Transition time from manic and mixed episodes to depression: a retrospective cohort study

Background For people with bipolar disorder, recovery from manic or mixed episodes is frequently complicated by depression. Depression after manic/mixed episodes may occur within a broader episode sequence pattern of mania-depression-euthymic interval, proposed as a bipolar disorder subtype for which lithium is effective. However, the window of risk for mania/mixed-to-depression transition remains unclear, as is the relationship with clinical factors and outcomes. Methods In this retrospective cohort study, we identified a cohort of 10,437 people with bipolar disorder (42,314 mood episodes; 90,727 person-years) within the NeuroBlu health record database (United States) with records from 1959 to 2025. We quantified the transition time from manic/mixed episodes to depression, and investigated associations with clinical features, medications and outcomes. Outcomes 25% of all manic episodes and 22% of all mixed episodes transitioned to depression within 1 month: an incidence >11-times higher than the overall per-month depression rate. By 6 months, the depression transition rate had plateaued. Short depression transition time ([≤]1 month) was associated with previous short transition times (post-mania RR=3.08, 95%CI: 2.65-3.58; post-mixed RR=2.52, 95%CI: 2.12-3.00), higher manic/mixed severity (post-mania RR=1.30 per 1 point CGI-S increase, 95%CI: 1.18-1.44; post-mixed RR=1.35, 95%CI: 1.15-1.57) and hospitalisation for the mania/mixed episode (post-mania RR=1.22, 95%CI: 1.09-1.37; post-mixed RR=1.71, 95%CI: 1.52-1.94). Among medications prescribed during hospital-associated manic/mixed episodes, lithium (post-mania RR=0.75, 95%CI: 0.62-0.91; post-mixed RR=0.72, 95%CI: 0.54-0.95), first-generation sedating antihistamines (post-mania: RR=0.74, 95%CI: 0.63-0.87) and other mood stabilisers (post-mania RR=0.82, 95%CI: 0.71-0.94, post-mixed RR=0.82, 95%CI: 0.72-0.94) were associated with longer transition time. Antipsychotics, antidepressants and benzodiazepines were not. Shorter transition time was associated with more depression-related hospital days (16% fewer days per month delay to depression, 95%CI: 4-25%, p=0.010). Interpretation It is important to monitor for depression soon after manic/mixed episodes. This depression may be predictable, and might be preventable with some medications prescribed during the manic/mixed episode.