Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published March 22, 2023


What were the three key findings of the trial by Lenze et al.?

Lenze et al. conducted a two-step, open-label trial that investigated the benefits and risks of augmentation (adding a medication to an existing antidepressant) versus replacing an antidepressant with one from a different class (switching) for treatment-resistant depression in adults 60 years of age or older. Read the NEJM Original Article here.

Clinical Pearls

Q: How was the primary effectiveness outcome of the trial by Lenze et al. chosen?

A: There is increasing awareness of the importance of involving patients in the design of clinical trials. In a survey involving older adults with treatment-resistant depression, patient stakeholders recommended psychological well-being as an outcome that matters. Psychological well-being encompasses satisfaction, happiness, cognitive engagement, meaning, and purpose. In this trial, the effectiveness and safety outcomes were chosen to reflect the stakeholder-driven trial design. The primary effectiveness outcome was psychological well-being.

Q: What were the two different steps in the trial?

A: In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks.

Morning Report Questions 

Q: What were the three key findings of the trial by Lenze et al.?

A: First, augmentation of existing antidepressant with aripiprazole was significantly better with respect to psychological well-being than a switch to bupropion, and the percentage of patients with remission, not adjusted for multiple comparisons, was numerically higher with either aripiprazole augmentation or bupropion augmentation than with a switch to bupropion. Second, bupropion augmentation was numerically similar in effectiveness to aripiprazole augmentation and was associated with a higher rate of falls than aripiprazole augmentation. These results suggest that in this trial population, aripiprazole augmentation may have been a better overall antidepressant strategy than bupropion augmentation or a switch to bupropion. Third, among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were low but similar.

Q: Describe some of the limitations of this trial.

A: The trial had no placebo group and patients were aware of their trial-group assignment, so the authors cannot rule out the possibility that patients may have been reacting positively to receiving two drugs rather than one and cannot determine whether any of the treatment strategies was better than no change in pharmacologic treatment. The trial enrolled approximately half its targeted sample; therefore, tests of effectiveness or safety may have been underpowered. Each step of the trial lasted 10 weeks, and the authors cannot assess whether longer exposure to a trial drug would have had different effectiveness or risks. Adherence to the treatment strategies was in the range of 50 to 70%, which highlights the challenge of managing treatment-resistant depression in real-world settings. The number of patients who belonged to traditionally underrepresented racial or ethnic groups was smaller than planned, possibly related to disparities of access.

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