Lithium treatment is associated with reduced mortality in bipolar disorder (BD), but the role of treatment continuity remains underexplored. This study investigated the association between patterns of lithium exposure and all-cause mortality in a population-based cohort.

We analyzed electronic health records from 15,384 individuals with BD in Catalonia, Spain (2010–2019). Patients were classified as having sustained, partial/intermittent, or no lithium exposure based on annual defined daily doses (DDDs). All-cause mortality was the primary outcome. Kaplan–Meier and Cox regression analyses (adjusted for sociodemographic, clinical, and treatment-related variables) estimated hazard ratios (HRs) for mortality risk. Interaction and sensitivity analyses were conducted to assess the role of comorbidity burden and dose effects.

Over the study period, 715 deaths were recorded. In fully adjusted models, sustained lithium exposure was associated with a significantly lower mortality risk compared to no exposure (HR = 0.69, 95% confidence interval [CI]: 0.51–0.93, p = 0.016). In the lithium-exposed subgroup, sustained use was also protective compared to partial/intermittent exposure (HR = 0.70, 95% CI: 0.51–0.97, p = 0.03). No significant interaction was observed between sustained lithium use and comorbidity burden. Sensitivity analyses confirmed this effect at lower dose thresholds but not at higher ones.

Sustained lithium use is associated with improved survival in BD. Discontinuous exposure does not confer the same benefit. Ensuring treatment continuity may maximize lithium’s protective effect and improve long-term outcomes.