Real-world effectiveness of mono- and combination therapies of mood stabilisers and antipsychotics in bipolar disorder: nationwide, within-individual study of 315 046 patients

BACKGROUND: Real-world evidence on pharmacotherapy for bipolar disorder remains limited; in particular, the effectiveness of combination therapies that are widely used in clinical practice has not been systematically assessed. AIMS: To assess the effectiveness of mono- and combination therapy with mood stabilisers and antipsychotics in preventing psychiatric hospitalisation. METHOD: This population-based cohort study used a within-individual design and data from the National Database of Health Insurance Claims and Specific Health Check-ups of Japan. Patients aged ≥20 years, with a primary diagnosis of bipolar disorder treated in psychiatric settings between 1 April 2013 and 31 March 2022, were included. Follow-up continued until 31 May 2023. Exposures included monotherapy with mood stabilisers or antipsychotics, and combination therapy involving (a) lithium plus another mood stabiliser or (b) lithium, valproate or lamotrigine plus a commonly prescribed antipsychotic. The primary outcome was time to psychiatric hospitalisation. Adjusted hazard ratios (aHRs) with 95% confidence intervals were estimated using stratified Cox regression. RESULTS: Among 315 046 patients (median follow-up 7.1 years), 83 621 (26.5%) experienced psychiatric hospitalisation. Monotherapy with lithium (aHR 0.67 [0.66-0.68]), valproate (aHR 0.71, 95% CI 0.70-0.73), lamotrigine (aHR 0.72, 95% CI 0.69-0.75) and carbamazepine (aHR 0.74, 95% CI 0.70-0.78) was associated with reduced hospitalisation compared with non-use of any mood stabilisers. Antipsychotic monotherapy with 15 agents, including aripiprazole (aHR 0.73, 95% CI 0.70-0.75) and zotepine (aHR 0.74, 95% CI 0.69-0.79), was also associated with reduced risk compared with non-use of any antipsychotics. Combination therapy with lithium plus carbamazepine (aHR 0.73, 95% CI 0.64-0.83), zotepine (aHR 0.82, 95% CI 0.72-0.93), aripiprazole (aHR 0.87, 95% CI0.82-0.92) or valproate (aHR 0.92, 95% CI 0.87-0.97) was associated with further reductions in hospitalisation risk compared with lithium monotherapy. CONCLUSIONS: This large, population-based study showed that monotherapy and combination therapy with mood stabilisers and antipsychotics varied in their effectiveness in preventing psychiatric hospitalisation. These findings may inform treatment decisions in the clinical management of bipolar disorder.