Transition time from manic and mixed episodes to depression: risk factors and outcomes

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Abstract 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; 1999-2025). Participants 100,776 people with bipolar disorder who had ≥1 record of each of manic/mixed episodes and depression. Median follow-up: 4.4 years [IQR: 1.8-6.6]. Total observation time: 638,373 person-years. Exposures Clinical features (previous short transition time, hospitalisation, clinical severity) and medications prescribed during the manic/mixed episode. Main Outcomes and Measures Transition time from manic/mixed episodes to depression. Results 100,776 people with bipolar disorder (524,351 mood episodes) were included (mean age at mood episode 41 years (SD=16), 61% female). 42% of manic and 29% of mixed episodes transitioned to depression within 1 month: an incidence up to 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=2.47, 95%CI: 2.39-2.56; post-mixed RR=3.62, 95%CI: 3.48-3.75), higher manic/mixed severity (post-mania RR=1.18 per 1 point CGI-S increase, 95%CI: 1.13-1.24; post-mixed RR=1.34, 95%CI: 1.27-1.42) and hospitalisation for the mania/mixed episode (post-mania RR=1.05, 95%CI: 1.01-1.10; post-mixed RR=1.33, 95%CI: 1.27-1.40). Among medications prescribed during hospital-associated manic/mixed episodes, lithium (post-mania RR=0.87, 95%CI: 0.80-0.95), and antiepileptic mood stabilisers (post-mania: RR=0.89, 95%CI: 0.84-0.94; post-mixed: RR=0.87, 95%CI: 0.81-0.92) were associated with longer transition time. Combination lithium/antipsychotic and valproate/antipsychotic were more protective than antipsychotics alone. Shorter transition time was associated with more depression-related hospital days (post-mania: 15% fewer days per month delay to depression, 95%CI: 11-20%; post-mixed: 8% fewer days, 95%CI: 4-10%). Conclusions and 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. Key points Question How quickly do manic and mixed episodes transition to depression, and what factors are associated with faster transition? Findings In this cohort study, 42% of manic and 29% of mixed episodes were followed by a rapid transition to depression (≤1 month). Previous rapid switch and higher manic/mixed severity were associated with faster transition to depression. Prescription of lithium and valproate were associated with delayed transition to depression including in comparison to antipsychotics alone. Shorter depression transition was associated with more hospital days. Meaning Rapid transition to depression after manic/mixed episodes is common, and may be anticipated and managed.

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