Treating Depression in Older Adults
Depression affects over 21 million adults in the United States each year. Yet the American Psychiatric Association has not updated its guidelines for the treatment of Major Depressive Disorder since 2010, despite two updates to the definition of depression (in the DSM V and DSM V-TR) in that same period. Equally troubling is the lack of specific guidance for treating depression in older adults, in whom both depression itself and the pharmacologic treatments for the disease are associated with poorer outcomes. The complexity increases when first-line therapy fails and clinicians must weigh the risks of next steps – augment with additional agents but add to polypharmacy, or switch to a new medication? While there are guidelines from Canada about approaching this challenge, those mostly extrapolate from studies conducted in younger adults.
Fortunately, in March 2023, the OPTIMUM trial was published, assessing the risks and benefits of augmenting versus switching antidepressants in older adults with treatment-resistant depression that did not respond to initial pharmacotherapy. However, before diving into those results, it’s important to understand the foundation upon which OPTIMUM is built – STAR*D and VAST-D.
Breaking Down The Depression Trials
STAR*D is the most cited evidence for depression treatment algorithms. The trial included around 4000 patients with depression, treated with citalopram. Those with an inadequate response could choose to either switch to an SSRI/SNRI/bupropion or augment citalopram with bupropion on buspirone, and were randomized to an option within the category they chose. If neither strategy worked, participants were again randomized to switch or augment their medications with other medications. In STAR*D, a third of participants achieved remission with citalopram, and all medications in both the switch and augment groups led to additional gains in remission. However, this trial had a glaring limitation – patients chose whether they would switch or augment therapy, thus limiting its ability to identify which strategy was best.
With this limitation in mind, the VAST-D trial evaluated 1522 patients with treatment resistant depression already on an SSRI, SNRI, or mirtazapine and randomized them to one of three-arms: 1) switch to bupropion, 2) augment with aripiprazole, or 3) augment with bupropion. Participants who augmented with aripiprazole were slightly more likely to achieve remission compared with those who switched to bupropion (28.9% versus 22.3%, p=0.02), with no apparent difference between augmenting with aripiprazole versus bupropion. Enrolling patients through the Veterans Health Administration, trial limitations included its mostly male (85%) and younger (mean age 54) population.
Enter OPTIMUM, which randomized 619 adults over sixty with treatment-resistant depression to 1) augmentation of existing antidepressant medication with aripiprazole, 2) augmentation with bupropion, or 3) a switch to bupropion. The results largely mirrored what was seen in VAST-D: those randomized to augmentation with aripiprazole had better well-being scores than those who switched to bupropion (difference in well-being score of 2.79 points, 95% CI 0.56 - 5.02, p 0.014), and a numerically higher incidence of remission. Patients who did not experience benefit were then randomized again to augmentation with lithium or switch to nortriptyline, which were both equally effective. While limited by some imbalance in baseline covariates (e.g. the augment-aripiprazole had higher PHQ9 scores) and an open-label design, the results still provide useful information specific to older adults. And notably, falls, which are typically associated with antipsychotic use, were actually highest in the augment-with-bupropion group, not with aripiprazole.
STAR*D, VAST-D, and OPTIMUM – what’s the takeaway?
As we wait for updated guidelines, it appears that in treatment-resistant depression, augmenting baseline antidepressant therapy is safe and more effective than switching agents, even in older adults. Aripiprazole may be a particularly attractive option, with a lower fall risk than other augmentation options–though we still need to be cognizant of polypharmacy and its contributions to morbidity in elderly patients. At the end of the day, also remember that there is a new nation-wide suicide and crisis lifeline telephone number – 988 – that’s available for all!
Read the Paper Here