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Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

ABSTRACT: OBJECTIVE:To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression. METHOD:This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks. RESULTS:Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks. CONCLUSIONS:In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00177671.

SUBMITTER: Sheffrin M

PROVIDER: S-EPMC2886714 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

Sheffrin Meera M Driscoll Henry C HC Lenze Eric J EJ Mulsant Benoit H BH Pollock Bruce G BG Miller Mark D MD Butters Meryl A MA Dew Mary Amanda MA Reynolds Charles F CF

The Journal of clinical psychiatry 20090210 2

<h4>Objective</h4>To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression.<h4>Method</h4>This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM- ...[more]

PMID: 19210951

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Project description: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.

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:Pharmacological treatment of major depressive disorder (MDD) typically involves a lengthy trial and error process to identify an effective intervention. This lengthy period prolongs suffering and worsens all-cause mortality, including from suicide, and is typically longer in late-life depression (LLD). Our group has recently demonstrated that during an open-label venlafaxine (serotonin-norepinephrine reuptake inhibitor) trial, significant changes in functional resting state connectivity occurred following a single dose of treatment, which persisted until the end of the trial. In this work, we propose an analysis framework to translate these perturbations in functional networks into predictors of clinical remission. Participants with LLD (N?=?49) completed 12-weeks of treatment with venlafaxine and underwent functional magnetic resonance imaging (fMRI) at baseline and a day following a single dose of venlafaxine. Data was collected at rest as well as during an emotion reactivity task and an emotion regulation task. Remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) ?10 for two weeks. We computed eigenvector centrality (whole brain connectivity) and activation during the emotion regulation and emotion reactivity tasks. We employed principal components analysis, Tikhonov-regularized logistic classification, and least angle regression feature selection to predict remission by the end of the 12-week trial. We utilized ten-fold cross-validation and Receiver Operator Curves (ROC) curve analysis. To determine task-region pairs that significantly contributed to the algorithm's ability to predict remission, we used permutation testing. Using the fMRI data at both baseline and after the first dose of treatment yielded a sensitivity of 72% and a specificity of 68% (AUC?=?0.77), a 15% increase in accuracy over baseline MADRS. In general, the accuracy at baseline was further improved by using the change in activation following a single dose. Activation of the frontal cortex, hippocampus, parahippocampus, caudate, thalamus, medial temporal cortex, middle cingulate, and visual cortex predicted treatment remission. Acute, dynamic trajectories of functional imaging metrics in response to a pharmacological intervention are a valuable tool for predicting treatment response in late-life depression and elucidating the mechanism of pharmacological therapies in the context of the brain's functional architecture.

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Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

Publications

Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

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