Comparative Effectiveness of Lithium‐ Vs. Valproate‐Based Combinations With Atypical Antipsychotics in Preventing Rehospitalization After a First Manic Episode of Bipolar I Disorder

BACKGROUND: Relapse after a first manic episode is common in bipolar I disorder and frequently leads to rehospitalization. Lithium and valproate, often prescribed with atypical antipsychotics, remain central to maintenance therapy; however, no randomized trials have directly compared these regimens in early-course illness. This study compared lithium plus atypical antipsychotics (Li + AAPs) versus valproate plus atypical antipsychotics (Val + AAPs) for preventing bipolar-related rehospitalizations after the first hospitalization for mania. METHODS: This was a new-user, propensity score-matched cohort study of patients discharged after their first hospitalization for acute mania, using Taiwan's National Health Insurance claims data (2011-2022). Patients initiating Li + AAPs or Val + AAPs within 30 days of discharge were followed for rehospitalization for any mood episode (manic, depressive, or mixed). Secondary outcomes included episode-specific rehospitalization and annualized hospitalization rates. RESULTS: Among 3,909 matched patients (1397 Li + AAP and 2,512 Val + AAP; mean [SD] age, 42.4 [14.2] years; 42.9% male), Li + AAPs were associated with a higher risk of rehospitalization for any mood episode compared to Val + AAPs (hazard ratio [HR], 1.18; 95% CI, 1.03-1.35), primarily driven by manic relapse (HR, 1.16; 95% CI, 1.01-1.35). No significant differences were observed for depressive or mixed episodes. The annual rehospitalization rate for any mood episodes was also higher with Li + AAPs (incidence rate ratio, 1.34; 95% CI, 1.17-1.54). CONCLUSIONS: In this nationwide cohort of patients with first-episode mania, Val + AAPs were associated with a lower risk of bipolar rehospitalization compared to Li + AAPs, suggesting potential early-phase maintenance advantages of valproate combinations over lithium combinations following first mania discharge.