Translating Research Into Practice
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A monthly column dedicated to reviewing the literature and sharing clinical implications.
Treatment-resistant depression (TRD) is a serious medical condition, which if not adequately treated can result in reduced psychological well-being and functional and cognitive decline among older adults. This study tries to determine whether augmentation of an antidepressant medication is a better treatment strategy than switching to another antidepressant among these individuals.
The Study
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.
Study Funding
Patient-Centered Outcomes Research Institute
Study Objectives
To investigate the benefits and risks of augmentation compared with switching strategies for TRD in older adults.
Methodology
This study was a 10-week, randomized, open-label, 2-step trial at 5 sites in the United States. Outcome assessors were blinded to assignments, while participants and investigators were not.
Inclusion criteria included the following: (1) men and women 60 years and older; (2) current major depressive disorder, single or recurrent; (3) failure to respond adequately to 2 or more antidepressant treatment trials; and (4) Patient Health Questionnaire-9 score of 6 or higher (changed to 10 or higher).
Step 1 of the trial consisted of random assignment to 1 of 3 treatment options: (1) augmentation with aripiprazole (2.5 mg to 15 mg qd max); (2) augmentation with bupropion ER (150 mg to 450 mg qd, target 300 mg); or (3) switch to bupropion ER (same dosage parameters).
Step 2 of the trial consisted of random assignment to 1 of 2 treatment options: (1) augmentation with lithium (150/300 mg to 1200 mg qd, target 0.6 mmol/L); or (2) switch to nortriptyline (25 mg to 1 mg/kg qd, target 80-120 ng/mL). Participants were assigned to step 2 if they had no remission or benefit from step 1 or if they were ineligible for step 1.
Primary effectiveness outcome was psychological well-being measured using the National Institutes of Health Toolbox Emotion Battery Subscales for Positive Affect and General Life Satisfaction (combined T-score of the average of the 2 subscales). Secondary effectiveness outcomes included remission of depression, changes in Montgomery-Asberg Depression Rating Scale (MADRS) score, and changes in social participation and physical function. Primary safety outcomes were falls and serious adverse events.
The study had a power of 80% to detect a between-group difference of 2.6 points in well- being scores. Analyses were conducted according to the intention-to-treat principle. Well-being was compared with repeated-measures analysis of variance with time-by-trial-group contrasts. A Benjamini-Hochberg step-down procedure was used for control of multiple comparisons. A P value less than .05 was considered significant for well-being scores and safety analysis.
Remission percentages were compared with generalized linear models with a Poisson link function for risk ratio estimates. Rates of falls were compared with a repeated-measures generalized linear model with a Poisson link function. Serious adverse events were compared with Cox models of time to event with Andersen and Gill extensions for repeated events.
Study Results
Following recruitment, 742 participants underwent open-label randomization. Then 619 participants were randomly assigned into 1 of the 3 step 1 groups, while 123 participants were randomly assigned directly into 1 of the 2 step 2 groups due to ineligibility for participation in step 1, usually due to a past use of a step 1 drug.
At the completion of step 1, 125 participants were deemed to have not experienced remission of depression and they were randomly assigned into step 2, for a total of 248 participants in step 2.
Participant demographics and clinical characteristics were consistent across treatment groups and steps. In step 1, mean age was 69.3 years, 66.7% of participants were female, and 84.3% of patients were White. In step 2, mean age was 68.5 years, 69.8% of patients were female, and 89.5% of patients were White.
Adherence rates in step 1 were approximately 70% for those assigned to augment with aripiprazole or bupropion, but only approximately 40% for those assigned to switch to bupropion. Adherence rates in step 2 were approximately 50% for both groups.
Primary Effectiveness Outcome
In step 1, improvement from baseline psychological well-being T scores were 4.83 points (95% CI, 3.28-6.38) for the aripiprazole-augmentation group, 4.33 points (95% CI, 2.76-5.91) for the bupropion-augmentation group, and 2.04 points (95% CI, 0.43-3.66) for the switch-to-bupropion group. However, the only statistically significant difference was between the aripiprazole-augmentation group and the switch-to-bupropion group with a difference of 2.79 points (95% CI, 0.56-5.02) and a significant P value of .014.
In step 2, improvements from baseline psychological well-being T scores were 3.17 points (95% CI, 1.12-5.22) for the lithium-augmentation group and 2.18 (95% CI, 0.10-4.26) for the switch-to-nortriptyline group. The difference between the groups was found to be 0.99 points but statistically insignificant.
Secondary Effectiveness Outcomes In step 1, MADRS score changes from baseline were −7.60 (95% CI, −9.20 to −5.99) for the aripiprazole-augmentation group, −7.23 (95% CI, −8.86 to −5.59) for the bupropion-augmentation group, and −4.14 (95% CI, −5.81 to −2.48) for the switch-to-bupropion group. Observed remission rates were 28.9% for the aripiprazole-augmentation group, 28.2% for the bupropion-augmentation group, and 19.3% for the switch-to-bupropion group.
These remission rates were compared against the switch-to-bupropion group and the resultant risk ratios were 1.50 (95% CI, 1.06-2.13) in the aripiprazole augmentation group and 1.49 (95% CI, 1.04-2.12) in the bupropion-augmentation group.
In step 2, MADRS score changes from baseline were −4.63 (95% CI, −6.78 to −2.49) for the lithium-augmentation group and −5.33 (95% CI, −7.52 to −3.14) for the switch-to-nortriptyline group. Observed remission rates were 18.9% in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group. The calculated risk ratio of the lithium-augmentation group compared with the switch-to-nortriptyline group was 0.84 (95% CI, 0.53-1.36).
The secondary effectiveness outcomes of changes in Patient-Reported Outcomes Measurement Information System scores measuring participant social participation and physical function were comparable between treatment groups of each step.
Study Strengths
1. Outcome measures were determined through feedback from real-world patients, and treatment interventions were determined through surveys of providers who treat older adults with TRD.
2. There was no industry involvement in funding, minimizing the risk of bias.
3. The study addresses a common clinical scenario and provides crucial data for treatment planning in the geriatric population.
4. The protocol simulated real-world barriers, such as cost to patients, increasing the applicability to a real-world clinical population.
Study Limitations
1. The study was not placebo controlled; participants may have responded to the placebo effect of receiving 2 drugs rather than 1.
2. The 10-week duration of the study limits our ability to draw conclusions about long-term effects.
3. The study population lacked racial and ethnic diversity, which may affect the generalizability of the findings.
Safety Outcomes
In step 1, the 10-week fall rates were 0.33 falls per participant in the aripiprazole-augmentation group, 0.55 falls per participant in the bupropion-augmentation group, and 0.38 falls per participant in the switch-to-bupropion group. Risk ratios comparing the fall rates of the treatment groups were calculated and the only statistically significant risk ratio was that comparing aripiprazole-augmentation and bupropion-augmentation: 0.59 (95% CI, 0.38-0.92; P = .02).
The rate of overall adverse events in each treatment group was low and the HRs between the groups were statistically insignificant. In step 2, the fall rates were 0.47 falls per participant in the aripiprazole-augmentation group and 0.38 falls per participant in the switch-to-nortriptyline group. The risk ratios between the groups were statistically insignificant. The rates of serious adverse events in the treatment groups were low and the HR between the groups was statistically insignificant.
Conclusions
There were 3 key findings from this high-quality effectiveness study: (1) augmentation with aripiprazole was significantly better at improving psychological well-being than switching to bupropion; (2) bupropion augmentation was similarly effective at improving well-being as aripiprazole augmentation but was also associated with a higher rate of falls; and (3) augmenting with lithium and switching to nortriptyline were similarly effective.
Practical Applications
Augmenting with aripiprazole was determined to be the best antidepressant strategy due to superior effectiveness and short-term safety outcomes in geriatric patients with TRD. However, this study did not assess long-term effects of medications, such as the known long-term metabolic adverse effects of aripiprazole.
Bottom Line
This high-quality effectiveness trial answers an important clinical question commonly seen in psychiatry. While the effect sizes were small, it did show that augmenting with aripiprazole was the most effective and safest treatment option, at least in the short term. However, clinicians should still consider the unique characteristics and values of their patients as well as the known long-term adverse effects of medications when considering treatment options for TRD in older adults.
Dr Marasinghe is a second-year psychiatry resident at Creighton University School of Medicine in Omaha, Nebraska. Dr Jalasutram is a first-year psychiatry resident at Creighton University School of Medicine.
Dr Ryan and Dr Mullen are fourth-year psychiatry residents at Creighton University School of Medicine.
Dr Tampi is a professor and chairman in the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut.
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. Cristancho P, Lenard E, Lenze EJ, et al. Corrigendum to optimizing outcomes of treatment-resistant depression in older adults (OPTIMUM): study design and treatment characteristics of the first 396 participants randomized. Am J Geriatr Psychiatry. 2019;27(10):1138-1152.
3. Salsman JM, Lai JS, Hendrie HC, et al. Assessing psychological well-being: self-report instruments for the NIH Toolbox. Qual Life Res. 2014;23(1):205-215.
