Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder

Bipolar Disorder Research Program, UT Southwestern Medical Center, Dallas, Texas 75390-9121, USA.
Journal of Affective Disorders (Impact Factor: 3.38). 05/2008; 107(1-3):145-54. DOI: 10.1016/j.jad.2007.08.015
Source: PubMed


This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder.
Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed.
Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18-40 and 41-55 year age groups (p<or=0.001 for both); and in three subgroups stratified by baseline severity of depressive symptoms using the Montgomery-Asberg Depression Rating Scale (p<0.05). The treatment-emergent adverse events reported in >or=5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population.
This post hoc analysis utilized pooled data from two short-term studies.
Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

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Available from: James M Eudicone, Jun 02, 2015
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    • "In order to ascertain if SGA have similar efficacy in treating manic symptoms in mixed episodes as in pure mania, we computed SMD for SGA separately for these two conditions. For this analysis, we compared the effect sizes of seven of the nine included RCTs (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) that reported data for pure manic and mixed episodes separately (Fig. 4 a and b). The SMD for SGA to placebo was comparable in both pure mania [−0.56, 95% CI −0.69, −0.42; total n¼ 1522] and mixed episodes [−0.44, 95% CI −0.59, −0.29; total n¼ 727]. "
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    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.
    Full-text · Article · Jun 2013 · Journal of Affective Disorders
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    • "Conversely, antidepressant treatment to treat only depressive symptoms can induce a manic switch (Baldessarini et al., 2012; Fornaro et al., 2012; Pacchiarotti et al., 2011a; Valenti et al., 2011). The drugs that showed positive effects in the subset of patients with mixed mania as defined in DSM-IV in placebocontrolled trials (asenapine, olanzapine, and valproate) (Azorin et al., 2013; Baker et al., 2003; Nivoli et al., 2012; Swann et al., 1997; Yatham et al., 2013), and to some extent those that showed separation from placebo in pooled analysis (aripiprazole and ziprasidone) (Stahl et al., 2010; Suppes et al., 2008), may be the best candidates for the treatment of the newly defined DSM-5 mixed states. Of note, there are very few data on the use of quetiapine in acute mixed states but positive adjunctive longterm data (Vieta et al., 2012), and ziprasidone (Patkar et al., 2012) has been tested in depressive mixed states (which did not exist in the DSM-IV). "
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    ABSTRACT: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) nomenclature for the co-occurrence of manic and depressive symptoms (mixed states) has been revised in the new DSM-5 version to accommodate a mixed categorical-dimensional concept. The new classification will capture subthreshold non-overlapping symptoms of the opposite pole using a "with mixed features" specifier to be applied to manic episodes in bipolar disorder I (BD I), hypomanic, and major depressive episodes experienced in BD I, BD II, bipolar disorder not otherwise specified, and major depressive disorder. The revision will have a substantial impact in several fields: epidemiology, diagnosis, treatment, research, education, and regulations. The new concept is data-driven and overcomes the problems derived from the extremely narrow definition in the DSM-IV-TR. However, it is unclear how clinicians will deal with the possibility of diagnosing major depression with mixed features and how this may impact the bipolar-unipolar dichotomy and diagnostic reliability. Clinical trials may also need to address treatment effects according to the presence or absence of mixed features. The medications that are effective in treating mixed episodes per the DSM-IV-TR definition may also be effective in treating mixed features per the DSM-5, but new studies are needed to demonstrate it.
    Full-text · Article · Apr 2013 · Journal of Affective Disorders
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    • "The APA Practice Guidelines (2002) recommended a combination of an antipsychotic and a mood stabilizer, although only limited data have been published on this treatment strategy. Most reports of treatment efficacy for combination antipsychotic/mood stabilizer regimens in MS are post-hoc analyses of samples of convenience in short trials that included both manic and MS patients (Keck et al., 2003; Suppes et al., 2008). Some of these studies lacked sufficient numbers of patients for subanalyses of patients with MS, and have only reported the effect of this treatment for manic, but not depressive symptoms(McElroy et al., 1992; Cassidy and Carroll, 2001). "
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    ABSTRACT: Mixed states are common and severe manifestations of bipolar disorder, with limited data on the differential efficacy of treatments on depressive and manic symptoms. This study assessed the effectiveness of open-label adjunctive risperidone in achieving sustained effectiveness in patients with mixed mania, with a specific focus on the differential benefits on manic and depressive symptomatology. Forty patients with bipolar disorder I, currently in a mixed manic episode, were treated with adjunctive risperidone. Behavioral measures at baseline and weeks 1, 2, 4, 8, 12, 16, and 20 were assessed using the following scales: the Young Mania Rating Scale, the Montgomery Asberg Depression Rating Scale (MADRS), and the Global Assessment Scale. The primary outcome measure was the proportion of patients who attained a sustained response on either depressive or manic symptomatology, defined as at least 50% reduction from the baseline on the Montgomery Asberg Depression Rating Scale or the Young Mania Rating Scale, maintained over at least 8 weeks without subsequent relapse during the 20-week trial. A significantly higher proportion of patients achieved a sustained response for mania than depression, 16/40 versus 6/40, respectively (McNemar's χ 8.33, P=0.004). Higher elevated mood at baseline and lower apparent sadness (P<0.016) each predicted a sustained response for mania (P<0.0001). Mixed manic patients who were treated with risperidone adjunctive to mood stabilizer/s for 20 weeks were significantly more likely to achieve a sustained response for manic than for depressive symptomatology.
    Full-text · Article · Dec 2012 · International clinical psychopharmacology
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