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara Ruggiero
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giovanni Bartolucci
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Marco Biscosi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Ottavia Marianna Ferrara
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Evelina Bernardi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Leonardo Monacelli
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Alessandro Michele Giannico
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | | | - Giulia Battisti
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Michele Ciliberto
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Caterina Brisi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Francesco Maria Lisci
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Antonio Maria D’Onofrio
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Antonio Restaino
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Luca Di Benedetto
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Maria Benedetta Anesini
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Gianluca Boggio
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Elettra Specogna
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Arianna Crupi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Emanuela De Chiara
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Emanuele Caroppo
- Department of Mental Health, Local Health Authority Roma 2, 00159 Rome, Italy;
| | - Valentina Ieritano
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Laura Monti
- Clinical Psychology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.M.); (D.P.R.C.)
| | - Daniela Pia Rosaria Chieffo
- Clinical Psychology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (L.M.); (D.P.R.C.)
- Department Women Children and Public Health, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Lucio Rinaldi
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giovanni Camardese
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Ilaria Cuomo
- ASL RM1, UOC SM Distretto XIII ASL Roma 1, CSM Via Boccea 271271, 00168 Rome, Italy;
| | - Roberto Brugnoli
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Georgios D. Kotzalidis
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Gabriele Sani
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Marianna Mazza
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.Go Agostino Gemelli 8, 00168 Rome, Italy; (T.C.); (S.M.); (F.B.); (S.B.); (S.R.); (R.C.); (G.M.); (S.M.); (A.B.); (L.L.G.); (D.S.); (A.Z.); (L.O.); (E.B.); (M.M.); (D.J.); (A.S.); (L.M.); (F.G.); (S.R.); (G.B.); (M.B.); (O.M.F.); (E.B.); (L.M.); (A.M.G.); (G.B.); (M.C.); (C.B.); (F.M.L.); (A.M.D.); (A.R.); (L.D.B.); (M.B.A.); (G.B.); (E.S.); (A.C.); (E.D.C.); (V.I.); (L.R.); (G.C.); (R.B.); (G.D.K.); (G.S.)
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
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Hart DA. Lithium Ions as Modulators of Complex Biological Processes: The Conundrum of Multiple Targets, Responsiveness and Non-Responsiveness, and the Potential to Prevent or Correct Dysregulation of Systems during Aging and in Disease. Biomolecules 2024; 14:905. [PMID: 39199293 PMCID: PMC11352090 DOI: 10.3390/biom14080905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 09/01/2024] Open
Abstract
Lithium is one of the lightest elements on Earth and it has been in the environment since the formation of the galaxy. While a common element, it has not been found to be an essential element in biological processes, ranging from single cell organisms to Homo sapiens. Instead, at an early stage of evolution, organisms committed to a range of elements such as sodium, potassium, calcium, magnesium, zinc, and iron to serve essential functions. Such ions serve critical functions in ion channels, as co-factors in enzymes, as a cofactor in oxygen transport, in DNA replication, as a storage molecule in bone and liver, and in a variety of other roles in biological processes. While seemingly excluded from a major essential role in such processes, lithium ions appear to be able to modulate a variety of biological processes and "correct" deviation from normal activity, as a deficiency of lithium can have biological consequences. Lithium salts are found in low levels in many foods and water supplies, but the effectiveness of Li salts to affect biological systems came to recent prominence with the work of Cade, who reported that administrating Li salts calmed guinea pigs and was subsequently effective at relatively high doses to "normalize" a subset of patients with bipolar disorders. Because of its ability to modulate many biological pathways and processes (e.g., cyclic AMP, GSK-3beta, inositol metabolism, NaK ATPases, neuro processes and centers, immune-related events, respectively) both in vitro and in vivo and during development and adult life, Li salts have become both a useful tool to better understand the molecular regulation of such processes and to also provide insights into altered biological processes in vivo during aging and in disease states. While the range of targets for lithium action supports its possible role as a modulator of biological dysregulation, it presents a conundrum for researchers attempting to elucidate its specific primary target in different tissues in vivo. This review will discuss aspects of the state of knowledge regarding some of the systems that can be influenced, focusing on those involving neural and autoimmunity as examples, some of the mechanisms involved, examples of how Li salts can be used to study model systems, as well as suggesting areas where the use of Li salts could lead to additional insights into both disease mechanisms and natural processes at the molecular and cell levels. In addition, caveats regarding lithium doses used, the strengths and weaknesses of rodent models, the background genetics of the strain of mice or rats employed, and the sex of the animals or the cells used, are discussed. Low-dose lithium may have excellent potential, alone or in combination with other interventions to prevent or alleviate aging-associated conditions and disease progression.
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Affiliation(s)
- David A Hart
- Department of Surgery, Faculty of Kinesiology, McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB T2N 4N1, Canada
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13
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Tondo L, Baldessarini RJ. Prevention of suicidal behavior with lithium treatment in patients with recurrent mood disorders. Int J Bipolar Disord 2024; 12:6. [PMID: 38460088 PMCID: PMC10924823 DOI: 10.1186/s40345-024-00326-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 02/02/2024] [Indexed: 03/11/2024] Open
Abstract
Suicidal behavior is more prevalent in bipolar disorders than in other psychiatric illnesses. In the last thirty years evidence has emerged to indicate that long-term treatment of bipolar disorder patients with lithium may reduce risk of suicide and attempts, with possibly similar benefits in recurrent major depressive disorder. We review and update selected research literature on effects of lithium treatment in reducing suicidal behavior and consider proposals that higher levels of lithium in drinking water may be associated with lower suicide rates. We summarize results of a growing number of randomized, controlled studies of lithium treatment for suicide prevention including comparisons with placebos or alternative treatments, and comment on the severe challenges of such trials. The basis of a proposed protective effect of lithium against suicidal behaviors remains uncertain but may include protective effects against recurrences of depressive phases of mood disorders, especially with mixed features or agitation, and possibly through beneficial effects on impulsivity, agitation and dysphoric mood.
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Affiliation(s)
- Leonardo Tondo
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
- International Consortium for Mood & Psychotic Disorder Research, McLean Hospital, Belmont, MA, USA.
- Lucio Bini Mood Disorder Centers, Centro Lucio Bini, 42 Via Crescenzio, Cagliari and Rome, 00193, Rome, Italy.
| | - Ross J Baldessarini
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- International Consortium for Mood & Psychotic Disorder Research, McLean Hospital, Belmont, MA, USA
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14
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Kotzalidis GD, Fiaschè F, Alcibiade A, Monti L, Di Segni F, Mazza M, Sani G. New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality. Expert Opin Pharmacother 2024; 25:435-446. [PMID: 38517222 DOI: 10.1080/14656566.2024.2334425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions. AREAS COVERED To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24-25 January 2024 using strategies like ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality. EXPERT OPINION Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.
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Affiliation(s)
- Georgios D Kotzalidis
- Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Fiaschè
- ASL RM1, Presidio Ospedaliero San Filippo Neri, Servizio Psichiatrico di Diagnosi e Cura, Rome, Italy
| | - Alessandro Alcibiade
- Marina Militare Italiana (Italian Navy), Defense Ministry of Italy, Rome, Italy
- Psychiatry Residency Training Programme, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Laura Monti
- UOS Clinical Psychology, Clinical Government, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Di Segni
- Psychiatry Residency Training Programme, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Marianna Mazza
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gabriele Sani
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Rome, Italy
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Iordache AM, Voica C, Roba C, Nechita C. Lithium Content and Its Nutritional Beneficence, Dietary Intake, and Impact on Human Health in Edibles from the Romanian Market. Foods 2024; 13:592. [PMID: 38397569 PMCID: PMC10888284 DOI: 10.3390/foods13040592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
Lithium (Li) is present in human nutrition based on food intake, and several studies recommend it for treating mood disorders, even if the biological proprieties and biochemical mechanisms represent the basis for its use as an essential element. The Li content was evaluated using the inductively coupled plasma mass spectrometry technique (ICP-MS) in 1071 food and beverage samples from the Romanian market. The results show that Li had a decreasing mean concentration in the food samples as follows: vegetables leafy > bulbous > fructose > leguminous > egg whites > root vegetables > milk products > egg yolks > meats. Approximately a quarter of all data from each dataset category was extreme values (range between the third quartile and maximum value), with only 10% below the detection limit. Mean Li concentration indicated higher values in red wine, white wines, beers, and fruit juice and lower in ciders and bottled waters. A particular interest was addressed to plants for teas and coffee seeds, which showed narrow amounts of Li. For both food and beverages, two similar matrices, including egg whites and yolks and white and red wines, were found to have significant differences, which explains the high variability of Li uptake in various matrices. For 99.65% of the analyzed samples, the estimated daily intake of Li was below the provisional subchronic and chronic reference dose (2 µg/kgbw/day) for adverse effects in several organs and systems. Even so, a risk occurs in consuming bulbous vegetables (Li > 13.47 mg/kg) and fructose solano vegetables (Li > 11.33 mg/kg). The present study's findings indicate that ingesting most of the analyzed beverages and food samples could be considered safe, even if future studies regarding Li content, nutritional aspects, and human cohort diseases must be conducted.
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Affiliation(s)
- Andreea Maria Iordache
- National Research and Development Institute for Cryogenics and Isotopic Technologies—ICSI Ramnicu Valcea, 4 Uzinei Street, 240050 Ramnicu Valcea, Romania;
| | - Cezara Voica
- National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103 Donat St., 400293 Cluj-Napoca, Romania
| | - Carmen Roba
- Faculty of Environmental Science and Engineering, Babes-Bolyai University, 30 Fântânele Street, 400294 400535 Cluj-Napoca, Romania;
| | - Constantin Nechita
- National Research and Development Institute for Forestry “Marin Drăcea”—INCDS, 128 Boulvard Eroilor, 077190 Voluntari, Romania
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16
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Dobosy P, Illés Á, Endrédi A, Záray G. Lithium concentration in tap water, bottled mineral water, and Danube River water in Hungary. Sci Rep 2023; 13:12543. [PMID: 37532748 PMCID: PMC10397251 DOI: 10.1038/s41598-023-38864-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 07/16/2023] [Indexed: 08/04/2023] Open
Abstract
Due to increased manufacture and recycling of lithium batteries across the world, we may anticipate a rise in lithium pollution in the aquatic environment and drinking water reservoirs. In order to investigate the current status regarding the lithium content in Hungarian tap waters, samples were collected from the public drinking water supply systems of 19 county seats in Hungary during seasonally selected times. Depending on the water sources, such as bank-filtrated river water, surface water from open reservoirs, and groundwater, the lithium concentrations varied between 0.90-4.23, 2.12-11.7 and 1.11-31.4 µg/L, respectively, while the median values were 3.52, 5.02 and 8.55 µg/L, respectively. The lithium concentration in the bottled Hungarian mineral waters was also determined since the daily intake of lithium can be influenced by the consumption of mineral waters. The concentrations ranged from 4.2 to 209 µg/L, while the median value was only 17.8 µg/L. Additionally, a correlation was only found between lithium and potassium concentrations. The lithium concentration was also assessed at ten sampling locations in the Hungarian segment of the Danube River since the Danube water is also a water source for additional drinking water utilities using bank filtration technology. The mean and median lithium concentrations were 2.78 and 2.64 µg/L, respectively.
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Affiliation(s)
- Péter Dobosy
- Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary
- National Laboratory for Water Science and Water Security, Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary
| | - Ádám Illés
- Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary
- National Laboratory for Water Science and Water Security, Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary
| | - Anett Endrédi
- Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary
| | - Gyula Záray
- Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary.
- National Laboratory for Water Science and Water Security, Institute of Aquatic Ecology, Centre for Ecological Research, Karolina út 29, Budapest, 1113, Hungary.
- Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, 1117, Hungary.
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17
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An investigation into the association between suicide mortality rate and lithium levels in potable water: a review study. Int Clin Psychopharmacol 2023; 38:73-80. [PMID: 36719336 DOI: 10.1097/yic.0000000000000432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
This study aimed to investigate the association between lithium levels in potable water and suicide mortality rates in the total inhabitants. We systematically searched Embase, PubMed/MEDLINE, Scopus, PubMed Central (PMC), Google Scholar databases, as well as medRxiv using the following keywords: drinking water, lithium, standardized mortality ratio (SMR), tap water, suicide, and ground water. Pearson regression analysis was used to test an association between variables with 95% confidence interval (CI). A value of P < 0.05 was considered significant. A total of 16 eligible articles were identified. Lithium concentrations in drinking water range from 0.4 to 32.9 μg/l. Average rates of suicide mortality (per 100 000 capita) range between 0.790 (±0.198) and 123 (±50). About 16 original studies confirmed the inverse relationship between lithium concentrations in potable water and suicide mortality rates (R = -0.576; R2 = 0.3323; 95% CI, -0.820 to -0.325; β = -0.3.2; P = 0.019). High lithium concentrations in potable water were associated with decreased suicide rates. We concluded that lithium concentration in potable water was inversely associated with suicide mortality rates among a total population. However, further research is required to clarify the relationship between lithium concentrations in drinking water and suicide rate.
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Duthie AC, Hannah J, Batty GD, Deary IJ, Starr JM, Smith DJ, Russ TC. Low-level lithium in drinking water and subsequent risk of dementia: Cohort study. Int J Geriatr Psychiatry 2023; 38:e5890. [PMID: 36747488 DOI: 10.1002/gps.5890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 01/31/2023] [Indexed: 02/08/2023]
Abstract
BACKGROUND Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. AIMS We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. METHOD Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. RESULTS The mean lithium level at all sampling sites was 1.45 μg/L (SD 1.83, range 0.5-18.2) and was 1.26 (SD 0.63, range 0.55-9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04-1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81-1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55-0.68 μg/L) in all deciles except the highest, corresponding with lithium levels 0.68-2.1 μg/L. CONCLUSIONS Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 μg/L.
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Affiliation(s)
| | | | - G David Batty
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
- Department of Epidemiology & Public Health, University College London, London, UK
| | - Ian J Deary
- Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, UK
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK
| | - John M Starr
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
- Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, UK
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK
| | - Daniel J Smith
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Tom C Russ
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
- Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, UK
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK
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19
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Freire C, Iribarne-Durán LM, Gil F, Olmedo P, Serrano-Lopez L, Peña-Caballero M, Hurtado-Suazo JA, Alvarado-González NE, Fernández MF, Peinado FM, Artacho-Cordón F, Olea N. Concentrations and predictors of aluminum, antimony, and lithium in breast milk: A repeated-measures study of donors. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 319:120901. [PMID: 36565913 DOI: 10.1016/j.envpol.2022.120901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
Aluminum (Al), antimony (Sb), and lithium (Li) are relatively common toxic metal(oid)s that can be transferred into breast milk and potentially to the nursing infant. This study assessed concentrations of Al, Sb, and Li in breast milk samples collected from donor mothers and explored the predictors of these concentrations. Two hundred forty-two pooled breast milk samples were collected at different times post-partum from 83 donors in Spain (2015-2018) and analyzed for Al, Sb, and Li concentrations. Mixed-effect linear regression was used to investigate the association of breast milk concentrations of these elements with the sociodemographic profile of the women, their dietary habits and utilization of personal care products (PCPs), the post-partum interval, and the nutritional characteristics of milk samples, among other factors. Al was detected in 94% of samples, with a median concentration of 57.63 μg/L. Sb and Li were detected in 72% and 79% of samples at median concentrations of 0.08 μg/L and 0.58 μg/L, respectively. Concentrations of Al, Sb, and Li were not associated with post-partum time. Al was positively associated with total lipid content of samples, weight change since before pregnancy, and coffee and butter intakes and inversely with meat intake. Li was positively associated with intake of chocolate and use of face cream and eyeliner and inversely with year of sample collection, egg, bread, and pasta intakes, and use of hand cream. Sb was positively associated with fatty fish, yoghurt, rice, and deep-fried food intakes and use of eyeliner and inversely with egg and cereal intakes and use of eyeshadow. This study shows that Al, Sb, and Li, especially Al, are widely present in donor breast milk samples. Their concentrations in the milk samples were most frequently associated with dietary habits but also with the lipid content of samples and the use of certain PCPs.
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Affiliation(s)
- Carmen Freire
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
| | | | - Fernando Gil
- Department of Legal Medicine, Toxicology and Physical Anthropology, University of Granada, 108016, Granada, Spain.
| | - Pablo Olmedo
- Department of Legal Medicine, Toxicology and Physical Anthropology, University of Granada, 108016, Granada, Spain.
| | - Laura Serrano-Lopez
- Neonatology Unit, Virgen de las Nieves University Hospital, 18014, Granada, Spain.
| | - Manuela Peña-Caballero
- Neonatology Unit, Virgen de las Nieves University Hospital, 18014, Granada, Spain; Human Milk Bank, Virgen de las Nieves University Hospital, 18012, Granada, Spain.
| | | | - Nelva E Alvarado-González
- Instituto Especializado de Análisis (IEA), Vicerrectoría de Investigación y Postgrado, Universidad de Panamá, Panama.
| | - Mariana F Fernández
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain; Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016, Granada, Spain.
| | - Francisco M Peinado
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain.
| | - Francisco Artacho-Cordón
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain; Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016, Granada, Spain.
| | - Nicolás Olea
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain; Department of Radiology and Physical Medicine, School of Medicine, University of Granada, 18016, Granada, Spain; Nuclear Medicine Unit, San Cecilio University Hospital, 18016, Granada, Spain.
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Toxic metals and essential elements contents in fruit juices and other non-alcoholic beverages from local markets in New Orleans, Louisiana. J Food Compost Anal 2023. [DOI: 10.1016/j.jfca.2023.105230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
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Fraga N, Benito D, Briaudeau T, Izagirre U, Ruiz P. Toxicopathic effects of lithium in mussels. CHEMOSPHERE 2022; 307:136022. [PMID: 36002063 DOI: 10.1016/j.chemosphere.2022.136022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/28/2022] [Accepted: 08/07/2022] [Indexed: 06/15/2023]
Abstract
The rising use of lithium (Li) in industrial processes, modern technology and medicine has generated concerns in the scientific community, in particular its potential impact on the environment. Unfortunately, there is only scarce information concerning the toxicity of lithium in marine organisms. The objective of this study is to determine the toxicity of Li using Mytilus galloprovincialis as model organism, based on acute and sublethal toxicity tests. In the first experiment, mussels were exposed for 9 days to a range of acute concentrations of Li (0, 2, 5, 13, 34, 89, 233 and 610 mg/L Li) in order to find the median lethal concentration. In the sublethal experiment, mussels were exposed to environmentally relevant concentrations of Li (0, 0.1, 1, 10 mg/L Li) for 21 days. Digestive gland and gonad samples were taken at day 0, 1, 7 and 21 for histopathological analysis. Samples of the whole mussels were taken for chemical analysis at day 0 and after 21 days. Results showed that M. galloprovincialis had a LC50 value of 153 mg/L Li after 9 days of exposure. Lower concentrations (environmentally relevant), led to Li bioaccumulation in a dose-dependent manner and histopathological effects in a time-dependent manner. Atrophy of the digestive alveoli epithelium and degeneration of the digestive gland were observed after 21 days of exposure. These findings open new perspectives for the understanding of the toxic effects of Li on marine organisms and evidence the need for further long-term research at different levels of biological organizations.
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Affiliation(s)
- Nadezhna Fraga
- CBET+ Research Group, Department of Zoology and Animal Cell Biology + One Health, Faculty of Science and Technology, University of the Basque Country (UPV-EHU), Sarriena Auzoa z/g, E-48940, Leioa-Bizkaia, Basque Country, Spain; Research Centre for Experimental Marine Biology and Biotechnology (PiE-UPV/EHU), University of the Basque Country (UPV/EHU), Areatza z/g, E-48620, Plentzia-Bizkaia, Basque Country, Spain
| | - Denis Benito
- CBET+ Research Group, Department of Zoology and Animal Cell Biology + One Health, Faculty of Science and Technology, University of the Basque Country (UPV-EHU), Sarriena Auzoa z/g, E-48940, Leioa-Bizkaia, Basque Country, Spain; Research Centre for Experimental Marine Biology and Biotechnology (PiE-UPV/EHU), University of the Basque Country (UPV/EHU), Areatza z/g, E-48620, Plentzia-Bizkaia, Basque Country, Spain
| | - Tifanie Briaudeau
- CBET+ Research Group, Department of Zoology and Animal Cell Biology + One Health, Faculty of Science and Technology, University of the Basque Country (UPV-EHU), Sarriena Auzoa z/g, E-48940, Leioa-Bizkaia, Basque Country, Spain; Research Centre for Experimental Marine Biology and Biotechnology (PiE-UPV/EHU), University of the Basque Country (UPV/EHU), Areatza z/g, E-48620, Plentzia-Bizkaia, Basque Country, Spain
| | - Urtzi Izagirre
- CBET+ Research Group, Department of Zoology and Animal Cell Biology + One Health, Faculty of Science and Technology, University of the Basque Country (UPV-EHU), Sarriena Auzoa z/g, E-48940, Leioa-Bizkaia, Basque Country, Spain; Research Centre for Experimental Marine Biology and Biotechnology (PiE-UPV/EHU), University of the Basque Country (UPV/EHU), Areatza z/g, E-48620, Plentzia-Bizkaia, Basque Country, Spain
| | - Pamela Ruiz
- CBET+ Research Group, Department of Zoology and Animal Cell Biology + One Health, Faculty of Science and Technology, University of the Basque Country (UPV-EHU), Sarriena Auzoa z/g, E-48940, Leioa-Bizkaia, Basque Country, Spain; Research Centre for Experimental Marine Biology and Biotechnology (PiE-UPV/EHU), University of the Basque Country (UPV/EHU), Areatza z/g, E-48620, Plentzia-Bizkaia, Basque Country, Spain.
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22
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Formation of lithium-selective sorbent in nanoreactors of the support based on titanium dioxide. APPLIED NANOSCIENCE 2022. [DOI: 10.1007/s13204-021-01832-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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23
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Rybakowski JK, Ferensztajn-Rochowiak E. Mini-review: Anomalous association between lithium data and lithium use. Neurosci Lett 2022; 777:136590. [PMID: 35346779 DOI: 10.1016/j.neulet.2022.136590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 01/14/2023]
Abstract
This mini-review aims to show a discrepancy between favorable data of lithium's therapeutic activity and the decreased use of the drug worldwide. The data point to lithium as the best mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most encouraging psychiatric use of lithium is the augmentation of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium is the most efficacious antisuicidal drug among all mood stabilizers. The drug also exerts antiviral, immunomodulatory, and neuroprotective effects which may be of major clinical value. On the other hand, the data of lithium use show that its therapeutic application in many countries has declined. A reason for this can be the introduction and heavy promotion of other mood-stabilizers, while lithium is an "orphan" drug with the minimal interest of any drug company. Probably, very important is also a perception of lithium as a "toxic drug", pointing to its side effects, mainly thyroid, renal and cognitive ones. In recent years, several proposals to turn back this anomalous association appeared, challenging a negative perception of lithium and optimizing its long-term administration. They show the data on lithium superiority over other mood stabilizers and point to the proper management of the lithium-induced side effects. This endeavor aims to allow a larger number of mood disorder patients to become beneficiaries of lithium use.
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Affiliation(s)
- Janusz K Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, 60-572 Poznan, ul. Szpitalna 27/33, Poland.
| | - Ewa Ferensztajn-Rochowiak
- Department of Adult Psychiatry, Poznan University of Medical Sciences, 60-572 Poznan, ul. Szpitalna 27/33, Poland
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24
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Araya P, Martínez C, Barros J. Lithium in Drinking Water as a Public Policy for Suicide Prevention: Relevance and Considerations. Front Public Health 2022; 10:805774. [PMID: 35252091 PMCID: PMC8891154 DOI: 10.3389/fpubh.2022.805774] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 01/24/2022] [Indexed: 12/07/2022] Open
Abstract
Although suicide is considered a major preventable cause of mortality worldwide, we do not have effective strategies to prevent it. Lithium has been consistently associated with lowering risk of suicide. This effect could occur at very low concentrations, such as trace doses of lithium in tap water. Several ecological studies and recent meta-analysis have suggested an inverse association between lithium in water and suicide in the general population, with a lack of knowledge of clinically significant side effects. This paper is aimed as a proposal to discuss the addition of lithium to drinking water to decrease the suicide rate. For this, we review the evidence available, use previous experiences, such as water fluoridation to prevent dental caries, and discuss the complexity involved in such a public policy. Considering the limited data available and the controversies contained in this proposal, we suggest that a consensus on lithium concentration in water is needed, where the suicide rates start to reduce, as happened with water fluoridation. This measure will require to develop community-controlled trials with strict monitoring of any side effects, where democratic procedures would constitute one of the most appropriate ways to validate its implementation according to the reality of each community.
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Affiliation(s)
- Pablo Araya
- Department of Escuela de Medicina PUC School of Medicine, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Camila Martínez
- Department of Escuela de Medicina PUC School of Medicine, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jorge Barros
- Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- *Correspondence: Jorge Barros
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25
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Investigation of the association between lithium levels in drinking water and suicide mortality in Hungary. J Affect Disord 2022; 298:540-547. [PMID: 34800573 DOI: 10.1016/j.jad.2021.11.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/13/2021] [Accepted: 11/14/2021] [Indexed: 01/16/2023]
Abstract
BACKGROUND In recent decades, a series of ecological studies from various countries have attempted to reveal whether there is an association between trace amounts of lithium in drinking water and suicide mortality. With some notable exceptions, results have indicated that there is an inverse association between these two variables. Since Hungary had extremely high rates of suicide with a persistent spatial pattern, we consider that our country is ideal to investigate this research question. METHODS We carried out our research on Hungarian data at the level of districts (n = 197). The dependent variable was the age- and gender-standardized mortality ratio for suicide (sSMR). Our main explanatory variable was the tap water lithium level (Li) from public drinking water supply systems using their own water source (n = 1 325). Those data, which give full national coverage, were aggregated to the level of districts. Confounding factors were religiosity, alcohol consumption and income. Various regression models were used for statistical calculations. RESULTS Findings from our most appropriate regression model - adjusted for relevant confounding variables and able to handle spatial autocorrelation and heteroscedasticity - suggest a significant (p < 0.05) and a trend-like (p < 0.1) negative association between Li and sSMR in the total population and among males, respectively. However, such an association was not found between these two variables among females. CONCLUSION In line with the majority of findings from other countries, our results indicate that the intake of lithium with drinking water may have a gender-dependent suicide-protective effect.
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26
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Mills J. Lithium: The Oldest-Known Metal in the Universe Can Prevent Suicide, and Nurses Should Be Using It More. Issues Ment Health Nurs 2022; 43:193-197. [PMID: 34797752 DOI: 10.1080/01612840.2021.1990584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Jeremy Mills
- Peninsula, a Division of Parkwest Medical Center, Knoxville, Tennessee, USA
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27
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Baranowski RW, Skelly LE, Josse AR, Fajardo VA. Exploring the Effects of Greek Yogurt Supplementation and Exercise Training on Serum Lithium and Its Relationship With Musculoskeletal Outcomes in Men. Front Nutr 2022; 8:798036. [PMID: 35004824 PMCID: PMC8729320 DOI: 10.3389/fnut.2021.798036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/23/2021] [Indexed: 11/13/2022] Open
Abstract
Dairy products can act as a dietary source of lithium (Li), and a recent study in university-aged males demonstrated that Greek yogurt (GY) supplementation augmented gains in fat free mass, strength and bone formation after 12 weeks of resistance exercise training compared to carbohydrate (CHO) pudding supplementation. Here, we performed secondary analyses to explore whether GY would alter serum Li levels and whether changes in serum Li would associate with changes in body composition, strength, and bone turnover markers. Results show that the GY group maintained serum Li levels after exercise training, whereas the CHO group did not. Maintaining/elevating serum Li levels was also associated with greater gains in strength and reductions in bone resorption. However, controlling for other dietary factors in GY such as protein and calcium weakened these associations. Thus, future studies should assess the causative role, if any, of dietary Li alone on strength and bone resorption in humans.
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Affiliation(s)
- Ryan W Baranowski
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada.,Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
| | - Lauren E Skelly
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, ON, Canada
| | - Andrea R Josse
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada.,Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada.,School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, ON, Canada
| | - Val A Fajardo
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada.,Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
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28
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Izumi T, Kanehisa M, Terao T, Shiotsuki I, Shirahama M, Satoh M, Muronaga M, Kohno K, Hirakawa H, Etoh M, Matsukawa T. Naturally absorbed lithium may prevent suicide attempts and deliberate self-harm while eicosapentaenoic acid may prevent deliberate self-harm and arachidonic acid may be a risk factor for deliberate self-harm: The updated different findings in new analyses. Front Psychiatry 2022; 13:1083739. [PMID: 36590619 PMCID: PMC9802576 DOI: 10.3389/fpsyt.2022.1083739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Since our previous investigation on the effects of trace lithium, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) on deliberate self-harm and suicide attempts in 2018, to our knowledge, no replication study has been conducted on this topic. SUBJECTS AND METHODS We increased 37 new patients and totally 234 patients were re-analyzed to further investigate the association of suicide-related behaviors with levels of trace lithium, EPA, DHA, and AA in a different way to avoid multicollinearity. RESULTS Higher lithium levels were significantly associated with fewer suicide attempts and deliberate self-harm, higher EPA levels were significantly associated with fewer deliberate self-harm, and higher AA levels were significantly associated with more deliberate self-harm. DISCUSSION Although the sample size was only slightly larger than the previous study, the present results were clearly different from the previous ones due to the use of different statistical analyses to avoid multicollinearity. CONCLUSION The present findings suggest that naturally absorbed lithium may protect against suicide and deliberate self-harm, while naturally absorbed EPA may protect against deliberate self-harm. However, naturally absorbed AA may be a risk factor for deliberate self-harm.
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Affiliation(s)
- Toshihiko Izumi
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | | | - Takeshi Terao
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | - Ippei Shiotsuki
- Psychiatric Medical Center, Oita Prefectural Hospital, Oita, Japan
| | | | - Moriaki Satoh
- Psychiatric Medical Center, Oita Prefectural Hospital, Oita, Japan
| | - Masaaki Muronaga
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | - Kentaro Kohno
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | - Hirofumi Hirakawa
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | - Masaki Etoh
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan
| | - Takehisa Matsukawa
- Department of Epidemiology and Environmental Health, Juntendo University School of Medicine, Tokyo, Japan.,Department of Forensic Medicine, Juntendo University School of Medicine, Tokyo, Japan
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29
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Naeem A, Aslam M, Mühling KH. Lithium: Perspectives of nutritional beneficence, dietary intake, biogeochemistry, and biofortification of vegetables and mushrooms. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 798:149249. [PMID: 34329936 DOI: 10.1016/j.scitotenv.2021.149249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 06/13/2023]
Abstract
Although lithium (Li) is not an essential nutrient for humans, low Li intakes are associated with increased suicide and homicide rates, aggressive behaviors, unipolar/bipolar disorders, acute mania, etc. On the other hand, Li is one of the most effective psychopharmacological agents used for the treatment of these psycho-behavioral disorders. The beneficial normothymic effect of Li could be achieved at lower doses, therefore, modern psychiatry has called to consider Li biofortification of foods to improve its dietary intake. The concept of agronomic biofortification of crops with Li is juvenile and there exist a limited number of studies, mainly focused on vegetables or mushrooms. This review, first of its kind, discusses the nutritional beneficence and dietary intake of Li, its biogeochemistry, and opportunities and challenges in the Li biofortification of food crops. Literature showed that dietary intake of Li in many countries of the world is insufficient, compared to the provisional recommended dietary allowance (RDA) of 1.0 mg day-1 for a 70 kg adult. Lithium contents of soils are widely variable and the metal has high mobility in soils, making it more prone to leaching, and available for plant uptake. Biofortification studies reveal that plants can accumulate significant quantities of Li in their edible tissues without yield loss and quality associated negative effects. At lower application rates, Li tissue concentration could reach to the level that consuming 100-200 g of Li-biofortified fresh vegetables or mushrooms could support its RDA. It seems impossible to enrich the plants with Li to the levels that allow their application in psychiatric treatments, which requires the dosage of 600-1200 mg day-1. However, there is need to refine the methods of Li biofortification strategies to obtains plant specific concentration of Li in edible parts so that consuming a specific amount could provide the proposed dietary intake requirement.
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Affiliation(s)
- Asif Naeem
- Institute for Plant Nutrition and Soil Science, Kiel University, Hermann Rodewald Strasse 2, D-24118 Kiel, Germany; Nuclear Institute for Agriculture and Biology (NIAB), Jhang Road, 38000 Faisalabad, Pakistan
| | - Muhammad Aslam
- Nuclear Institute for Agriculture and Biology (NIAB), Jhang Road, 38000 Faisalabad, Pakistan
| | - Karl H Mühling
- Institute for Plant Nutrition and Soil Science, Kiel University, Hermann Rodewald Strasse 2, D-24118 Kiel, Germany.
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30
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31
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Kabzińska K, Cisek-Woźniak A, Czajeczny D, Mruczyk K, Wójciak RW. The influence of Li + ions on pepsin and trypsin activity in vitro. J Trace Elem Med Biol 2021; 66:126763. [PMID: 33915410 DOI: 10.1016/j.jtemb.2021.126763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 02/16/2021] [Accepted: 04/14/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The paper presents a study on the influence of different lithium carbonate and lithium citrate concentration on proteolytic enzymes, namely pepsin and trypsin, in vitro. Lithium can directly affect enzyme activity. Its influence on many bodily functions in both ill and healthy people has been proven. METHODS To assess the influence of Li+ ions concentration and the substrate/enzyme ratio on pepsin and trypsin activity in vitro, 60 factorial experiments were conducted (each repeated 30 times). MAIN FINDINGS For both enzymes, statistically significant changes in their activity under the influence of lihium carbonate and lithium citrate were observed. The biggest increase in enzyme activity reached even 198.6 % and the largest decrease in enzyme activity reached about 50 %. CONCLUSIONS The study shows that both organic and inorganic forms of lithium salts cause changes in the activity of digestive enzymes. Different concentrations of lithium carbonate and lithium citrate stimulate or inhibit the activity of trypsin and pepsin.
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Affiliation(s)
- Karolina Kabzińska
- Department of Clinical Psychology, Poznan University of Medical Sciences, Poland.
| | | | - Dominik Czajeczny
- Department of Clinical Psychology, Poznan University of Medical Sciences, Poland
| | - Kinga Mruczyk
- Department of Dietetics, Poznan University of Physical Education, Poland
| | - Rafał W Wójciak
- Department of Clinical Psychology, Poznan University of Medical Sciences, Poland
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32
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Liaugaudaite V, Naginiene R, Raskauskiene N, Mickuviene N, Bunevicius A, Sher L. Relationship between Lithium Levels in Drinking Water and Suicide Rates: A Nationwide Study in Lithuania. Arch Suicide Res 2021; 25:340-352. [PMID: 31596179 DOI: 10.1080/13811118.2019.1674226] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
To investigate an association of lithium levels in the drinking water with suicide mortality rates in Lithuania. Methods: Samples from public drinking water systems were taken in all districts of Lithuania. Lithium levels were determined using the ion chromatography method. For the statistical calculations, lithium levels were averaged per district municipality and plotted against suicide standardized mortality rates (SMR) per 100,000 populations, within the 5-year period from 2012 to 2016. Results: We found that lithium concentrations in drinking water were significantly negatively associated with total suicide rates in a nonlinear way. Conclusion: Lithium intake with drinking water may affect suicide rates in some geographical areas.
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33
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Position sensitive measurement of trace lithium in the brain with NIK (neutron-induced coincidence method) in suicide. Sci Rep 2021; 11:6823. [PMID: 33767316 PMCID: PMC7994404 DOI: 10.1038/s41598-021-86377-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/15/2021] [Indexed: 12/22/2022] Open
Abstract
Mood disorder is the leading intrinsic risk factor for suicidal ideation. Questioning any potency of mood-stabilizers, the monovalent cation lithium still holds the throne in medical psychiatric treatment. Furthermore, lithium`s anti-aggressive and suicide-preventive capacity in clinical practice is well established. But little is still known about trace lithium distribution and any associated metabolic effects in the human body. We applied a new technique (neutron-induced coincidence method “NIK”) utilizing the 6Li(n,α)3H reaction for the position sensitive, 3D spatially resolved detection of lithium traces in post-mortem human brain tissue in suicide versus control. NIK allowed, for the first time in lithium research, to collect a three dimensional high resolution map of the regional trace lithium content in the non lithium-medicated human brain. The results show an anisotropic distribution of lithium, thus indicating a homeostatic regulation under physiological conditions as a remarkable link to essentiality. In contrast to suicide we could empirically prove significantly higher endogenous lithium concentrations in white compared to gray matter as a general trend in non-suicidal individuals and lower lithium concentrations in emotion-modulating regions in suicide.
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34
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Eyre-Watt B, Mahendran E, Suetani S, Firth J, Kisely S, Siskind D. The association between lithium in drinking water and neuropsychiatric outcomes: A systematic review and meta-analysis from across 2678 regions containing 113 million people. Aust N Z J Psychiatry 2021; 55:139-152. [PMID: 33045847 DOI: 10.1177/0004867420963740] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Lithium in drinking water may have significant mental health benefits. We investigated the evidence on the association between lithium concentrations in drinking water and their neuropsychiatric outcomes. METHODS We conducted a systematic review and meta-analysis and searched Pubmed, Embase, Web of Science, PsycINFO and CINAHL up to 19 January 2020, for peer-reviewed research examining the association between lithium concentrations in drinking water and neuropsychiatric outcomes. We used a pairwise analysis and a random effects model to meta-analyse suicide rates and psychiatric hospital admissions. We assessed for publication bias using Egger's test and Duval and Tweedie's Trim and Fill analysis. RESULTS Twenty-seven studies including 113 million subjects were included in this systematic review. Meta-analysis of 14 studies including 94 million people found higher lithium concentrations were associated with reduced suicide rates (r = -0.191, 95% confidence interval = [-0.287, -0.090], p < 0.001) and meta-analysis of two studies including 5 million people found higher lithium concentrations were associated with fewer hospital admissions (r = -0.413, 95% confidence interval = [-0.689, -0.031], p = 0.035). We found significant heterogeneity between studies (Q = 67.4, p < 0.001, I2 = 80.7%) and the presence of publication bias (Egger's test; t value = 2.90, p = 0.013). Other included studies did not provide sufficient data to analyse other neuropsychiatric outcomes quantitatively. CONCLUSION Higher lithium concentrations in drinking water may be associated with reduced suicide rates and inpatient psychiatric admissions. The relationship with other neuropsychiatric outcomes and complications remains unclear. Further research is required before any public health recommendations can be made.Trial registration number: The study was registered with PROSPERO, number CRD42018090145.
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Affiliation(s)
| | | | - Shuichi Suetani
- School of Medicine, Griffith University, Southport, QLD, Australia.,Metro South Mental Health and Addiction Services, Brisbane, QLD, Australia.,Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD, Australia.,Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
| | - Joseph Firth
- NICM Health Research Institute, School of Science and Health, Western Sydney University, Sydney, Australia.,Division of Psychology and Mental Health, University of Manchester, Manchester, UK
| | - Steve Kisely
- Metro South Mental Health and Addiction Services, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Dan Siskind
- Metro South Mental Health and Addiction Services, Brisbane, QLD, Australia.,Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD, Australia.,School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
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35
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Kugimiya T, Ishii N, Kohno K, Kanehisa M, Hatano K, Hirakawa H, Terao T. Lithium in drinking water and suicide prevention: The largest nationwide epidemiological study from Japan. Bipolar Disord 2021; 23:33-40. [PMID: 32780508 DOI: 10.1111/bdi.12983] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The aims of the present study thus were (a) to further investigate the association between lithium levels in drinking water and suicide rates by adjusting relevant factors using the so far largest available dataset in Japan, (b) to confirm sex differences, (c) to estimate the effects of long-term exposure to trace lithium, (d) to investigate the effects of drinking bottled instead of tap water, and (e) to exploratorily investigate which lithium levels may be associated with lower suicide rates. METHODS Mean lithium levels in drinking water of all 808 cities and wards (ie, 785 cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to mean suicide standardized mortality ratios (SMRs) during the 7 years from 2010 to 2016. Multiple regression analyses adjusted for the size of each population were used to investigate the association of lithium levels with suicide SMRs with adjustments for relevant factors. RESULTS The adjusted model showed significant inverse associations of lithium levels with total and male SMRs, but not with female SMRs. Neither the proportion of residents who continued to live in the same city nor the consumption of bottled water changed the association between lithium levels and suicide SMRs. Finally, it was 30 μg/L or more that was associated with lower suicide SMRs. CONCLUSIONS The present findings reconfirm the inverse association between lithium levels in drinking water and suicide rates particularly in the male population.
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Affiliation(s)
- Tsuyoshi Kugimiya
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Nobuyoshi Ishii
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Kentaro Kohno
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Masayuki Kanehisa
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Koji Hatano
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Hirofumi Hirakawa
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
| | - Takeshi Terao
- Department of Neuropsychiatry, Oita University Faculty of Medicine, Yufu city, Japan
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López Steinmetz LC, López Steinmetz RL, Diaz SL, Godoy JC. Lithium in drinking water, altitude, and suicide rates in rural areas of Argentinean Andes. Spat Spatiotemporal Epidemiol 2021; 36:100393. [PMID: 33509433 DOI: 10.1016/j.sste.2020.100393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 11/07/2020] [Accepted: 11/16/2020] [Indexed: 10/22/2022]
Abstract
The Lithium Triangle in the Andean plateau involves high altitude (>3,000 m asl) hydrological systems having high lithium graded waters. This research was carried-out in rural areas of north westernmost Argentinean Andes and was aimed: 1) to determine concentrations of lithium in drinking waters; 2) to calculate suicide mortality rates based on available official data (2003-2013); 3) to analyze bivariate differences between lithium concentrations in drinking water, mean rates of suicide mortality, altitude of sampling sites, and water sources; 4) to analyze bivariate correlations between lithium concentrations in drinking water, mean rates of suicide mortality, and altitude; 5) to test predictive models for mean rates of suicide mortality, when considering the predictors lithium concentrations in drinking water, altitude, and water sources. Lithium determinations in drinking waters were performed by Microwave Plasma-Atomic Emission Spectrometer. Nonparametric tests were applied to analyze differences and correlations. Generalized linear models (GLM) were used to fitting models for mean rates of suicide. Drinking waters contained up to 2.98 mg L-1 of lithium. Mean rates of suicide mortality (per 100,000 inhabitants) were high, ranging from 19.12 (± 19.83) to 30.22 (± 16.70). Lithium but not altitude was positively correlated with suicide mortality when analyzing bivariate correlations (Li: rho = 0.76, p-value < 0.001). However, when GLM were calculated, a significant interaction effect was found between lithium and altitude (p-value < 0.001). This interaction effect would act in some way restraining the suicide mortality rates.
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Affiliation(s)
- Lorena Cecilia López Steinmetz
- Instituto de Investigaciones Psicológicas (IIPsi), Facultad de Psicología, Universidad Nacional de Córdoba, Boulevard de la Reforma esquina Enfermera Gordillo s/n, Ciudad Universitaria, Córdoba X5000, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Universidad Siglo 21, Sede Campus, Boulevard de los Alemanes s/n, Córdoba 5000, Argentina.
| | - Romina Lucrecia López Steinmetz
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Instituto de Ecorregiones Andinas (INECOA-UNJu-CONICET) and Instituto de Geología y Minería, Universidad Nacional de Jujuy, Av. Bolivia 1661, Jujuy 4600, Argentina.
| | - Silvina Laura Diaz
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; Instituto de Biología Celular y Neurociencia Prof. E de Robertis (IBCN), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, piso3, Ciudad Autónoma de Buenos Aires C1121ABG, Argentina.
| | - Juan Carlos Godoy
- Instituto de Investigaciones Psicológicas (IIPsi), Facultad de Psicología, Universidad Nacional de Córdoba, Boulevard de la Reforma esquina Enfermera Gordillo s/n, Ciudad Universitaria, Córdoba X5000, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
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Memon A, Rogers I, Fitzsimmons SMDD, Carter B, Strawbridge R, Hidalgo-Mazzei D, Young AH. Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies. Br J Psychiatry 2020; 217:667-678. [PMID: 32716281 DOI: 10.1192/bjp.2020.128] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The prevalence of mental health conditions and national suicide rates are increasing in many countries. Lithium is widely and effectively used in pharmacological doses for the treatment and prevention of manic/depressive episodes, stabilising mood and reducing the risk of suicide. Since the 1990s, several ecological studies have tested the hypothesis that trace doses of naturally occurring lithium in drinking water may have a protective effect against suicide in the general population. AIMS To synthesise the global evidence on the association between lithium levels in drinking water and suicide mortality rates. METHOD The MEDLINE, Embase, Web of Science and PsycINFO databases were searched to identify eligible ecological studies published between 1 January 1946 and 10 September 2018. Standardised regression coefficients for total (i.e. both genders combined), male and female suicide mortality rates were extracted and pooled using random-effects meta-analysis. The study was registered with PROSPERO (CRD42016041375). RESULTS The literature search identified 415 articles; of these, 15 ecological studies were included in the synthesis. The random-effects meta-analysis showed a consistent protective (or inverse) association between lithium levels/concentration in publicly available drinking water and total (pooled β = -0.27, 95% CI -0.47 to -0.08; P = 0.006, I2 = 83.3%), male (pooled β = -0.26, 95% CI -0.56 to 0.03; P = 0.08, I2 = 91.9%) and female (pooled β = -0.13, 95% CI -0.24 to -0.02; P = 0.03, I2 = 28.5%) suicide mortality rates. A similar protective association was observed in the six studies included in the narrative synthesis, and subgroup meta-analyses based on the higher/lower suicide mortality rates and lithium levels/concentration. CONCLUSIONS This synthesis of ecological studies, which are subject to the ecological fallacy/bias, supports the hypothesis that there is a protective (or inverse) association between lithium intakes from public drinking water and suicide mortality at the population level. Naturally occurring lithium in drinking water may have the potential to reduce the risk of suicide and may possibly help in mood stabilisation, particularly in populations with relatively high suicide rates and geographical areas with a greater range of lithium concentration in the drinking water. All the available evidence suggests that randomised community trials of lithium supplementation of the water supply might be a means of testing the hypothesis, particularly in communities (or settings) with demonstrated high prevalence of mental health conditions, violent criminal behaviour, chronic substance misuse and risk of suicide.
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Affiliation(s)
- Anjum Memon
- Department of Primary Care and Public Health, Brighton and Sussex Medical School, UK
| | - Imogen Rogers
- Department of Primary Care and Public Health, Brighton and Sussex Medical School, UK
| | | | - Ben Carter
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
| | - Rebecca Strawbridge
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
| | - Diego Hidalgo-Mazzei
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Bipolar and Depressive Disorders Unit, Department of Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic de Barcelona, IDIBAPS, CIBERSAM, Spain
| | - Allan H Young
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
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Sudo M, Hashimoto K, Yoshinaga M, Azimi MD, Fayaz SH, Hamajima N, Kondo-Ida L, Yanagisawa K, Kato M. Lithium promotes malignant transformation of nontumorigenic cells in vitro. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 744:140830. [PMID: 32721671 DOI: 10.1016/j.scitotenv.2020.140830] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/11/2020] [Accepted: 07/07/2020] [Indexed: 06/11/2023]
Abstract
Because of the deficiency of water caused by the regional disparities of rainfall due to global warming, attention has been given to the use of well water as drinking water in developing countries. Our fieldwork study in Afghanistan showed that there was a maximum value of 3371 μg/L and an average value of 233 μg/L of lithium in well drinking water. Since the level of lithium in well water is higher than the levels in other countries, we investigated the health risk of lithium. After confirming no influence of ≤1000 μM lithium on cell viability, we found that lithium at concentrations of 100 and 500 μM promoted anchorage-independent growth of human immortalized keratinocytes (HaCaT) and lung epithelial cells (BEAS-2B) but not that of human keratinocytic carcinoma cells (HSC-5) or lung epithelial carcinoma cells (A549). The same concentrations of lithium also promoted phosphorylation of c-SRC and MEK/ERK but not that of AKT in the keratinocytes. Inhibitors of c-SRC (PP2) and MEK (PD98059) suppressed the lithium-induced increase in anchorage-independent growth of the keratinocytes. Our results suggested that lithium promoted transformation of nontumorigenic cells rather than progression of tumorigenic cells with preferential activation of the c-SRC/MEK/ERK pathway. Since previous pharmacokinetics studies indicated that it is possible for the serum level of lithium to reach 100 μM by drinking 2.5 L of water containing 3371 μg/L of lithium per day, the high level of lithium contamination in well drinking water in Kabul might be a potential oncogenic risk in humans.
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Affiliation(s)
- Makoto Sudo
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazunori Hashimoto
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Voluntary Body, International Health Care in Universities, Nagoya, Japan
| | - Masafumi Yoshinaga
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mohammad Daud Azimi
- Department of Human Resources, Ministry of Public Health, Kabul, Afghanistan
| | - Said Hafizullah Fayaz
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Administrative Office of the President, Deputy Public Relations and Outreach, Kabul, Afghanistan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Lisa Kondo-Ida
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Molecular and Cancer Medicine, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Kiyoshi Yanagisawa
- Department of Molecular and Cancer Medicine, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Masashi Kato
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Voluntary Body, International Health Care in Universities, Nagoya, Japan; Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan.
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Lithium in Portuguese Bottled Natural Mineral Waters-Potential for Health Benefits? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17228369. [PMID: 33198207 PMCID: PMC7696288 DOI: 10.3390/ijerph17228369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/23/2020] [Accepted: 11/08/2020] [Indexed: 11/17/2022]
Abstract
There is increasing epidemiologic and experimental evidence that lithium (Li) exhibits significant health benefits, even at concentrations lower than the therapeutic oral doses prescribed as treatment for mental disorders. The aim of this study is to determine the content of Li in 18 brands of bottled natural mineral waters that are available on the Portuguese market and from which the sources are found within the Portuguese territory, to provide data for Li intake from drinking water. Analyses of Li were performed by inductively coupled plasma-mass spectrometry. The results indicate highly different Li concentrations in natural mineral waters: one group with low Li concentrations (up to 11 µg Li/L) and a second group with Li concentrations higher than 100 µg/L. The highest Li concentrations (>1500 µg Li/L) were observed in the highly mineralized Na-HCO3 type waters that are naturally carbonated (>250 mg/L free CO2). As a highly bioavailable source for Li dietary intake these natural mineral waters have potential for Li health benefits but should be consumed in a controlled manner due to its Na and F− contents. The consumption of as little as 0.25 L/day of Vidago natural mineral water (2220 µg Li/L), can contribute up to 50% of the proposed daily requirement of 1 mg Li/day for an adult (70 kg body weight). In future, Li epidemiological studies that concern the potential Li effect or health benefits from Li in drinking water should consider not only the Li intake from tap water but also intake from natural mineral water that is consumed in order to adjust the Li intake of the subjects.
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Abstract
OBJECTIVES A narrative review of past, present, and future of lithium use in psychiatry. METHODS The most important references on the topic were reviewed with special emphasis on the author's works. RESULTS The history of medical and psychiatric use of lithium dates back to more than one and a half-century ago. However, modern psychiatric history began with the publication of John Cade, in 1949, showing a therapeutic effect of lithium in mania. Currently, lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of the bipolar disorder. The second most important use of lithium is probably augmentation of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts anti-suicidal, immunomodulatory, and neuroprotective action. The drug may protect against dementia and some promising effects of lithium in neurodegenerative disorders have been observed. CONCLUSION Given the clinical and biological properties of lithium, this drug is presently greatly underutilized in mood disorders. Therefore, the efforts should be undertaken for challenging a skepticism about the use of lithium and optimizing its long-term administration. In such a way, more patients with mood disorders can become the beneficiaries of lithium's therapeutic action. KEY POINTS Lithium is a drug of choice as a mood-stabiliser for the maintenance treatment of bipolar disorder. Augmentation of antidepressants by lithium is one of the best strategies in treatment-resistant depression. Lithium exerts anti-suicidal, immunomodulatory, and neuroprotective action and may protect against dementia. Despite the evidence for the efficacy and added favourable properties, lithium is greatly underutilised in mood disorders. Challenging a scepticism about the use of lithium and optimising its long-term administration can make more patients with mood disorders the beneficiaries of lithium's therapeutic action.
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Affiliation(s)
- Janusz K Rybakowski
- Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.,Department of Psychiatric Nursing, Poznan University of Medical Sciences, Poznan, Poland
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Barroilhet SA, Ghaemi SN. When and how to use lithium. Acta Psychiatr Scand 2020; 142:161-172. [PMID: 32526812 DOI: 10.1111/acps.13202] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/30/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Lithium is an old proven medication, but it is infrequently used in current practice. This review examines evidence for its benefits and risks and provides clinical guidance to its use. METHOD Narrative review. RESULTS Besides its benefit in bipolar illness, lithium has important underappreciated proven benefits in prevention of unipolar depression and suicide. Emerging data support neurobiological benefits for cognition and possible dementia prevention. Likely benefits also exist in low doses for mood temperaments (cyclothymia and hyperthymia). High doses (over 1.0 mmol/L) should be avoided since they increase side effects, complications associated with long-term use, and risk of toxicity. Conversely, low dosing can be legitimate, especially for suicide and dementia prevention. Nuisance side effects of lithium may affect adherence, and medically serious side-effects can occur. Managing strategies are available for side effects. CONCLUSION Lithium is the most effective medication in psychiatry, because it has disease-modifying, not just symptomatic, effects. It is effective not only for bipolar illness but also for prevention of suicide, episodes of unipolar depression, mood temperaments, and possibly dementia. Its many benefits need better appreciation, while lowered dosing can reduce risks.
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Affiliation(s)
- S A Barroilhet
- Psychiatry, Faculty of Medicine, University Psychiatric Clinic, University of Chile, Santiago, Chile.,Psychiatry, Tufts University School of Medicine, Boston, MA, USA
| | - S N Ghaemi
- Psychiatry, Tufts University School of Medicine, Boston, MA, USA.,Psychiatry, Harvard Medical School, Boston, MA, USA
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Del Matto L, Muscas M, Murru A, Verdolini N, Anmella G, Fico G, Corponi F, Carvalho AF, Samalin L, Carpiniello B, Fagiolini A, Vieta E, Pacchiarotti I. Lithium and suicide prevention in mood disorders and in the general population: A systematic review. Neurosci Biobehav Rev 2020; 116:142-153. [PMID: 32561344 DOI: 10.1016/j.neubiorev.2020.06.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/06/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023]
Abstract
Suicide contributes to 1-4 % of deaths worldwide every year. We conducted a systematic review aimed at summarizing evidence on the use of lithium for the prevention of suicide risk both in mood disorders and in the general population. We followed the PRISMA methodology (keywords: "lithium", "suicide" AND "suicidal" on Pubmed, Cochrane CENTRAL, Clinicaltrial.gov, other databases). Inclusion criteria: lithium therapy in mood disorder or found in drinking water or scalp in the general population. Exclusion criteria: no lithium administration. From 918 screened references, 18 prospective (number of participants: 153786), 10 retrospective (number of participants: 61088) and 16 ecological studies (total sample: 2062) were included. Most of the observational studies reported a reduction in suicide in patients with mood disorders. All studies about lithium treatment's duration reported that long-term lithium give more benefits than short-term lithium in suicide risk The evidence seems to attribute an intrinsic anti-suicidal property of lithium, independent of its proven efficacy as a mood stabilizer.
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Affiliation(s)
- L Del Matto
- Department of Molecular Medicine, University of Siena School of Medicine and Department of Mental Health, University of Siena Medical Center (AOUS), Viale Mario Bracci 16, 53100, Siena, Italy
| | - M Muscas
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy
| | - A Murru
- Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain
| | - N Verdolini
- Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain
| | - G Anmella
- Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain
| | - G Fico
- Department of Psychiatry, University of Campania Luigi Vanvitelli, Largo Madonna delle Grazie, 80139, Naples, Italy
| | - F Corponi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - A F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre of Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - L Samalin
- CHU Clermont-Ferrand, Department of Psychiatry, EA 7280, Clermont-Ferrand University, Clermont-Ferrand, France
| | - B Carpiniello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Italy
| | - A Fagiolini
- Department of Molecular Medicine, University of Siena School of Medicine and Department of Mental Health, University of Siena Medical Center (AOUS), Viale Mario Bracci 16, 53100, Siena, Italy
| | - E Vieta
- Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain.
| | - I Pacchiarotti
- Bipolar Disorders and Depressive Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, iDiBAPS, CiBeRSAM, Barcelona, Catalonia, Spain
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Plasma Lithium Levels in a General Population: A Cross-Sectional Analysis of Metabolic and Dietary Correlates. Nutrients 2020; 12:nu12082489. [PMID: 32824874 PMCID: PMC7468710 DOI: 10.3390/nu12082489] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
Initial evidence suggests that lithium might affect life expectancy and the risk for different disease conditions, but most studies were conducted in patients on lithium medication. Little is known about the association of blood lithium levels within the physiological range with cardiometabolic risk factors and diet. We measured plasma lithium in a community-based sample from Northern Germany (samples taken between 2010 and 2012). All participants (aged 25-82 years) underwent standardized examinations and completed a semi-quantitative food frequency questionnaire. Of several variables tested, the estimated glomerular filtration rate (eGFR) was statistically significantly (inversely) associated with lithium levels, mainly in individuals with slightly impaired renal function (eGFR < 75 mL/min/1.73 m2). Besides, lithium levels were positively associated with age and alcohol intake. Using reduced rank regression, we identified a dietary pattern explaining 8.63% variation in plasma lithium levels. Higher lithium levels were associated with higher intakes of potatoes, leafy vegetables, root vegetables, fruits, tea, beer, wine and dietetic products and lower intakes of pasta, rice, pork, chocolate, sweets, soft drinks, other alcoholic beverages, sauces and snacks. Our observations suggest that plasma lithium levels are associated inversely with kidney function, particularly in individuals with slightly impaired renal function, and positively with age and alcohol intake. Lithium at physiological levels was moderately related to an exploratory dietary pattern.
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Kozaka N, Takeuchi S, Ishii N, Terao T, Kuroda Y. Association between lithium in tap water and suicide mortality rates in Miyazaki Prefecture. Environ Health Prev Med 2020; 25:26. [PMID: 32593289 PMCID: PMC7321541 DOI: 10.1186/s12199-020-00865-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
Background Most studies have reported that suicide mortality rates are negatively associated with lithium levels in tap water; however, a few studies showed either no association or a positive association. Thus, the association between suicide mortality and lithium levels in tap water remains controversial. To clarify the association, our study evaluated the association between lithium levels in tap water and suicide mortality rates in Miyazaki Prefecture of Japan, after adjusting for confounding factors. Methods We measured lithium levels in tap water across the 26 municipalities of Miyazaki Prefecture in Japan. We examined the standardized mortality ratio (SMR) for suicide in each municipality and used the data as the average suicide SMRs over 5 years (2009–2013). Weighted least-squares regression analysis, adjusted for the size of each municipality’s population, was used to investigate the association between lithium levels in tap water and suicide SMRs. In addition to a crude model, in an adjusted model, potential confounding factors (proportion of elderly people, proportion of one-person households, annual marriage rate, annual mean income, unemployment rate, the density of medical doctors per 100,000 people, annual total rainfall, and proportion of people with a college education or higher) were added as covariates. Results We showed that male and female suicide SMRs were not associated with lithium levels in tap water in Miyazaki Prefecture. After adjusting for confounders, male suicide SMRs were significantly and positively associated with the proportion of elderly people in the population and annual total rainfall, and female suicide SMRs were associated with the proportion of elderly people in the population. Conclusions No association between lithium levels in tap water and suicide mortality rates was found in Miyazaki Prefecture.
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Affiliation(s)
- Naomi Kozaka
- Department of Public Health, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
| | - Shouhei Takeuchi
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, 1-1-1 Manabino, Nagayo, Nishisonogi, Nagasaki, 851-2195, Japan
| | - Nobuyoshi Ishii
- Department of Neuropsychiatry, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Takeshi Terao
- Department of Neuropsychiatry, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Yoshiki Kuroda
- Department of Public Health, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.
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Ewuzie U, Nnorom IC, Eze SO. Lithium in drinking water sources in rural and urban communities in Southeastern Nigeria. CHEMOSPHERE 2020; 245:125593. [PMID: 31855764 DOI: 10.1016/j.chemosphere.2019.125593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 11/24/2019] [Accepted: 12/08/2019] [Indexed: 05/12/2023]
Abstract
There is a dearth of data on lithium content of domestic water sources in Nigeria. This study reported the lithium concentration in ground and surface water sources used for drinking in Southeastern Nigeria. Thirteen (13) natural springs, 24 streams, 7 hand-dug wells and 80 boreholes, making a total of 124 water samples were collected from strategic locations and analysed by ICP-OES. The distribution of lithium according to water sources and lithostratigraphic units as well as dietary contribution of lithium through drinking water was investigated. Average lithium concentrations in water samples from all sources were between 0.09 and 1.54 μg/L (overall mean ± SEM: 1.0 ± 0.2 μg/L). Results according to the geological formations of the areas studied indicated that only water sources located within the Benin Formation and Bende-Ameki Formation contained lithium in the range of <0.21-7.24 and < 0.21-1.97 μg/L respectively, whereas lithium was not detected in samples located within the Nsukka and Mamu lithostratigraphic units. Total intakes of lithium from water consumption (0.64 L for children and 2 L for adults) for all water sources were 79 and 247 μg/day for children and adults respectively, while the average daily intake of lithium from the water sources ranged from 0.004 to 0.066 and 0.002-0.044 μg/kg body weight for children (15 kg) and adults (70 kg) respectively. Drinking water in the study areas contributes only about 0.02-0.47% of the U.S. EPA estimated daily intake (9.3-44.3 μg/kg) of Lithium.
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Affiliation(s)
- Ugochukwu Ewuzie
- Analytical/Environmental Chemistry Unit, Department of Pure and Industrial Chemistry, Abia State University, Uturu, Nigeria.
| | - Innocent C Nnorom
- Analytical/Environmental Chemistry Unit, Department of Pure and Industrial Chemistry, Abia State University, Uturu, Nigeria; Visiting Research Fellow, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom
| | - Sunday O Eze
- Analytical/Environmental Chemistry Unit, Department of Pure and Industrial Chemistry, Abia State University, Uturu, Nigeria
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Barjasteh-Askari F, Davoudi M, Amini H, Ghorbani M, Yaseri M, Yunesian M, Mahvi AH, Lester D. Relationship between suicide mortality and lithium in drinking water: A systematic review and meta-analysis. J Affect Disord 2020; 264:234-241. [PMID: 32056756 DOI: 10.1016/j.jad.2019.12.027] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Lithium at therapeutic doses has protective effects against suicide in clinical practice. This meta-analysis aimed to investigate the relationship between lithium concentration in drinking water and suicide mortality in the general population. METHODS A systematic search was conducted in Web of Knowledge, PubMed, ScienceDirect, and Scopus to find papers reporting the crude relationship between drinking water lithium and suicide incidence in the general population until June 2019. The pooled effect measure was expressed as odds ratio (OR) and 95% confidence interval (CI) using the random-effects model. RESULTS We retrieved 308 English original articles, of which 13 ecologic studies with a total sample size of 939 regions and one cohort study with a sample size of 3,740,113 people were eligible for the meta-analysis. A significant relationship was found between the lithium concentration in drinking water and reduced suicide mortality (OR= 0.42; 95% CI: 0.27-0.67; p-value <0.01). Ten studies reported gender-specific responses to lithium, with the pooled estimates as follows: OR= 0.54; 95% CI: 0.35-0.84; p-value <0.01 for men, OR= 0.70; 95% CI: 0.48-1.01; p-value =0.057 for women, and OR= 0.63; 95% CI: 0.47-0.83; p-value <0.01 for total. LIMITATIONS The study was limited to the assessment of the crude relationship between lithium exposure and suicide rate without considering the role of confounders. CONCLUSIONS Lithium in drinking water is dose-dependently associated with reduced suicide mortality at least in ecological studies. However, we need well-designed clinical trials to confirm the protective effect of drinking water lithium intake against suicide.
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Affiliation(s)
- Fateme Barjasteh-Askari
- Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Department of Environmental Health Engineering, School of Health, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran; Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mojtaba Davoudi
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Environmental Health Engineering, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Homayoun Amini
- Department of Psychiatry & Psychosomatic Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ghorbani
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran; Department of Public Health, School of Health, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mehdi Yaseri
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Yunesian
- Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Department of Research Methodology and Data Analysis, Institute for Environmental Research (IER),Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Mahvi
- Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Center for Solid Waste Research, Institute for Environmental Research, Tehran University of Medical Sciences, Tehran, Iran.
| | - David Lester
- Distinguished Professor of Psychology, Emeritus, Stockton University, Galloway, NJ, USA
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Seidel U, Baumhof E, Hägele FA, Bosy-Westphal A, Birringer M, Rimbach G. Lithium-Rich Mineral Water is a Highly Bioavailable Lithium Source for Human Consumption. Mol Nutr Food Res 2019; 63:e1900039. [PMID: 31051049 DOI: 10.1002/mnfr.201900039] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/27/2019] [Indexed: 01/24/2023]
Abstract
SCOPE Lithium is an important trace element in human nutrition and medicine. Mineral and medicinal waters may represent a significant source of dietary lithium intake. METHODS AND RESULTS The lithium concentration of 360 German mineral and 21 medicinal waters is determined. Based on a systematic screening, three different mineral waters exhibiting low (1.7 µg L-1 ), medium (171 µg L-1 ), and high lithium (1724 µg L-1 ) concentrations are chosen for an acute bioavailability study in male healthy volunteers. In Germany, a north-east to south-west gradient of analyzed lithium concentrations is observed in the 381 tested waters. The lithium concentration in the water is significantly correlated with its sodium (r = 0. 810), potassium (r = 0.716), and magnesium (r = 0.361), but not with its calcium concentration. In a randomized cross-over trial, volunteers (n = 3×10 each) drink 1.5 L of the respective mineral waters, and lithium concentrations in serum and urine are monitored over 24 h. Consumption of the mineral waters with a medium and high lithium content results in a dose-dependent response in serum lithium concentrations and total urinary lithium excretion. CONCLUSION Lithium-rich mineral and medicinal waters may be an important and highly bioavailable lithium source for human consumption.
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Affiliation(s)
- Ulrike Seidel
- Kiel University, Institute of Human Nutrition and Food Science, Devision of Food Science, 24118, Kiel, Germany
| | - Elena Baumhof
- Kiel University, Institute of Human Nutrition and Food Science, Devision of Food Science, 24118, Kiel, Germany
| | - Franziska A Hägele
- Kiel University, Institute of Human Nutrition and Food Science, Devision of Food Science, 24118, Kiel, Germany
| | - Anja Bosy-Westphal
- Kiel University, Institute of Human Nutrition and Food Science, Devision of Food Science, 24118, Kiel, Germany
| | - Marc Birringer
- Fulda University of Applied Science, Devision of Nutritional, Food and Consumer Science, 36037, Fulda, Germany
| | - Gerald Rimbach
- Kiel University, Institute of Human Nutrition and Food Science, Devision of Food Science, 24118, Kiel, Germany
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48
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Szklarska D, Rzymski P. Is Lithium a Micronutrient? From Biological Activity and Epidemiological Observation to Food Fortification. Biol Trace Elem Res 2019; 189:18-27. [PMID: 30066063 PMCID: PMC6443601 DOI: 10.1007/s12011-018-1455-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022]
Abstract
Lithium compounds have been widely used in psychopharmacology, particularly in the treatment of bipolar disorder. Their normothymic and neuroprotective properties when used at high doses have been well established. However, a number of observations suggest that environmentally relevant lithium doses may also exert beneficial health effects, leading to a decrease in the rate of suicides and levels of violence. Despite the fact that this element is not officially considered to be a micronutrient, some authors have suggested provisional recommended intakes set at 1000 μg/day for a 70-kg adult (14.3 μg/kg body weight). The present paper reviews the biological action of lithium, its bioavailability and metabolism, and content in different foodstuffs and water. It also assesses epidemiological data on potential correlations between lithium intake and suicide rate as well as examines the concept of fortifying food with this element as a strategy in the primary prevention of mood disorders and pre-suicidal syndrome.
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Affiliation(s)
- Daria Szklarska
- Department of Environmental Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806, Poznań, Poland
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806, Poznań, Poland.
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Ge W, Jakobsson E. Systems Biology Understanding of the Effects of Lithium on Cancer. Front Oncol 2019; 9:296. [PMID: 31114752 PMCID: PMC6503094 DOI: 10.3389/fonc.2019.00296] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/01/2019] [Indexed: 12/27/2022] Open
Abstract
Lithium has many widely varying biochemical and phenomenological effects, suggesting that a systems biology approach is required to understand its action. Multiple lines of evidence point to lithium as a significant factor in development of cancer, showing that understanding lithium action is of high importance. In this paper we undertake first steps toward a systems approach by analyzing mutual enrichment between the interactomes of lithium-sensitive enzymes and the pathways associated with cancer. This work integrates information from two important databases, STRING, and KEGG pathways. We find that for the majority of cancer pathways the mutual enrichment is statistically highly significant, reinforcing previous lines of evidence that lithium is an important influence on cancer.
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Affiliation(s)
- Weihao Ge
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Eric Jakobsson
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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50
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The polygenic nature of telomere length and the anti-ageing properties of lithium. Neuropsychopharmacology 2019; 44:757-765. [PMID: 30559463 PMCID: PMC6372618 DOI: 10.1038/s41386-018-0289-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/29/2018] [Accepted: 11/27/2018] [Indexed: 12/27/2022]
Abstract
Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p < 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01), compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy.
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