TOPLINE:

In older adults with depression that was unresponsive to treatment, overall cognitive functioning did not differ with antidepressant strategies; however, adding aripiprazole or switching to nortriptyline modestly improved inhibitory control. 

METHODOLOGY:

• Researchers conducted an analysis of a randomized clinical trial (2017-2019) to evaluate which drugs were better for improving cognition in older adults with depression.
• They included adults aged 60 years or older with treatment-resistant depression from five academic medical centers in the US and Canada.
• Patients were randomly assigned to have aripiprazole or bupropion added to their current antidepressant regimen or to switch to bupropion alone; cognitive data were available for 391 patients.
• Patients who were ineligible for the first treatments or not in remission after step 1 were randomly assigned to start lithium or to switch to nortriptyline alone; cognitive data were available for 182 patients (mean age range for both steps, 68.1-69.8 years; 59%-70% women).
• The primary outcome was cognitive function after 10 weeks of treatment following each randomization step, evaluated using a composite score on tests for inhibitory control, attention, executive function, and memory.

TAKEAWAY:

• The composite score for cognition improved over 10 weeks after step 1 (P < .0001), with no differences between drug strategies. After step 2, overall scores did not change.
• Adding aripiprazole was associated with a 2.5-point gain on an inhibitory control test, whereas adding bupropion showed no change (P = .0052). Switching to bupropion alone showed a small but nonsignificant improvement.
• Switching to nortriptyline was associated with improved performance on the inhibitory control test (P = .021), but adding lithium was not associated with improvements.
• None of the cognitive changes observed were related to changes in symptoms of depression. Falls were most frequent with bupropion addition, and serious side effects were similar across groups.

IN PRACTICE:

“Our study has important clinical implications and, in particular, provides some reassurance regarding the use of aripiprazole augmentation or nortriptyline monotherapy in treatment-resistant late-life depression,” the authors of the study wrote.

SOURCE:

This study was led by Hanadi A. Oughli, MD, of University of California in Los Angeles. It was published online on November 11, 2025, in The Lancet Healthy Longevity.

LIMITATIONS:

This study lacked a placebo group. The mean age of patients was less than 70 years, limiting generalizability. Not all antidepressant strategies were evaluated.

DISCLOSURES:

This study received funding from the National Institute of Mental Health and Patient-Centered Outcomes Research Institute. Several authors reported financial relationships such as receiving salaries, consulting fees, research grants, and royalty income from multiple sources, including the National Center for Translational Sciences, universities, or pharmaceutical and healthcare companies. One author reported having a pending patent.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.