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Original Investigation |

Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression An Analysis of the IRL-GRey Randomized Clinical Trial

Shriya H. Kaneriya, BA1; Gregg A. Robbins-Welty, BS1; Stephen F. Smagula, PhD2; Jordan F. Karp, MD2; Meryl A. Butters, PhD2; Eric J. Lenze, MD3; Benoit H. Mulsant, MD4; Daniel Blumberger, MD4; Stewart J. Anderson, PhD5; Mary Amanda Dew, PhD2,6,7,8,9; Francis Lotrich, MD, PhD2; Howard J. Aizenstein, MD, PhD2; Breno S. Diniz, MD, PhD10,11; Charles F. Reynolds III, MD2,12
[+] Author Affiliations
1University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
2Department of Psychiatry, Western Psychiatric Institute and Clinic of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
3Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
4Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
5Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
6Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
7Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
8Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
9Department of Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania
10Department of Mental Health, Federal University of Minas Gerais School of Medicine, Belo Horizonte, Minas Gerais, Brazil
11Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston
12Department of Behavioral and Community Health Sciences, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
JAMA Psychiatry. 2016;73(4):329-336. doi:10.1001/jamapsychiatry.2015.3447.
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Importance  Safe, efficacious, second-line pharmacological treatment options exist for the large portion of older adults with major depressive disorder who do not respond to first-line pharmacotherapy. However, limited evidence exists to aid clinical decision making regarding which patients will benefit from which second-line treatments.

Objective  To test the moderating role of pretreatment executive function, severity of anxiety, and severity of medical comorbidity in remission of treatment-resistant late-life depression after aripiprazole augmentation.

Design, Setting, and Participants  As follow-up to a 12-week randomized clinical trial of aripiprazole augmentation for first-line treatment-resistant late-life depression (Incomplete Response in Late-Life Depression: Getting to Remission [IRL-GRey]), we evaluated the effects of the following potential moderators and their interactions with treatment: baseline assessments of executive function (set shifting measured by the Trail Making Test) and response inhibition control (measured by a Color-Word Interference task), anxiety symptoms, and medical comorbidity. Analyses were conducted in May and June 2015.

Interventions  Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily.

Main Outcomes and Measures  Remission of treatment-resistant late-life depression (defined as a Montgomery-Åsberg Depression Rating Scale score of ≤10 at both of the last 2 consecutive visits).

Results  Of 181 trial participants (103 female [56.9%]) who were 60 years of age or older and whose major depression had failed to remit with venlafaxine hydrochloride monotherapy, 91 received aripiprazole and 90 received placebo. Remission occurred in 40 (43%) who received aripiprazole and 26 (29%) who received placebo. Baseline set shifting moderated the efficacy of aripiprazole augmentation (odds ratio [OR], 1.66 [95% CI, 1.05-2.62]; P = .03 for interaction with treatment). 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%; number needed to treat, 4; OR, 4.11 [95% CI, 1.83-9.20]). Among participants with a Trail Making Test scaled score of less than 7, aripiprazole and placebo were equally efficacious (OR, 0.64 [95% CI, 0.15-2.80]). 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. Medical comorbidity and Color-Word Interference test performance were neither general predictors nor treatment-moderating factors.

Conclusions and Relevance  Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT00892047

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Figure.
Remission Rates in the Aripiprazole Arm vs the Placebo Arm Stratified by the Presence of Set-Shifting Impairment (A) and High Anxiety (B)

High anxiety is associated with lower remission rates but no difference in aripiprazole-placebo separation (anxiety is a general prognostic factor that does not moderate the efficacy of aripiprazole). In contrast, set-shifting impairment is a treatment moderator. In the absence of set-shifting impairment, aripiprazole is clearly superior to placebo; however, in the presence of set-shifting impairment, there is no difference between the 2 treatment arms (Table 4).

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