ST. LOUIS — In older adults with treatment-resistant depression, adding a second medication to their existing antidepressant medication leads to greater improvements in psychological well-being and a higher remission rate from depression, compared to switching to a different medication, according to a new study.
The two-step, open-label trial published in The New England Journal of Medicine examined the benefits and risks of augmenting (adding a second medication to an existing antidepressant) or switching antidepressants with one from a different class in older adults with treatment-resistant depression, which has not been extensively studied.1
That is especially important for VA clinicians, who treat an older population with a high rate of depression. The new study also adds to data provided by the 2017 VAST-D clinical trial conducted by the VA at 35 sites. That study also asked if there is a difference among pharmacotherapeutic approaches for treating patients with depression unresponsive to an antidepressant course. The 12-week follow-up of a randomized clinical trial of 1,522 veterans with major depressive disorder (85% men) unresponsive to previous antidepressant treatment, 29% achieved remission after augmenting their antidepressant with the antipsychotic aripiprazole vs. 22% who switched to the antidepressant bupropion. Other remission comparisons were not significant.
In that study, published in JAMA, augmentation with aripiprazole resulted in a statistically significant, but only modestly increased, likelihood of remission during 12 weeks of treatment compared with switching to bupropion alone.2
At 54.4, the age of participants in the VAST-D study were slightly younger than those in the more recent trial, 60, and who were mostly from a primary care setting. The trial was conducted at five sites: Washington University in St. Louis (coordinating site); Columbia University; the University of California, Los Angeles; the University of Pittsburgh; and the University of Toronto.
In this randomized controlled trial, patients on existing antidepressant medication were recruited and then assigned to get augmented with either of two medications (aripiprazole or bupropion), which are popular augmentation medications. Or they were switched to bupropion, which is also popular as a switch option. If patients were ineligible for this first step, or they took part in this step and didn’t remit, then they were eligible for a second step, which was essentially a separate clinical trial that tested augmentation with lithium or a switch to nortriptyline.
Each step lasted about 10 weeks, with up to 10 additional weeks allowed to accommodate any delays in initiating treatment changes and assessing outcomes. Patients were followed with calls or in-person visits every other week with a trial clinician, who assessed depression severity using the nine-item Patient Health Questionnaire (PHQ-9), as well as adherence to medication and the occurrence of adverse events. The trial clinician provided guidance to the managing provider on whether to adjust the trial medication on the basis of symptoms and side effects.
The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. A secondary outcome was remission of depression.
“Treatment-resistant depression is a major issue in all adults,” Eric Lenze, M.D., professor and head of psychiatry at Washington University School of Medicine in St. Louis, told U.S. Medicine. “Probably 30% of people suffering from depression have it. Older adults are not more likely than younger adults.”
Augmentation Leads to Improvements
“In our study, we found that augmenting, or adding a second medication, led to greater improvements in psychological well-being and a higher remission rate from depression, compared to switching to a different medication,” Lenze added.
In step one, a total of 619 patients were enrolled. Of these patients, 211 were assigned to aripiprazole augmentation, 206 were assigned to bupropion augmentation, and 202 were switched to bupropion. Well-being scores improved by 4.83 points, 4.33 points and 2.04 points, respectively.
The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P=0.014). The between-group differences were not significant for aripiprazole augmentation vs. bupropion augmentation or for bupropion augmentation vs. a switch to bupropion.
Remission from depression occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation.
In step two, a total of 248 patients were enrolled. Of these patients, 127 were assigned to lithium augmentation, and 121 were switched to nortriptyline. Changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission from depression occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group. Rates of falling were similar in the two groups, according to the study.
The study found that, in older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a higher incidence of remission. In patients where augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar.
Lenz noted that the findings were broadly consistent with the VA Augmentation and Switching Treatments for Improving Depression Outcomes “VAST-D” study, which was done for treatment-resistant depression in veterans.
In older adults, treatment failure for depression is associated with decreased psychological well-being, disability and cognitive decline, according to the NEJM study. The most important finding, according to the authors, is that there’s hope for older adults whose depression does not respond to the first or second treatment that is tried. These patients should keep trying.
Healthcare professionals who have older adult patients with treatment-resistant depression should “use these findings to get their patients the best treatment option to maximize their chances for recovery,” Lenze wrote in an email. “Treatment-resistant depression is treatable. This clinical trial helps patients and providers find the best treatment option.”
- Lenze EJ, Mulsant BH, Roose SP, Lavretsky H, Reynolds CF 3rd, Blumberger DM, Brown PJ, Cristancho P, Flint AJ, Gebara MA, Gettinger TR, Lenard E, Miller JP, Nicol GE, Oughli HA, Pham VT, Rollman BL, Yang L, Karp JF. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression. N Engl J Med. 2023 Mar 23;388(12):1067-1079. doi: 10.1056/NEJMoa2204462. Epub 2023 Mar 3. PMID: 36867173.
- Mohamed S, Johnson GR, Chen P, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017;318(2):132–145. doi:10.1001/jama.2017.8036
