How to Choose TRD Augmentation by Age and Baseline BMI
How should clinicians choose between bupropion augmentation, aripiprazole augmentation, and switching to bupropion for treatment-resistant depression using age and baseline BMI?
Patients with treatment-resistant depression often need a next-step medication strategy after inadequate antidepressant response, but the best option changes when long-term harms are weighed against symptom benefit. This guide applies to adults being considered for switching to bupropion, adding bupropion, or augmenting with aripiprazole, and focuses on the age and baseline BMI features that changed treatment ranking in the article's risk-benefit model.
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Confirm that the patient fits the treatment-resistant depression population studied
Use this framework for a patient with a depressive episode that has shown insufficient response to at least 1 prior antidepressant trial, recognizing that treatment-resistant depression is commonly defined as insufficient response to 2 or more antidepressant therapies of appropriate dose and duration. The article's underlying trials primarily involved patients with 2 or more failed antidepressant trials, although some VAST-D participants had only 1 prior failed trial.
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Classify the patient's age group
Place the patient into one of the age strata used in the model: 18 to 64 years, 65 to 84 years, or 85 to 89 years. Age mattered because fall-related harms from combination bupropion were modeled only in adults 50 years or older and were most influential in the oldest subgroup.
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Determine baseline BMI category before comparing options
Classify baseline BMI as nonelevated or elevated, using elevated BMI as 25 or greater as defined in the model. This distinction is critical because relative net weight gain with aripiprazole was tracked in the base case only in subgroups with elevated baseline BMI, where additional weight gain was considered most clinically relevant.
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Use bupropion augmentation as the default preferred strategy in adults younger than 85 years
For adults younger than 85 years, combination therapy with bupropion was the preferred treatment in the base case over both switching to bupropion and aripiprazole augmentation. In adults under 65 years, the incremental net health benefit of combination bupropion over switching to bupropion was equivalent to remission of depression about 3 weeks earlier on average.
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Adjust for fall risk when the patient is older
In older adults, weigh the increased fall risk associated with combination bupropion more heavily, especially in the 85 to 89 year age group. In the base case, fall harms did not outweigh the benefits of combination bupropion over switching to bupropion at any age, but they were pronounced enough in adults aged 85 to 89 years to change the ranking against aripiprazole in the nonelevated-weight subgroup.
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Prefer aripiprazole over bupropion augmentation only in the oldest nonelevated-weight subgroup
For adults aged 85 to 89 years with nonelevated weight, aripiprazole augmentation was the preferred treatment in the base case. In that subgroup, aripiprazole offered 3.0 more depression-free day equivalents than combination bupropion and 10.9 more than switching to bupropion.
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Do not make switching to bupropion the preferred strategy based on this model alone
Switching to bupropion was not the preferred treatment for any subgroup in the base case. It remained useful as a comparator, but the model favored combination bupropion overall and favored aripiprazole only in the oldest nonelevated-weight subgroup.
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Explain uncertainty explicitly in the oldest patients
When the patient is aged 85 to 89 years, discuss that treatment ranking was least stable in this group. Among adults aged 85 to 89 years with nonelevated weight, probabilistic sensitivity analysis favored aripiprazole in 58.8% of runs, combination bupropion in 36.0%, and switching to bupropion in 5.2%.
Clinical Considerations
- The model included only 1 year of treatment, although many patients with treatment-resistant depression need ongoing treatment and may face different long-term risk-benefit profiles.
- The article modeled only selected long-term harms, specifically serious falls, clinically significant weight gain, and tardive dyskinesia, and did not include other known adverse effects such as akathisia or insomnia.
- Generalizability is limited because OPTIMUM focused on older adults and VAST-D involved veterans who were generally male and had high rates of comorbid PTSD.
- Some VAST-D participants had failed only 1 prior antidepressant trial, so not all underlying trial participants met the most common definition of treatment-resistant depression.
Bottom Line
For most adults with treatment-resistant depression, especially those younger than 85 years, bupropion augmentation offered the best overall modeled balance of benefit and harm, with aripiprazole preferred only for adults aged 85 to 89 years who had nonelevated weight.
