REVIEW OF: Lenze BH et al, N Engl J Med 2023;388:1067–1079

STUDY TYPE: Randomized open-label controlled trial

When older adults struggle with treatment-resistant depression, should clinicians add to their existing medication or switch to a different one? To answer this, Lenze and colleagues conducted a multicenter trial involving 742 adults aged 60 years and older, all of whom had failed at least 2 prior antidepressant trials. 

The trial had a pair of 10-week phases. In Phase 1, 619 participants continued their current antidepressant and were randomly assigned to either augmentation with aripiprazole (starting at 2.5 mg/day, titrated up to 15 mg/day), augmentation with bupropion (starting at 150 mg/day, targeting 300 mg/day, and allowing up to 450 mg/day), or a complete switch to bupropion. Psychological well-being, assessed using NIH Toolbox subscales, was the primary outcome, with remission rates and safety data as secondary measures. Phase 2 enrolled 248 patients: 125 who did not respond in Phase 1 and 123 new participants. These individuals were randomized to either lithium augmentation (starting at 150–300 mg/day, up to 1200 mg/day, targeting serum levels of 0.6 mmol/L) or switching to nortriptyline (starting at 25 mg/day, titrated to around 1 mg/kg/day, targeting levels of 80–120 ng/mL).

The results from Phase 1 favored augmentation over switching. Adding aripiprazole led to significantly greater improvements in well-being compared to switching to bupropion (+2.79 points, p=0.014), and remission rates were highest in the aripiprazole group (28.9%) compared to switching (19.3%). Bupropion augmentation showed similar efficacy to aripiprazole (28.2% remission). In Phase 2, lithium augmentation and switching to nortriptyline had nearly identical outcomes, with modest gains in well-being and remission rates of 18.9% and 21.5%, respectively.

The efficacy data might make aripiprazole look like the clear winner, and in many ways, it is—but the side effect profiles still deserve close attention. In this trial, aripiprazole had the lowest fall rate among all groups (0.33 falls per patient), whereas bupropion augmentation and lithium carried the highest fall risks (0.55 and 0.47 falls per patient, respectively), with more injurious falls reported. Anxiety, agitation, and insomnia were more frequent in those augmenting with aripiprazole or switching to bupropion. GI distress, dry mouth, dizziness, and balance issues were most common in both bupropion groups, likely contributing to the elevated fall risk. 

Study limitations include recruitment challenges, mid-trial eligibility adjustments, and the lack of blinding, which raises concerns about bias. Rapid medication discontinuation may have also influenced outcomes, and the predominantly White, well-educated sample limits generalizability.

Carlat Take

This study provides guidance on how to manage treatment-resistant depression in older adults. Augmentation—not switching—comes out on top, with aripiprazole leading the pack in terms of effectiveness and safety. It significantly improved psychological well-being and had the lowest fall rate of all strategies tested. Still, while aripiprazole was generally well tolerated in this study, prior studies have shown it can cause akathisia and parkinsonism at higher rates than placebo. Bupropion augmentation, while nearly as effective, came with a higher risk of falls. Although lithium augmentation and nortriptyline were decent second-line options, they added complexity and only modest benefits.