In adults 60 years and older with treatment-resistant depression, what is the best pharmacologic approach?
There are several takeaways from this trial. Aripiprazole augmentation and bupropion augmentation produce similar modest improvements, and either is a reasonable option. Although injurious falls appear to be more common with bupropion, the authors inexplicably don't 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.
Plan de l'etude:
Randomized controlled trial (nonblinded)
Researchers in this 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 2 antidepressants and who had a Patient Health Questionnaire-9 (PHQ-9) score of 10 or more (range 0 - 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 - 60). This was an open-label randomized trial with 2 phases. In the first phase, the 618 participants were randomized into 1 of 3 groups for 10 weeks: (1) aripiprazole augmentation (starting at 2.5 mg once daily up to maximum of 15 mg once daily, (2) bupropion augmentation (starting at 150 mg once daily up to maximum of 450 mg once daily), or (3) switching from their current medication to bupropion 150 mg to 450 mg. At baseline, their 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 switch 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 while that for bupropion augmentation and the switch to bupropion was not, but numerically and clinically the results were very similar for both kinds of augmentation. Injurious falls were numerically more common with bupropion augmentation (25% vs 17% for aripiprazole and 19% for switch to bupropion, significance not reported).
In phase 2, patients who did not achieve remission (plus the 248 people who didn't qualify for phase 1 because of previous use of the assigned therapies) were randomized to 10 weeks of lithium augmentation (starting at 150 mg to 300 mg, maximum 1200 mg per day and target 0.6 mmol/L drug level) or switch to nortriptyline (starting 25 mg per day, increasing to 1 mg per kg and 80 to 120 ng/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), while remission rates were 18.9% and 21.5%, respectively (risk ratio 0.84; 95% CI 0.53 - 1.36). Injurious falls were more common with lithium (21.2% vs 13.2%). The cost of generic aripiprazole varied wildly, from $2.54 at Walmart to $238.00 at Walgreens (www.goodrx.com, 3/27/23), so patients should shop around. Generic bupropion costs ranged from $5 to $30.
Mark H. Ebell, MD, MS
University of Georgia