| Summary: | Importance Randomized controlled trials have demonstrated increased all-cause mortality in elderly patients with dementia treated with newer antipsychotics. It is unknown whether this risk generalizes to non-elderly adults using newer antipsychotics as augmentation treatment for depression. Objective This study examined all-cause mortality risk of newer antipsychotic augmentation for adult depression. Design Population-based new-user/active comparator cohort study. Setting National healthcare claims data from the US Medicaid program from 2001–2010 linked to the National Death Index. Participants Non-elderly adults (25–64 years) diagnosed with depression who after ≥3 months of antidepressant monotherapy initiated either augmentation with a newer antipsychotic or with a second antidepressant. Patients with alternative indications for antipsychotic medications, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded. Exposure Augmentation treatment for depression with a newer antipsychotic or with a second antidepressant. Main outcome All-cause mortality during study follow-up ascertained from the National Death Index. Results The analytic cohort included 39,582 patients (female = 78.5%, mean age = 44.5 years) who initiated augmentation with a newer antipsychotic (n = 22,410; 40% = quetiapine, 21% = risperidone, 17% = aripiprazole, 16% = olanzapine) or with a second antidepressant (n = 17,172). The median chlorpromazine equivalent starting dose for all newer antipsychotics was 68mg/d, increasing to 100 mg/d during follow-up. Altogether, 153 patients died during 13,328 person-years of follow-up (newer antipsychotic augmentation: n = 105, follow-up = 7,601 person-years, mortality rate = 138.1/10,000 person-years; antidepressant augmentation: n = 48, follow-up = 5,727 person-years, mortality rate = 83.8/10,000 person-years). An adjusted hazard ratio of 1.45 (95% confidence interval, 1.02 to 2.06) indicated increased all-cause mortality risk for newer antipsychotic augmentation compared to antidepressant augmentation (risk difference = 37.7 (95%CI, 1.7 to 88.8) per 10,000 person-years). Results were robust across several sensitivity analyses. Conclusion Augmentation with newer antipsychotics in non-elderly patients with depression was associated with increased mortality risk compared with adding a second antidepressant. Though these findings require replication and cannot prove causality, physicians managing adults with depression should be aware of this potential for increased mortality associated with newer antipsychotic augmentation.
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