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

ABSTRACT: 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.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.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.Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily.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).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.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.clinicaltrials.gov Identifier: NCT00892047.

SUBMITTER: Kaneriya SH

PROVIDER: S-EPMC4823175 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Kaneriya Shriya H SH Robbins-Welty Gregg A GA Smagula Stephen F SF Karp Jordan F JF Butters Meryl A MA Lenze Eric J EJ Mulsant Benoit H BH Blumberger Daniel D Anderson Stewart J SJ Dew Mary Amanda MA Lotrich Francis F Aizenstein Howard J HJ Diniz Breno S BS Reynolds Charles F CF

JAMA psychiatry 20160401 4

<h4>Importance</h4>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.<h4>Objective</h4>To test the moderating role of pretreatment executive function, severity of anxiety, and severity of medical comorbidity in remission of ...[more]

PMID: 26963689

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Project description:BackgroundTreatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo.MethodsWe did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047.FindingsFrom July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.InterpretationIn adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.FundingNational Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Project description:IntroductionAmong randomised controlled trials for depressed adolescents, the extent of variation in how depressive symptom outcomes are defined is unknown. The variability in which potential predictors of these outcomes are tested is also unclear. This paper is a protocol describing the methods of a planned scoping review. The scoping review will examine and summarise how change in depressive symptoms have been described in RCT treatment studies to date. This review will report the measures used to describe change in depressive symptoms and whether the measure was used as a continuous or binary outcome or both. This review will describe how dichotomous outcome terms are defined to describe change in depression severity. This review will also examine predictors, moderators and mediators of change in depressive symptoms within RCTs.Methods and analysisIn this paper, we describe the protocol for our scoping review. Following the format outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, a research librarian will develop an operationalised search strategy, which we will apply to the MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature databases. We will search for papers from inception to 6 February 2020. A hand search for key citations will also be conducted. Investigator-raters will screen articles, first via the titles and abstracts and then through full-text reviews. We will include articles with randomised control design which assess the treatment of adolescents with major depressive disorder. We will systematically extract and synthesise prespecified data which includes: definition of depression used for participant inclusion, measures used to evaluate changes in depression, type of outcome used (continuous, binary or both), definitions of dichotomous terms to denote change in depression (eg, response, remission, recovery, etc) and reported predictors/moderators/mediators of change.Ethics and disseminationEthics approval is not required. Findings will be presented in journal publications and at conferences.

Project description:BackgroundThe benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied.MethodsWe conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. 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 (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression.ResultsIn step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch 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, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission 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 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission 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.ConclusionsIn 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 numerically higher incidence of remission. Among patients in whom 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. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Project description:BackgroundLate-life depression (LLD) is associated with a fragile antidepressant response and high recurrence risk. This study examined what measures predict recurrence in remitted LLD.MethodsIndividuals of age 60 years or older with a Diagnostic and Statistical Manual - IV (DSM-IV) diagnosis of major depressive disorder were enrolled in the neurocognitive outcomes of depression in the elderly study. Participants received manualized antidepressant treatment and were followed longitudinally for an average of 5 years. Study analyses included participants who remitted. Measures included demographic and clinical measures, medical comorbidity, disability, life stress, social support, and neuropsychological testing. A subset underwent structural magnetic resonance imaging (MRI).ResultsOf 241 remitted elders, approximately over 4 years, 137 (56.8%) experienced recurrence and 104 (43.2%) maintained remission. In the final model, greater recurrence risk was associated with female sex (hazard ratio [HR] = 1.536; confidence interval [CI] = 1.027-2.297), younger age of onset (HR = 0.990; CI = 0.981-0.999), higher perceived stress (HR = 1.121; CI = 1.022-1.229), disability (HR = 1.060; CI = 1.005-1.119), and less support with activities (HR = 0.885; CI = 0.812-0.963). Recurrence risk was also associated with higher Montgomery-Asberg Depression Rating Scale (MADRS) scores prior to censoring (HR = 1.081; CI = 1.033-1.131) and baseline symptoms of suicidal thoughts by MADRS (HR = 1.175; CI = 1.002-1.377) and sadness by Center for Epidemiologic Studies-Depression (HR = 1.302; CI, 1.080-1.569). Sex, age of onset, and suicidal thoughts were no longer associated with recurrence in a model incorporating report of multiple prior episodes (HR = 2.107; CI = 1.252-3.548). Neither neuropsychological test performance nor MRI measures of aging pathology were associated with recurrence.ConclusionsOver half of the depressed elders who remitted experienced recurrence, mostly within 2 years. Multiple clinical and environmental measures predict recurrence risk. Work is needed to develop instruments that stratify risk.

Dataset Information

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

Publications

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

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