Association between maintenance doses of mood stabilizers and antipsychotics and risk of readmission in first-episode bipolar disorder

Physicians aim to identify the lowest effective dose for maintenance pharmacotherapy in bipolar disorder, but evidence remains limited. We aimed to investigate the association between maintenance doses of mood stabilizers and antipsychotics and relapse risk in patients with first-episode bipolar disorder. Using the Korean National Health Insurance Database, we identified patients aged 19-60 years with a first admission for bipolar disorder between 2002 and 2022. After discharge from the first admission (acute phase), maintenance doses of mood stabilizers and antipsychotics were assessed as absolute doses (defined daily doses [DDDs]/day) and relative doses (percentages of the acute-phase dose) during follow-up. The outcome was readmission for mood disorders. Hazard ratios (HRs) and 95% confidence intervals (CIs) for readmission according to time-varying maintenance doses were estimated using time-dependent Cox regression. A negative dose-response relationship between mood stabilizer dose and readmission was observed below 0.4 DDDs/day (absolute) and 80% (relative) in both the continuous and categorical analyses. For antipsychotics, a progressively higher risk of readmission was observed below 0.5 DDDs/day and 50%, with a near plateau above these levels. Joint dose-category analyses suggested that increased readmission risk associated with low-dose mood stabilizers or antipsychotics was attenuated when the other class was used above the observed dose threshold. In time-stratified analyses, these associations were significant after three years of follow-up. This study found that maintenance doses of mood stabilizers and antipsychotics below specific levels were associated with increased readmission risk in first-episode bipolar disorder, which may help inform clinically cautious dose reduction strategies.