Augmentation therapy with aripiprazole gets a win for difficult-to-treat depression

The addition of the antipsychotic drug aripiprazole to current antidepressant medications may help improve the symptoms of clinical depression in older adults who have not responded to standard treatments, as reported in a study.

Furthermore, this strategy of augmentation of existing antidepressants with aripiprazole is more effective than a switch to another antidepressant medication and leads to a numerically higher incidence of remission, according to investigators led by Dr Eric Lenze of the Department of Psychiatry at Washington University in St. Louis, Missouri, US.

In the first step of the study, which involved 619 patients at least 60 years old with tough-to-treat depression, well-being scores over 10 weeks of treatment improved by 4.83 points among the 211 patients who were assigned to aripiprazole augmentation, by 4.33 points among the 206 who were assigned to bupropion augmentation, and by 2.04 points among the 202 who were assigned to a switch to bupropion. [New Engl J Med 2023;doi:10.1056/NEJMoa2204462]

The difference in well-being scores between the aripiprazole-augmentation and the switch-to-bupropion groups was significant (2.79 points, 95 percent confidence interval [CI], 0.56–5.02; p=0.014), while the difference between the aripiprazole-augmentation and bupropion-augmentation groups or between the bupropion-augmentation and the switch-to-bupropion groups was not.

Augmentation therapy with aripiprazole helped 28.9 percent of patients achieve remission. This remission rate was similar to that achieved with bupropion augmentation (28.2 percent) but was lower than that achieved with a switch to bupropion (19.3 percent).

In terms of the frequency of falling, the highest recorded was in the bupropion-augmentation group.

For people with clinical depression who do not respond to their medications, some clinicians prescribe a switch to different antidepressants with the goal of finding one that works, while others prescribe another class of drugs to find out if a combination of medications helps. Both strategies have been recommended for older adults with treatment-resistant depression.

“Often, unless a patient responds to the first treatment prescribed for depression, physicians follow a pattern in which they try one treatment after another until they land on an effective medication,” Lenze said, emphasizing the importance of having an evidence-based strategy that clinicians can rely on to help their patients feel better as quickly as possible.

“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being—which means how positive and satisfied patients felt—and this is good news. However, even that approach helped only about 30 percent of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” Lenze admitted.

When aripiprazole augmentation fails

Lenze and colleagues acknowledged earlier on that there was going to be a substantial proportion of study participants who would not respond to their assigned treatments. So, the investigators had added a second step in the trial wherein the participants who did not benefit from step-1 treatment (n=248) were randomly assigned to either augmentation therapy with lithium (n=127) or a switch to nortriptyline (n=121). Treatment lasted for another 10 weeks.

Well-being scores improved by 3.17 points with lithium augmentation and by 2.18 points with a switch to nortriptyline, with a corresponding difference of 0.99 point (95 percent CI, −1.92 to 3.91). In addition, remission rates were lower relative to those recorded in the first step of the study: 18.9 percent of patients in the lithium-augmentation group and 21.5 percent in the switch-to-nortriptyline group.

Fall frequency was similar in the two groups.

Lithium and nortriptyline had been the most used antidepressive medications until other, newer drugs were developed and approved more than two decades ago. Lenze stressed that these older drugs are a bit more complicated to use than newer ones.

“Lithium, for example, requires blood testing to ensure its safety, and it's recommended that patients taking nortriptyline receive electrocardiograms periodically to monitor the heart’s electrical activity,” he said. “Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases.”

Most older adults, as Lenze noted, are likely to be already taking several medications for other conditions such as high blood pressure, cardiac issues, or diabetes. So, the problem of managing clinical depression that does not respond to two drugs becomes particularly more difficult.

"[S]witching to new antidepressants every few weeks or adding other psychiatric drugs can be complicated. In addition, because depression and anxiety in older adults may accelerate cognitive decline, there's an urgency to find more effective treatment strategies,” Lenze explained.

“There definitely is something that makes depression harder to treat in this population—a population that's only going to keep getting larger as our society gets older,” he added.