{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:02:49Z","timestamp":1790053369395,"version":"4.0.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lithium and valproate are widely prescribed mood stabilizers, but their comparative long-term associations with mortality and dementia remain uncertain. We compared the risks of all-cause mortality and incident dementia among adults initiating lithium or valproate using a large multinational electronic health record network.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (2004\u20132024), a multinational electronic health record network. Adults aged \u226540\u202fyears initiating lithium or valproate were identified after excluding patients with pre-existing dementia, epilepsy, intracranial injury, kidney transplantation, advanced chronic kidney disease, or acute kidney injury. The primary analysis followed an intention-to-treat approach based on the first recorded prescription of lithium or valproate. Propensity score matching incorporated demographic, clinical, psychiatric, and treatment-related characteristics, resulting in 22,098 patients in each treatment group. A 30-day prescription-confirmed analysis and lag-time analyses were performed as supportive and sensitivity analyses, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During follow-up, 884 deaths occurred among lithium initiators and 1,585 among valproate initiators. The corresponding five-year Kaplan\u2013Meier-estimated cumulative event probabilities for all-cause mortality were 6.61 and 10.65%, respectively. Lithium initiation was associated with a lower recorded risk of all-cause mortality than valproate initiation [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.53\u20130.63;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001]. Incident dementia occurred in 495 lithium initiators and 754 valproate initiators, with corresponding five-year Kaplan\u2013Meier-estimated cumulative event probabilities of 3.51 and 4.85%, respectively. Lithium initiation was also associated with a lower recorded risk of incident dementia (HR 0.68, 95% CI 0.60\u20130.76;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001). Findings remained directionally consistent in the supportive prescription-confirmed and lag-time analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Lithium initiation was associated with lower recorded risks of all-cause mortality and incident dementia than valproate initiation. These associations remained directionally consistent across supportive and sensitivity analyses, although residual confounding inherent to observational studies cannot be excluded.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1847655","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:20:58Z","timestamp":1790050858000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of lithium versus valproate initiation with all-cause mortality and incident dementia: a multinational real-world cohort study"],"prefix":"10.3389","volume":"17","author":[{"given":"Da-Han","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Medical Education, Taichung Veterans General Hospital","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsien","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Taichung Veterans General Hospital","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ju","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital","place":["Taichung, Taiwan"]},{"name":"Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University","place":["Taichung, Taiwan"]},{"name":"Rong-Hsing Research Center for Translational Medicine, College of Life Sciences, National Chung Hsing University","place":["Taichung, Taiwan"]},{"name":"School of Medicine, Chung Shan Medical University","place":["Taichung, Taiwan"]},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, School of Medicine, China Medical University","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiau-Shian","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Medicine, National Yang Ming Chiao Tung University","place":["Taipei, Taiwan"]},{"name":"School of Public Health, National Defense Medical Center","place":["Taipei, Taiwan"]},{"name":"Department of Psychiatry, Taipei Veterans General Hospital","place":["Taipei, Taiwan"]},{"name":"Nankung Psychiatric Hospital","place":["Keelung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Hsun","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Taichung Veterans General Hospital","place":["Taichung, Taiwan"]},{"name":"Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1016\/s0140-6736(13)60770-9","article-title":"Dementia in China: east-west collaboration bears fruit","volume":"381","author":"Prince","year":"2013","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/s41537-025-00680-4","article-title":"Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea","volume":"11","author":"Park","year":"2025","journal-title":"Schizophrenia"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1038\/mp.2011.47","article-title":"Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice","volume":"16","author":"Beurel","year":"2011","journal-title":"Mol 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