Ziprasidone Plus a Mood Stabilizer in Subjects With Bipolar I Disorder: A 6-Month, Randomized, Placebo-Controlled, Double-Blind Trial

Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 02/2010; 71(2):130-7. DOI: 10.4088/JCP.09m05482yel
Source: PubMed


To evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania.
Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone plus mood stabilizer or placebo plus mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (log-rank test). The study was conducted from December 2005 to May 2008.
A total of 127 and 113 subjects were randomly assigned to ziprasidone and placebo, respectively. Intervention for a mood episode was required in 19.7% and 32.4% of ziprasidone and placebo subjects, respectively. The time to intervention for a mood episode was significantly longer for ziprasidone than placebo (P = .0104). The median time to intervention for a mood episode among those requiring such an intervention (n = 61) was 43.0 days for ziprasidone versus 26.5 days for placebo. The time to discontinuation for any reason was significantly longer for ziprasidone (P = .0047). Adjunctive ziprasidone treatment was well tolerated. Among treatment-emergent adverse events occurring in > or = 5% of subjects in either treatment group during period 2, only tremor occurred more frequently in the ziprasidone versus placebo group (6.3% vs 3.6%).
Ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania. Identifier: NCT00280566.

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    • "Whereas a single mood stabilizer may be effective for less complicated forms of the illness, more complicated symptom pictures (eg, mixtures of depressive and hypomanic symptoms or rapid mood swings) may require combinations of treatments with different actions.42–47 Yet most clinical trials have been of monotherapy, with a few studies of addition of olanzapine, quetiapine, or ziprasidone to lithium or valproate in patients without comorbidity, complexity, or suicidality,48–50 leaving trial and error as the primary method of finding the right combination treatment in more complicated clinical settings. New agents that may be more effective for complex presentations of bipolar disorder, those that have fewer interactions with other medications used for this condition, and agents that can treat bipolar depression without destabilizing the mood disorder are therefore urgently needed. "
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    ABSTRACT: Bipolar disorder is a prevalent disorder that tends to become progressive without treatment and with inadequate treatment. Second generation (atypical) antipsychotic drugs have increasingly been used as adjunctive treatment or monotherapy for mania, but they have the potential for significant adverse effects and their role in maintenance treatment remains unclear. Asenapine is a new atypical antipsychotic medication formulated in a sublingual preparation that has been studied for mania but not maintenance therapy. Evidence indicating efficacy, adverse effects, and potential benefits and drawbacks of using asenapine in the treatment of bipolar disorder based on currently available published data are summarized.
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    • "For this reason, this guideline does not make a special note or recommendation for specifi c combination treatments as other guidelines , e.g., CANMAT (Yatham et al. 2009) did, unless there is clear evidence for a special synergistic action of medication – which, as far as we can tell, has not been proven for any of the most researched and prescribed combination regimens. Positive placebo-controlled RCTs exist for combination treatments of mood stabilizers, usually valproate or lithium, with all atypical antipsychotics that have a licence for bipolar maintenance treatment – aripiprazole (Marcus et al. 2011), quetiapine (Vieta et al. 2008c; Suppes et al. 2009), risperidone (Yatham et al. 2003) and ziprasidone (Bowden et al. 2010). The 18-month RCT of olanzapine ϩ mood stabiliser vs. placebo ϩ mood stabilizer is the exception as it was underpowered at end point due to a high attrition rate, contributing to olanzapine ' s separation from placebo only on secondary, post-hoc outcomes (Tohen et al. 2004). "
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    • "One study by Weisler et al. (2003), [68] is also cited in guidelines and other papers as supporting evidence but could only be found as an abstract. Bowden et al. (2010), [69] conducted a 6 month, randomized double-blind trial of ziprasidone or placebo added to either lithium or valproate in patients with continued symptoms of bipolar I disorder (mania or mixed episode). Participants first received ziprasidone and lithium or valproate for an 8 week open label stabilization phase. "
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