Monotherapy vs. combination therapy for post mania maintenance treatment: A population based cohort study

In recent years, the use of atypical antipsychotics and combination therapy for relapse prevention in bipolar disorder has increased substantially. However, real-world data on the comparative effectiveness of these treatment options are largely non-existent. We conducted a population-based cohort study, using data from Swedish national registers. All patients aged 18-75 years who were hospitalized for mania 2006-2014 and filled at least one prescription of lithium, valproate, olanzapine, quetiapine, aripiprazole or any combination of these drugs were included, and followed for up to one year after hospital discharge, generating follow-up data from 5 713 hospitalizations. We used Cox proportional hazard regression models to study time to treatment failure for each individual drug and combination therapy, using lithium as comparator. Treatment failure was defined as treatment discontinuation, switch, or rehospitalization, and the results were adjusted for clinical and sociodemographic factors. We found that treatment failure occurred in 85% of cases and that the majority of combination therapies were associated with lower risks of treatment failure compared to monotherapies. Patients combining lithium + valproate + quetiapine had the lowest risk of treatment failure (adjusted HR [AHR] 0.40, 95% CI 0.30-0.54), followed by patients on lithium + valproate + olanzapine (AHR 0.55, 95% CI 0.45-0.68). In contrast, monotherapies with antipsychotics were associated with significantly higher risks of treatment failure compared to single use of lithium. In conclusion, our results support experimental findings, suggesting that combination therapy is more effective than monotherapy after a manic episode.