Comparative risk of early-onset dementia with lithium versus valproate in bipolar disorder: A real-world cohort study

Bipolar disorder is associated with an elevated risk of dementia. While lithium may exert neuroprotective effects, its comparative impact on early-onset dementia versus valproate, a mood stabilizer with potential neurotoxicity remains unclear in younger populations. This study aimed to compare the risk of early-onset dementia between patients with bipolar disorder initiating lithium versus valproate therapy.

This retrospective, active-comparator, new-user cohort study using the TriNetX global health research network. The study period was from January 1, 2015, to December 31, 2024. We identified patients aged 18-60 years newly diagnosed with bipolar disorder who initiated either lithium or valproate. Patients with prevalent dementia were excluded. Propensity score matching (1:1) was used to balance baseline characteristics including comorbidities and renal function. The primary outcome was incident dementia within 5 years of the index date. Hazard ratios (HRs) were estimated using Cox proportional hazards models.

The matched cohort included 82,172 patients (41,086 per group; mean age 37.4 years; 54.4% female). Over the 5-year follow-up, lithium initiation was associated with a lower risk of dementia compared with valproate (HR 0.815, 95% CI 0.717-0.926; p = 0.002). This comparative association remained consistent across extended 10-year follow-up, complete-case, and all-cause mortality sensitivity analyses.

Observational design precludes causal inference; lack of granular dosage data prevents dose-response analysis.

Lithium is associated with a lower risk of early-onset dementia compared to valproate.