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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.