Examining valproate’s potential anticancer effect among patients with bipolar disorder: a territory-wide active-comparator new user study spanning two decades

Preclinical studies have suggested potential anticancer effects of valproate, but clinical evidence is limited and inconclusive. This study aims to reexamine the relationship between valproate use and cancer incidence, using lithium as an active comparator in a cohort of patients with bipolar disorder. A retrospective, active-comparator, new-user cohort study was conducted using a territory-wide public healthcare database in Hong Kong. Patients diagnosed with bipolar disorder between 2003 and 2023 and initiating monotherapy of either lithium or valproate were included. Those with prior cancer diagnoses or concurrent use of other mood stabilizers were excluded. Cancer incidence was the primary outcome, analyzed using inverse probability of treatment weighting (IPTW) and modified Poisson regression. The study included 5,875 valproate users and 1,439 lithium users. After a median follow-up of 2.96 years, 126 cases of cancer were observed (16 in lithium users and 110 in valproate users). There was no significant difference between valproate and lithium use among patients with bipolar disorder, with an adjusted incidence rate ratio (aIRR) of 1.13 (95% CI 0.66–1.91) for valproate compared to lithium. Results were consistent across subgroup and sensitivity analysis. Our findings do not suggest an anticancer effect from valproate but highlight the importance of weighing the other distinct safety and tolerability profiles of valproate and lithium against individual clinical presentations to ensure optimal and individualized care.