Association of lithium versus valproate initiation with all-cause mortality and incident dementia: a multinational real-world cohort study.

Authors

Da-Han Hou, Yu-Hsien Wu, Ming-Ju Wu, Shiau-Shian Huang, Po-Hsun Hou

Published in

Frontiers in neurology. Volume 17. Pages 1847655. Epub Sep 22, 2026.

Abstract

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.
We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (2004-2024), a multinational electronic health record network. Adults aged ≥40 years 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.
During follow-up, 884 deaths occurred among lithium initiators and 1,585 among valproate initiators. The corresponding five-year Kaplan-Meier-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) 0.53-0.63; p < 0.001]. Incident dementia occurred in 495 lithium initiators and 754 valproate initiators, with corresponding five-year Kaplan-Meier-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 0.60-0.76; p < 0.001). Findings remained directionally consistent in the supportive prescription-confirmed and lag-time analyses.
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.

PMID:
42839929
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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