Abstract
Objective: In treatment-resistant depression (TRD), augmentation with aripiprazole (A-ARI) or combination therapy by adding bupropion (C-BUP) has been reported as more effective than switching to bupropion (S-BUP), but C-BUP risks falls in older adults, and A-ARI risks weight gain and tardive dyskinesia (TD). The aim of this study was to clarify whether the enhanced effectiveness outweighs such risks. Methods: In this risk-benefit decision analysis, lifetime quality-adjusted life-years (QALYs) following 1 year of A-ARI or C-BUP vs S-BUP treatment were simulated in a health-state transition model tracking depression remission, falls, weight gain, and TD, in age and baseline body mass index (BMI) subgroups, using data from the VAST-D and OPTIMUM trials and other literature. QALYs were converted to depression-free day-equivalents (DFDs), the QALYs gained from 1 day of remitted versus active depression. Results: Simulated adults aged 18-64 years experienced a net benefit of C-BUP over S-BUP of 20.7 DFDs, equivalent to about 3 weeks of faster remission of depressive symptoms. In older adults, especially those aged 85+ years, this benefit over S-BUP was partially but not fully offset by a risk of falls. In adults aged 18-64 years, A-ARI was estimated to offer only 8.0 DFDs after subtracting the expected harms from TD, and this was further reduced to -22.8 DFDs once metabolic harms were considered, in those overweight at baseline. Overall, C-BUP was preferred over A-ARI in all subgroups except ages 85-89 years with BMI<25, in whom A-ARI was preferred. Conclusion: In our model, C-BUP better balanced efficacy and tolerability in TRD in adults under 85 years than did S-BUP or A-ARI. A-ARI was least-preferred in overweight adults. These results may inform shared decision-making and clinical guidelines.