نبذة مختصرة : 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.
Competing Interests: None of these conflicts alter our adherence to PLOS ONE policies on sharing data and materials. Dr. Gerhard reports grants from NIA and NIMH during the conduct of the study; grants and personal fees from Bristol-Myers Squibb; personal fees from Eisai, Merck, Pfizer, Lilly, and IntraCellular Therapies outside the submitted work. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus and Teva. He received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. All activities are outside the submitted work. Dr. Setoguchi reports grants from NIA, Cystic Fibrosis Foundation, Pfizer, Janssen, and BMS, and personal fees from Pfizer, Merck, Janssen, and Medtronic. Dr. Strom reports grants from NIMH, personal fees from Astra Zeneca, personal fees from Bayer, personal fees from Lundbeck, personal fees from Janssen, personal fees from McVeigh Associates, other from National Academy of Medicine, personal fees from Celgene, personal fees from Insmed, personal fees from McKesson Specialty, personal fees from Innovative Science Solutions, personal fees from Amag Pharmaceuticals, outside the submitted work. Dr. Tan reports grants from NIMH during the conduct of the study. Dr. Crystal reports grants from AHRQ and NIMH during the conduct of the study. Dr. Olfson reports personal fees from Lundbeck Pharmaceuticals, outside the submitted work; Dr. Stroup reports grants from NIH, grants from PCORI, personal fees from Medscape, personal fees from MD Magazine, outside the submitted work. All other authors have no competing interests.
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