REVIEW OF: Findling RL et al, J Child Adolesc Psychopharmacol 2022;32(3):143–152   

STUDY TYPE: Double-blind randomized placebo-controlled trial with open-label extension        

FDA-approved medications for bipolar disorder (BD) in children include lithium, risperidone, olanzapine, quetiapine, aripiprazole, and asenapine. Ziprasidone is a dopamine and 5-HT2A antagonist with a more neutral metabolic profile that has FDA approval for BD in adults.        

In 2009, Pfizer was denied FDA approval for ziprasidone for pediatric BD largely due to the lack of long-term data, high QT prolongation, higher rates of adverse effects in children, and high loss to follow-up (www.tinyurl.com/2wabwbr5). Pfizer was fined for illegally promoting ziprasidone for off-label uses, including for pediatric patients; in the following year, the FDA reported concerns about Pfizer’s clinical trials of ziprasidone (www.tinyurl.com/yc436fe4; www.tinyurl.com/yx3zmrbt).        

In 2013, Pfizer funded a four-week double-blind randomized placebo-controlled trial for BD I manic or mixed episodes in subjects ages 10–17 years (Findling RL et al, J Child Adolesc Psychopharmacol 2013;23(8):545). In that study, ziprasidone was effective, with a fairly impressive 0.5 effect size, and only one subject had a QTc interval over 460 msec. In a 26-week open-label extension of that trial, ziprasidone was well tolerated—there were no clinically significant changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose.        

In this 2022 study, Pfizer funded a replication of the 2013 trial, with 86 subjects randomized to ziprasidone and 85 to placebo. Ziprasidone outperformed placebo with an effect size of 0.58. This is somewhat lower than other trials of second-generation antipsychotics, which show a pooled effect size of 0.65 (Correll CU et al, Bipolar Disord 2010;12:116). There was no clinically significant effect on BMI or metabolic parameters. The main side effects of ziprasidone in descending order included somnolence, fatigue, nausea, extrapyramidal side effects, and loss of appetite. The discontinuation rates were 26.7% in the treatment group and 11.8% in the placebo group. The mean QTc prolongation for those treated with ziprasidone was a relatively inconsequential 5.44 msec, with only one patient moving into the abnormal range (eg, >460 msec).        

CARLAT TAKE        

In these industry-funded studies, ziprasidone shows a reasonable effect size for pediatric mania and is associated with minimal if any metabolic impact. While we need more non-industry-funded research to look at efficacy, we recommend that prescribers consider using ziprasidone and lurasidone over other second-generation antipsychotics because of their apparent milder metabolic impact, monitoring for metabolic, neurologic, and cardiac side effects.