Over half of older adults with MDD do not adequately respond to first-line pharmacotherapy with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors. In September 2015, Charles Reynolds III, M.D., a professor of geriatric psychiatry at the University of Pittsburgh, and colleagues published findings that showed that adding aripiprazole to the treatment regimen of patients aged 60 and older whose major depression had failed to remit after 12 weeks of venlafaxine monotherapy helped more patients achieve remission than those who did not take the combination of medications.
As a follow-up to this trial, the researchers examined the potential moderating effects of executive dysfunction, comorbid anxiety, and medical burden in remission of treatment-resistant late-life depression after 12 weeks of aripiprazole augmentation. (All of these factors have been implicated in contributing to poor antidepressant responses in late-life depression, but they have not previously been examined in second-line therapies.)
Prior to starting the 12 weeks of venlafaxine extended-release treatment, study participants were given a series of neuropsychological tests, including the Color-Word Interference task, which measures response inhibition, and the Trail Making Test tasks, which measures set-shifting (the ability to shift attention from one task to another). Researchers also used the Brief Symptom Inventory and Cumulative Illness Rating Scale for Geriatrics to assess comorbid anxiety and medical burden, respectively.
Of the 181 trial participants whose major depression had failed to remit with venlafaxine hydrochloride monotherapy (150 mg/day to 300 mg/day for 12 weeks), 91 received aripiprazole (target dose 10 mg/day), and 90 received placebo. Remission occurred in 40 (43%) who received aripiprazole and 26 (29%) who received placebo. Set-shifting performance was found to moderate the effectiveness of aripiprazole augmentation; among participants with a Trail Making Test scaled score of 7 or higher, the odds of remission were significantly higher with aripiprazole than with placebo (53% vs 28%). Among participants with a Trail Making Test scaled score of less than 7, aripiprazole and placebo were equally efficacious. Greater severity of anxiety at baseline predicted a lower remission rate but did not moderate aripiprazole efficacy; each standard deviation greater anxiety severity was associated with 50% reduced odds of remission in both aripiprazole and placebo arms. Neither medical morbidity nor response inhibition was related to remission.
“Our findings support set-shifting performance as a moderator of short-term remission (i.e., influencing the efficacy of aripiprazole) and distinguish anxiety as a general short-term prognostic variable (predictor),” the authors wrote. “Further examining a wider range of pretreatment factors, including other aspects of cognition, as well as the neurobiological basis of these observed effects, will continue to improve our understanding of how treatments work and for whom they do or do not work.”
In a related editorial, Warren Taylor, M.D., an associate professor of psychiatry at Vanderbilt University Medical Center, offered several reflections on the implications of the findings for clinical treatment and clinical trial methodology.
“Although this study’s findings require replication, the potential for using a common, easy-to-administer neuropsychological test to personalize antidepressant treatment decisions for older adults is appealing. However, even with this approach, remission rates continue to be lower than we would like,” Taylor wrote. “This study’s findings are thus a step forward, but it also highlights the need for more effective interventions, particularly for individuals with executive dysfunction or substantial comorbid anxiety.”
For related information, see the Psychiatric News article “Combining Aripiprazole, Venlafaxine Reduces Depressive Symptoms in Older Adults.”
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