The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Second Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Bristol-Myers Squibb, Wallingford, CT 06492, USA.
Journal of Clinical Psychopharmacology (Impact Factor: 3.24). 05/2008; 28(2):156-65. DOI: 10.1097/JCP.0b013e31816774f9
Source: PubMed


Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score >18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.

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    • "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) "
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    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.
    Full-text · Article · May 2015 · The International Journal of Neuropsychopharmacology
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    • "The 11 trials included one trial with risperidone (Mahmoud et al., 2007), three with quetiapine (Garakani et al., 2008; Bauer et al., 2009; El-Khalili et al., 2010), two with an olanzapinefluoxetine combination (Thase et al., 2007), and five with aripiprazole (Berman et al., 2007, 2009; Marcus et al., 2008; Lin et al., 2011; Kamijima et al., 2013). Two trials investigated the efficacy of atypical antipsychotics in the non-TRD population (Garakani et al., 2008; Lin et al., 2011), and the remaining nine trials did so in the TRD population. "
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    ABSTRACT: Atypical antipsychotic augmentation was demonstrated to be efficacious in treatment resistant depression (TRD) in previous meta-analyses. We investigate whether there are differences in the effect size of atypical antipsychotic augmentation in major depressive disorder according to the degree of treatment resistance. A comprehensive search of four databases identified eleven randomized controlled trials. The eleven trials, which included 3,341 participants, were pooled using a random-effects meta-analysis. Atypical antipsychotic augmentation of antidepressant therapy showed superior efficacy compared to antidepressant monotherapy in TRD in terms of both response and remission rates (response, risk ratio (RR) = 1.38 (95% CI= 1.25 to 1.53); remission, RR = 1.62 (95% CI= 1.42 to 1.85)). In addition, regarding response rates in the TRD trials, atypical antipsychotic augmentation exhibited significantly different effect sizes according to the degree of treatment resistance (TRD 1: RR= 1.24; TRD 2: RR=1.37; TRD 2-4: RR=1.58). In non-TRD trials, atypical antipsychotic augmentation failed to show superior efficacy over antidepressant monotherapy in terms of remission rates (RR = 0.89 (95% CI= 0.69 to 1.14)). Atypical antipsychotic augmentation of antidepressant therapy exhibits greater effect size in patients with a higher degree of treatment resistance. This finding strengthens the rationale for considering atypical antipsychotic augmentation among depressed patients with multiple previous treatment failures in clinical practice. The efficacy of atypical antipsychotic augmentation for non-TRD seems to be different from that for TRD, and, thus, further studies of non-TRD populations are needed. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Mar 2015 · The International Journal of Neuropsychopharmacology
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    • "Aripiprazole, a D2R/D3R partial agonist, has demonstrated to be clinically effective enhancing the effects of standard antidepressant drugs in core depressive symptoms of treatment-resistant depressed patients [32] [62] [63]. Another pharmacological evidence supporting the antidepressant effect of D3R activation is given by pramipexole, a D3R preferring D2R/D3R agonist. "
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    ABSTRACT: Over the last decade accumulating evidence suggests that brain dopamine (DA) has a role in depression, particularly given the high comorbidity of depression with Parkinson's Disease (PD) and the antidepressant effects of the DA receptor subtype 3 (D3R) agonist pramipexole. The present study assesses the role of D3R in depression. Here we hypothesized that D3R mediates the antidepressant effects of DA. Thus, genetic deficiency of D3R in D3R knockout (D3RKO) mice would yield animals with chronic depressive symptoms. Whereas D3R deficient mice did not show significant alterations in locomotion when tested in the openfield, these animals showed anxiety-like symptoms measured as a significant increase in thigmotaxis at the openfield and a significantly lower time spent in the lit compartment at the light/dark exploration test. D3RKO animals also showed depressive-like symptoms as measured by increased immobility time in the Porsolt forced swim test and the tail suspension test, as well as anhedonia measured in the non-motor dependent sucrose test. In conclusion, D3R deficiency results in anxiety-like and depressive-like symptoms that cannot be attributed to motor dysfunction. Words: 181.
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