Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder

Abstract

Objective: The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder.

Methods: Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings.

Results: In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms.

Conclusion: These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile.

Clinical trials registry: NCT00257166 and NCT00265330 at ClinicalTrials.gov.

Figures

FIG. 1.

Study design for randomized controlled and open-label extension trials. aDose titration: 20 mg/day start (night), increased by 20 mg every 2 days to target dose. bFlexible dose: ziprasidone 40–80 mg/day (<45 kg), ziprasidone 120–160 mg/day (≥45 kg). DB, double-blind; OLE, open-label extension; RCT, randomized controlled trial.

FIG. 2.

Primary (A, B) and secondary (C, D) efficacy endpoints for RCT and OLE phases (ITT analysis set). ap<0.05, bp<0.01, cp<0.001. For RCT period, baseline is day 1. For OLE periods, baseline is last available observation from the RCT period. CGI-S, Clinical Global Impressions–Severity; CI, confidence interval; ITT, intention to treat; OLE, open-label extension; RCT, randomized controlled trial; YMRS, Young Mania Rating Scale.

FIG. 3.

Primary efficacy endpoint by additional diagnostic criteria (post-hoc) for RCT phase (ITT analysis set). ap<0.05, bp<0.01, cp<0.001. n=the number of subjects with a YMRS score at baseline and with at least one post-baseline measurement windowed to a study visit. ADHD, attention-deficit/hyperactivity disorder; Hx, history; ITT, intention to treat; LS, least squares; RCT, randomized controlled trial; Sx, symptoms; YMRS, Young Mania Rating Scale.