Cognitive changes in older adults receiving pharmacotherapy for treatment-resistant depression: a secondary analysis of the OPTIMUM randomised controlled trial

Background: The cognitive effects of various antidepressant strategies for treatment-resistant depression in older adults are unclear. We aimed to evaluate acute cognitive changes associated with various pharmacotherapy treatment strategies for treatment-resistant depression in older adults. Methods: We did a prespecified secondary analysis of the OPTIMUM trial, which was a pragmatic, randomised, comparative effectiveness trial of various augmentation or switch pharmacotherapy strategies, enrolling adults aged 60 years or older with treatment-resistant depression. Participants were recruited from five academic medical centres (four in the USA and one in Canada). In Step 1 (n=391), participants were randomly assigned 1:1:1 to augmentation of their antidepressant with aripiprazole (to a maximum of 15 mg per day) or bupropion (to a maximum of 450 mg per day) or to a switch to bupropion (same dose as the bupropion-augmentation group). In Step 2 (n=182), participants who were ineligible for Step 1 or did not reach remission in this step were randomly assigned 1:1 to augmentation with lithium (titrated to attain a plasma concentration range of 0·4–0·8 mEq/L) or to a switch to nortriptyline (to reach a therapeutic plasma concentration of 80–120 ng/mL). Each step lasted 10 weeks, with 12 months of follow-up after completion of Step 1 or Step 2. The primary outcome was cognitive function at the end of Step 1 and Step 2, as evaluated with the National Institutes of Health (NIH) Toolbox Fluid Cognition Composite Score, part of the NIH Toolbox Cognition Battery. The primary outcome was analysed in the intention-to-treat population. An exploratory post-hoc analysis conducted in both the intention-to-treat and per-protocol populations examined changes in the individual cognitive tasks constituting the Fluid Cognition Composite Score. OPTIMUM was registered with ClinicalTrials.gov (NCT02960763) and is complete. Findings: Between Feb 22, 2017, and Dec 31, 2019, 742 participants were enrolled in the OPTIMUM study. In Step 1, 619 (83%) participants were randomly assigned to aripiprazole augmentation (n=211), bupropion augmentation (n=206), or a switch to bupropion monotherapy (n=202); cognitive data were available for 128, 136, and 127 participants, respectively. 248 participants were enrolled in Step 2 and randomly assigned to lithium augmentation (n=127) or to a switch to nortriptyline monotherapy (n=121); cognitive data were available for 89 and 93 participants, respectively. Over 10 weeks, there were no significant differences between pharmacotherapy strategies in the Fluid Cognition Composite Score. In Step 1, a time × group interaction was observed for the Flanker Inhibitory Control and Attention test (F[2,266]=3·97; p=0·020), with a contrast analysis showing that aripiprazole augmentation was associated with an increase in inhibitory control compared with bupropion augmentation (t=–2·82, p=0·0052). In Step 2, a time × group interaction was observed for the same test (F[1,176]=5·20; p=0·024), explained by a significant increase in inhibitory control with nortriptyline monotherapy (change in least square mean +2·0, t=2·33; p=0·021) versus no increase with lithium augmentation (–0·7; t=–0·89; p=0·37). Changes in depressive symptoms during treatment were not correlated with cognitive changes. In Step 1, the rate of falls was highest with bupropion augmentation, whereas in Step 2, rates of falls were similar in the lithium augmentation and notriptyline monotherapy groups. The rates of serious adverse events were similar in the three groups in Step 1 (0·07–0·12) and the two groups in Step 2 (0·09–0·10). Interpretation: Overall, global cognitive functioning did not differ between treatments. Aripiprazole augmentation and switch to nortriptyline might have some modest advantages in inhibitory control compared with bupropion or lithium augmentation. Funding: The US National Institute of Mental Health and the Patient-Centered Outcomes Research Institute.