This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30 mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15 mg/day for tolerability and, subsequently, increased to 30 mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as > or = 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression - Bipolar Version Severity and Improvement scores. The 30 mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.
"One study was excluded as the number of subjects in the SGA and placebo groups was not given (Tohen et al., 1999). Ten studies (Sachs et al., 2006; Tohen et al. 2012; Keck et al., 2003a, 2003b; Yatham et al., 2003; Keck et al., 2003a, 2003b, 2009; Vieta et al., 2005; McIntyre et al., 2010; Vieta et al., 2010; Szegedi et al., 2012) did not provide data on the mean change in YMRS scores for the mixed episode subgroup of patients with BD and were excluded. We therefore included 9 double-blind placebo-controlled trials in our meta-analysis (Houston et al., 2009; Azorin et al., 2013; Suppes et al., 2008; Khanna et al., 2005; McIntyre et al., 2009; Sachs et al., 2002; Tohen et al., 2002; Keck et al., 2003a, 2003b; Berwaerts et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The literature on the treatment mixed episodes in Bipolar Disorder [BD] is sparse. Second generation antipsychotics [SGA] have documented efficacy in mania, but not mixed episodes. The objective of this meta-analysis was to ascertain the efficacy of SGA, either as mono- and/or adjunctive therapy, in the treatment of acute mixed episodes of BD, compared to placebo. METHODS: A MEDLINE search for English language publications of randomized controlled trials [RCTs] comparing SGA with placebo in the treatment of an acute manic/mixed episode of BD, during the period 1990-2012, was performed using the terms 'atypical antipsychotics', 'SGA', 'mixed episodes', 'dysphoric mania' and each SGA independently. 9 RCTs reporting data on 1289 mixed episode patients treated with aripiprazole, asenapine, olanzapine, paliperidone-ER, risperidone, and ziprasidone, either as monotherapy or as adjunctive therapy, versus placebo, for 3-6 weeks, were included in the meta-analysis. We extracted data on the number of patients, SGA, duration of study and mean change in mania and depression scores from baseline to endpoint. Standardized mean difference between SGA and placebo for the mean baseline-to-endpoint change in mania and depression rating scores was calculated, with a 95% confidence limit. RESULTS: SGA, either alone or in combination with mood stabilizers, had superior efficacy in treating manic symptoms of mixed episodes compared to placebo (-0.41, 95% CI -0.53, -0.30; overall effect p<0.00001). SGA were equally effective for manic symptoms in mixed episodes and pure mania (p=0.99). SGA had superior efficacy in treating depressive symptoms of mixed episodes (-0.30, 95% CI -0.47, -0.13; p<0.001) compared to placebo in two trials reporting this information. LIMITATIONS: Thirteen relevant studies could not be included as data for mixed-episodes were not presented separately. CONCLUSIONS: SGA are effective in treating acute mixed episodes of BD, with predominant manic symptoms. Their efficacy in treating depressed mixed episodes remains unclear.
"Additional inclusion and exclusion criteria for each study have been previously published (El Mallakh et al., 2010; Keck et al., 2003, 2009; Sachs et al., 2006; Vieta et al., 2005; Young et al., 2009). Subjects meeting criteria for an active substance-use disorder for the 3 months preceding the study were excluded. "
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes. METHODS: Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-Åsberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately. RESULTS: There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed. LIMITATIONS: Exclusion criteria of studies may limit generalizability of findings. DISCUSSION: All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.
"Importantly, and in agreement with previous studies (Keck et al. 2003; Sachs et al. 2006), improvements in mania symptoms with aripiprazole treatment seen in this study were not associated with a worsening of depressive symptoms. The mean change from baseline to Week 3 in the CGI-BP Severity of Illness (depression) scores and MADRS Total scores were not signifi cantly different between treatment groups. "
[Show abstract][Hide abstract] ABSTRACT: Objective. To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. Methods. Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. Results. A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (-11.3 vs. -5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (-0.4 vs. -0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. Conclusions. Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated.
The World Journal of Biological Psychiatry 04/2012; 15(2). DOI:10.3109/15622975.2012.669047 · 4.18 Impact Factor
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