Adding aripiprazole beat switching drugs in resistant depression in older adults
In a 619-patient NEJM trial of treatment-resistant depression after 60, augmenting an antidepressant with aripiprazole improved well-being more than switching to bupropion. The margin was modest.
| Group | Value (%) |
|---|---|
| Aripiprazole augmentation | 28.9 |
| Bupropion augmentation | 28.2 |
| Switch to bupropion | 19.3 |
In older adults whose depression had not responded to antidepressants, adding low-dose aripiprazole to the drug they were already taking improved well-being more than switching them to a different antidepressant, in a 619-patient randomised trial [s1]. The advantage was real but modest — a 2.79-point difference on a well-being scale — and even in the best-performing group, remission reached fewer than a third of patients [s1].
That is a useful, undersold result: for late-life treatment-resistant depression, augmenting a failing antidepressant tends to beat abandoning it, but no strategy in the trial worked for most people.
How the trial was built
The OPTIMUM trial enrolled adults 60 years of age or older with treatment-resistant depression and ran in two open-label steps [s1]. In step 1, 619 patients were randomly assigned in equal thirds: 211 to augmentation of their existing antidepressant with aripiprazole, 206 to augmentation with bupropion, and 202 to a switch from their antidepressant to bupropion [s1]. Each step lasted about 10 weeks [s1].
The primary outcome was not remission but psychological well-being, measured on National Institutes of Health Toolbox scales for positive affect and general life satisfaction, scored to a population mean of 50, with higher scores better [s1]. Remission of depression was a secondary outcome [s1].
What the numbers showed
Well-being scores improved by 4.83 points with aripiprazole augmentation, 4.33 with bupropion augmentation, and 2.04 with a switch to bupropion [s1]. The one comparison that cleared its statistical bar was aripiprazole augmentation versus switching: a difference of 2.79 points (95% confidence interval 0.56 to 5.02; P=0.014, against a prespecified threshold of 0.017) [s1]. The other contrasts — aripiprazole versus bupropion augmentation, and bupropion augmentation versus switching — were not significant [s1].
Remission tracked the same direction. It occurred in 28.9% of the aripiprazole-augmentation group, 28.2% of the bupropion-augmentation group, and 19.3% of the switch-to-bupropion group [s1]. In other words, adding a second drug lifted the remission rate by roughly nine or ten percentage points over switching, but left seven in ten patients still depressed.
The same ranking in a larger, broader trial
OPTIMUM did not appear out of nowhere. An earlier and larger trial, VAST-D, had tested the same question in a broader population — 1,522 patients (mean age 54.4 years, 85.2% men) with major depression unresponsive to treatment [s2]. It found the same ordering. Remission at 12 weeks reached 28.9% with aripiprazole augmentation, 26.9% with bupropion augmentation, and 22.3% with a switch to bupropion; augmentation with aripiprazole significantly exceeded switching (relative risk 1.30, 95% confidence interval 1.05 to 1.60; P=0.02), while the other comparisons did not separate [s2]. That two trials in different populations land in the same place is what makes the modest signal credible.
VAST-D also sharpens the safety picture in a way specific to aripiprazole, an antipsychotic used here off its original purpose. The adverse effects more frequent in the aripiprazole group were somnolence, akathisia — a distressing restlessness — and weight gain [s2]. Those are the trade-offs a prescriber weighs against a remission gain that, in both trials, fell short of the majority of patients.
The safety signal, and the second step
The gain did not come free. The rate of falls was highest in the bupropion-augmentation group [s1] — a serious matter in older patients, for whom a fall can be more consequential than the depression being treated. That is part of why this piece carries a held risk rating: the choice turns on dose, drug interactions and fall risk that belong to a clinician, not a summary.
Patients who did not benefit from or were ineligible for step 1 moved to step 2, where 248 were randomised to augmentation with lithium or a switch to nortriptyline [s1]. Here the trial found no meaningful separation: well-being improved by 3.17 points with lithium augmentation and 2.18 with the nortriptyline switch, a difference of 0.99 points whose confidence interval (−1.92 to 3.91) straddled zero [s1]. Remission with lithium augmentation was 18.9% [s1].
What it settles
It settles that, for depression that resists treatment in later life, augmenting an antidepressant with aripiprazole modestly outperforms switching to bupropion on well-being, and that the augmentation strategies produced higher remission than switching [s1]. It does not make aripiprazole a cure: the absolute well-being gain was small, most patients did not remit, and the fall risk of one comparator is a live concern [s1]. The consistency with VAST-D extends the finding beyond the over-60s, but so do that trial's own cautions — akathisia and weight gain are the price of the augmentation strategy that worked best [s2]. This article describes evidence and is not medical advice.
Sources
- Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression — New England Journal of Medicine, 2023-03-03
- Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment — JAMA, 2017-07-11
Sources
- Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression — New England Journal of Medicine , March 3, 2023
- Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment — JAMA , July 11, 2017
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