Advantage of Augmenting Antidepressant Over Switching Qualified in New Analysis

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The Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM)study finding that combining, rather than switching antidepressants is more likely effective for late life treatment resistant depression (TRD) has been recently qualified by the investigators, after completing a preplanned analysis to assess moderators of therapeutic response.^1,2

In the original OPTIMUM study, augmentation of the current antidepressant with aripiprazole was superior to switching to bupropion in measures of psychological well being. In addition, more patients (albeit numerically rather than statistically) attained remission by augmenting with either aripiprazole or bupropion than by switching to bupropion.

In the current analysis, the investigators assessed whether any of 5 factors which have been negatively associated with antidepressant treatment outcomes in late life depression had moderated the effect of augmentation vs switching. The hypothesized moderators were age, executive dysfunction, comorbid medical burden, comorbid anxiety, and degree of treatment resistance.

"Identifying moderators that influence the effectiveness of these treatment strategies advances personalized medicine," the investigators indicated. "For example, a moderator that can be assessed by a clinician, such as age, helps the clinician choose the optimal treatment strategy based on individual characteristics in day-to-day practice."

Executive dysfunction was measured using the National Institutes of Health Toolbox fluid cognition composite, comorbid medical burden with the Cumulative Illness Rating Scale-Geriatric, and comorbid anxiety with the Patient Reported Outcomes Measurement Information System anxiety scale. The number of prior antidepressant trials, either augmentation or switching, that the participant had undergone without adequate response served as a proxy for the degree of treatment resistance.

Of the 5 factors, only severity of treatment resistance, corresponding to 3 or more unsuccessful antidepressant trials, was found to negate the advantage of augmentation that had been apparent across the OPTIMUM cohort. The investigators note that this finding was independent of specific medications or whether the previous trials involved augmentation or switching. They were not able to identify moderators for remission, as this was attained in less than a third of the study participants.

The study’s lead author, Helena Kim, MD, PhD, Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Canada, discussed the finding and the implication for treating TRD in older patients with Psychiatric Times.

"Switching performed poorly in patients with late life treatment resistant depression regardless of the number of previous trials," Kim noted. "Augmentation allowed patients to still benefit from pharmacotherapy, but only in those with less than 3 trials. This suggests that those with more trials should be considered for alternative treatments.”

Principal investigator Benoit Mulsant, MD, MS, also of the Department of Psychiatry, University of Toronto, suggested that these alternative treatments could include repetitive transcranial magnetic stimulation, ketamine, and electroconvulsive therapy.

Mulsant also suggested, however, that antidepressant selection, with consideration of tolerability, could enhance the likelihood of success in trials and obviate need to consider alternative treatments. An example would be sertraline first line; venlafaxine second line; venlafaxine plus aripiprazole, or venlafaxine plus either bupropion or nortriptyline third line.

"Psychotherapy can be used for milder depression as first line or added to antidepressant at any point," Mulsant said. "Then, as a fourth step, consider alternative treatments."

Mulsant pointed out that with a "trial and error" approach, the 4 steps could require 1 year or longer. "To accelerate response, we need to be able to identify subgroups of patients who are more or less likely to benefit from specific steps," he said.

The investigators had not found moderation effect from the other hypothesized factors despite multiple methods of analysis. To assess possible effect of age, for example, they examined it as both a continuous variable, and by setting a threshold, eg, for "very old." Similarly, executive dysfunction was assessed using the different thresholds of "impaired" and "very impaired."

Kim and Mulsant indicate that they will be doing additional work using decision tree analysis to identify subgroups of patients who are more or less likely to benefit from various treatments, toward their goal of improving personalization of pharmacotherapy.

"I hope to see future research focused on ensuring that the identification of modifiers and predictors of antidepressant response becomes directly relevant to real-world clinical decision making," Kim said. "Our work using decision-tree analyses is an example of how we can begin addressing these questions, with the ultimate goal of advancing personalized medicine in psychiatry."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. 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.

2. Kim HK, Karp JF, Lavretsky H, et al. Moderators of antidepressant augmentation versus switch in the OPTIMUM randomized controlled trial. Br J Psychiatry. 2025:1-8.