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Am Fam Physician. 2023;108(3):online

Clinical Question

What is the best pharmacologic approach in adults 60 years and older with treatment-resistant depression?

Bottom Line

There are several takeaways from the trial. Aripiprazole and bupropion augmentation produce similar modest improvements, and both are a reasonable option. Although injurious falls appear to be more common with bupropion, the authors did not report weight gain and hyperglycemia, which are both known adverse effects of aripiprazole. In the second comparison, a switch to nortriptyline seems preferable to lithium augmentation based on the simplicity of dosing and a lower risk of injurious falls. (Level of Evidence = 1b−)


Researchers in the Patient-Centered Outcomes Research Institute–sponsored trial identified adults 60 years and older who had not achieved remission of their depressive symptoms after trials of at least two antidepressants and had a Patient Health Questionnaire-9 (PHQ-9) score of 10 or more (range = 0 to 27). At baseline, patients had a mean age of 69 years, 67% were women, and the mean PHQ-9 score was 16. The primary outcome was patient-reported symptoms based on the Positive Affect and General Life Satisfaction subscales of the National Institutes of Health Toolbox Emotion Battery. Remission was defined as a score of 10 or lower on the Montgomery-Åsberg Depression Rating Scale (MADRS; range = 0 to 60). It was an open-label randomized trial with two phases.

In the first phase, 618 participants were randomized into one of three groups for 10 weeks: (1) aripiprazole augmentation (starting at 2.5 mg once daily up to a maximum of 15 mg once daily, (2) bupropion augmentation (starting at 150 mg once daily up to a maximum of 450 mg once daily), or (3) switching from their current medication to bupropion, 150 to 450 mg daily. At baseline, self-reported symptom scores were 33.2 to 33.7 points. At 10 weeks, the improvement in symptom scores was 4.83 points for aripiprazole augmentation, 4.33 points for bupropion augmentation, and 2.0 points for switching to bupropion. Rates of remission were 28.9%, 28.2%, and 19.3%, respectively. Improvement in the MADRS scores followed a similar pattern. The authors make much of the fact that the difference between aripiprazole augmentation and the switch to bupropion was statistically significant, whereas the difference between bupropion augmentation and the switch to bupropion was not, although numerically and clinically, the results were similar for both kinds of augmentation. Injurious falls were numerically more common with bupropion augmentation (25% vs. 17% for aripiprazole and 19% for switching to bupropion, significance not reported).

In phase 2, patients who did not achieve remission (plus 248 people who did not qualify for phase 1 because of previous use of the assigned therapies) were randomized to 10 weeks of lithium augmentation (starting at 25 mg per day, increasing by 1 mg per kg and 80 to 120 ng per mL drug level). The improvement in the MADRS score was 4.6 points with lithium augmentation and 5.3 points with the switch to nortriptyline (P = .57), whereas remission rates were 18.9% and 21.5%, respectively (risk ratio = 0.84; 95% CI, 0.53 to 1.36). Injurious falls were more common with lithium (21.2% vs. 13.2%). The cost of aripiprazole varied wildly, from $2.54 at Walmart to $238 at Walgreens (, accessed March 27, 2023), therefore patients should shop around. Bupropion costs ranged from $5 to $30.

Study design: Randomized controlled trial (nonblinded)

Funding source: Government

Allocation: Concealed

Setting: Outpatient (any)

Reference: Lenze EJ, Mulsant BH, Roose SP, et al. Antidepressant augmentation versus switch in treatment-resistant geriatric depression. N Engl J Med. 2023;388(12):1067-1079.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.

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