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

Importance 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 subtype for which lithium is likely effective. However, the window of risk for mania/mixed-to-depression transition remains unclear, as are its clinical associations. Objective To determine the rate of transition from manic/mixed episodes to depression, and identify risk factors and outcomes. Design: Retrospective cohort study. Setting: NeuroBlu health record database (United States; 1959 to 2025). Participants: 10,806 people with bipolar disorder (44,691 mood episodes; 112,742 person-years), defined as having [≥]1 record of each of manic/mixed episodes and depression. Median follow-up: 7.0 years [IQR: 4.0-12.4]. Exposures: Clinical features (previous short transition, hospitalisation, clinical severity) and medications prescribed during the manic/mixed episode. Main Outcomes, Measures: Transition time from manic/mixed episodes to depression. Results 10,806 people with bipolar disorder (44,691 mood episodes) were included (mean age at mood episode 43.3 years (SD=15.3), 62% female). 28% of manic and 23% of mixed episodes transitioned to depression within 1 month: an incidence >10-times higher than the overall per-month depression rate. The depression transition rate plateaued by 6 months. Short depression transition time ([≤]1 month) was associated with previous short transition (post-mania RR=2.50, 95%CI: 2.15-2.90; post-mixed RR=2.84, 95%CI: 2.34-3.44), higher manic/mixed severity (post-mania RR=1.26 per 1 point CGI-S increase, 95%CI: 1.16-1.37; post-mixed RR=1.42, 95%CI: 1.29-1.55) and hospitalisation for the mania/mixed episode (post-mania RR=1.30, 95%CI: 1.14-1.47; post-mixed RR=1.71, 95%CI: 1.49-1.95). Among medications prescribed during hospital-associated manic/mixed episodes, lithium (post-mania RR=0.75, 95%CI: 0.62-0.91; post-mixed RR=0.64, 95%CI: 0.47-0.88), antiepileptic mood stabilisers (post-mania: RR=0.79, 95%CI: 0.69-0.89; post-mixed: RR=0.66, 95%CI: 0.57-0.78), antipsychotics for mania (RR=0.80, 95%CI: 0.71-0.91) and antidepressants for mixed episodes (RR=0.82, 95%CI: 0.72-0.94) were associated with longer transition time. Shorter transition time was associated with more depression-related hospital days (post-mania: 17% fewer days per month delay to depression, 95%CI: 9-24%; post-mixed: 12% fewer, 95%CI: 5-19%). Conclusions, Relevance It is important to monitor for depression soon after manic/mixed episodes. This depression may be predictable, and might be modifiable by some medications prescribed during the manic/mixed episode.