A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy among Depressed Outpatients with Inadequate Response to Prior Antidepressant Therapy (ADAPT-A Study)
Clinical Trials and Network Institute (CTNI), Massachusetts General Hospital, Boston, MA 02114, USA. Psychotherapy and Psychosomatics
(Impact Factor: 9.2).
02/2012; 81(2):87-97. DOI: 10.1159/000332050
We assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in major depressive disorder (MDD) patients with inadequate response to prior ADT.
As per the sequential parallel comparison design, 225 MDD subjects were randomized to adjunctive treatment with aripiprazole 2 mg/day or placebo across two 30-day phases, with a 2:3:3 randomization ratio to drug/drug (aripiprazole 2 mg/day in phase 1; 5 mg/day in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1; aripiprazole 2 mg/day in phase 2). Eligible subjects were patients whose MDD was independently deemed 'valid' with SAFER criteria. Subjects had been receiving ADT for ≥8 weeks, and had inadequate response to ≥1 and <4 adequate ADTs in the current episode, as defined by the Antidepressant Treatment Response Questionnaire.
The pooled, weighted response difference between aripiprazole 2 mg/day and placebo in the two phases was 5.6% (p = 0.18; NS). The aripiprazole 2 mg/day-placebo difference on the Montgomery-Asberg Depression Rating Scale pooled across the two phases was -1.51 (p = 0.065; NS). Other secondary endpoint analyses showed nonsignificant pooled differences favoring aripiprazole over placebo. Of the 225 randomized subjects in phase 1, 2 dropped out in both arms, while in phase 2, of 138 phase 1 placebo nonresponders, 9 dropped out on aripiprazole and 5 on placebo. There were only minimal differences in adverse event rates between treatments, except for constipation, weight gain, and dry mouth, more common on aripiprazole.
This study provides clear support for the tolerability of low-dose aripiprazole as an ADT-augmenting agent, with marginal efficacy.
Figures in this publication
Available from: Yuqing Zhang
- "After screening 5 259 citations (Figure 1), 17 articles were included in this review (Shelton et al., 2001, 2005; Corya et al., 2006; Khullar et al., 2006; Mattingly et al., 2006; Berman et al., 2007, 2009; Mahmoud et al., 2007; McIntyre et al., 2007; Thase et al., 2007; Marcus et al., 2008; Reeves et al., 2008; Bauer et al., 2009; Keitner et al., 2009; El-Khalili et al., 2010; Fava et al., 2012; Kamijima et al., 2013) comprised of 18 RCTs with a total of 4 422 patients treated with seven different types (and dosages) "
[Show abstract] [Hide abstract]
ABSTRACT: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).
Systematic searches resulted in 18 RCTs (total N=4422) of seven different types and different dosages of atypical antipsychotics and placebo that were included in the review.
All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (SMDs ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (ORs ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250-350 mg daily) had a significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250-350 mg daily).
All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.
© The Author 2015. Published by Oxford University Press on behalf of CINP.
The International Journal of Neuropsychopharmacology 05/2015; DOI:10.1093/ijnp/pyv060 · 4.01 Impact Factor
- "SPCD provides a large reduction in P-value with an increase in power (Papakostas et al, 2014; Fava et al, 2012). "
[Show abstract] [Hide abstract]
ABSTRACT: One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a non-linear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from 5 RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of ~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by ~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the 'true' TE by controlling false negative results associated with excessively high placebo response.Neuropsychopharmacology accepted article preview online, 21 April 2015. doi:10.1038/npp.2015.105.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2015; 40(11). DOI:10.1038/npp.2015.105 · 7.05 Impact Factor
Available from: Chi-Un Pae
- "arable to those with AC or SW . Moreover , augmentation did not cause significantly greater weight gain . These results may be attributable to the lower aripiprazole dose used in our study than in the three RCTs ( Berman et al . , 2009 , 2007 ; Marcus et al . , 2008 ) . The tolerability of low - dose AT has also been demonstrated in a recent RCT ( Fava et al . , 2012 ) . Our study has several strengths . First , this is the first patient preference - based study comparing the effectiveness and tolera - bility among three treatment strategies to overcome partial or non - response to current antidepressants carried out in routine practice . Moreover , the uniformly Korean population is another strengt"
[Show abstract] [Hide abstract]
ABSTRACT: There has been no studies comparing the clinical benefits of aripiprazole augmentation (AT), antidepressant combination (AC), and switching to a different antidepressant (SW) in patients with major depressive disorder (MDD) patients partially or not responding to an initial antidepressant. AT, AC, or SW was chosen by patients. The primary efficacy measure was the proportion of patients showing an improvement in the Clinical Global Impression-Clinical Benefit (CGI-CB) score at week 8. Secondary efficacy measures included changes in CGI-CB, CGI-Severity (S) and subjective satisfaction scores. Remission and responder analysis were also employed. A total of 295 patients were enrolled. The most preferred strategy was AT (n = 156, 52.9%), followed by AC (n = 93, 31.5%) and SW (n = 46, 15.6%). The improver was significantly higher in AT (74.1%) compared with AC (48.1%; p < 0.001) and similar to SW (73.5%, p = 0.948), whereas no significant difference was found between AC and SW. Similar results were also found in the most secondary endpoint measures proving a superiority of AT over AC without differences between AT and SW. Tolerability profiles were similar across the three groups; however, the mean weight gain for SW (-0.1 kg) was significantly less than that for AC (1.3 kg, p < 0.05). Patients preferred AT to AC or SW when an antidepressant was ineffective in treating their depression. Among the three treatment strategies, overall AT yielded greater clinical benefit than did AC and SW. Adequately powered, well-controlled clinical trials are strongly warranted to confirm our findings due to methodological shortcomings.
Journal of Psychiatric Research 11/2013; 49(1). DOI:10.1016/j.jpsychires.2013.11.001 · 3.96 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.