Studies of antipsychotics in child prenpresented at the 48th Annual New Clinical Drugs Evaluation Unit (NCDEU) Meeting, conducted by the NIMH in Phoenix, May 27-30, provide some data where there have been relatively little on the increasing use of these agents.
In a panel discussion on ethics applications in child and adolescent psychopharmacology research and practice, panel chair Christopher Kratochvil, MD, University of Nebraska, noted, “while children have additional protections as a vulnerable population in research, recognition of underserved treatment needs is driving demand for psychopharmacology progress.”
As psychopharmacotherapy in children may be expanding faster than its evidence base, however, there is also increasing concern that risk-benefit is not being adequately assessed. In the October issue of the Archives of Pediatric and Adolescent Medicine, a retrospective cohort study of antipsychotic use in children and adolescents reveals that these agents are associated with increased risk of adverse metabolic and cardiovascular events.1 Neurological adverse events in this cohort were reported separately in the Journal of Child Neurology.2
Two investigations of antipsychotic safety and efficacy were presented at the NCDEU meeting by Paul Wang, MD, of Pfizer Global Research and Discovery. The manufacturer-supported studies of ziprasidone(Drug information on ziprasidone) (Geodon) in pediatric type I bipolar disorder assessed, respectively, acute effects in a 4-week double-blind trial, and longterm safety and tolerability over a 26-week open-label extension. Atotal of 150 participants aged 10 to 17 years were randomized in a 1:2 ratio to receive either placebo or ziprasidone in daily doses that ranged from 80 to 160 mg. The principal measure of efficacy was improvement in the Young Mania Rating Scale (YMRS) score. Safety was ascertained through monitoring of treatment-emergent adverse events, vital signs, laboratory and ECG measures, and movement disorder scales.
In the short-term, controlled trial, Wang and colleagues found a statistically significant greater mean reduction in YMRS total score (13.83) in those treated with ziprasidone than the 8.61 reduction with placebo. The most commonly reported adverse effects with ziprasidone were sedation (22%), somnolence (25%), nausea (13%), and dizziness (11%). No changes in mean body mass index (BMI) or levels of lipids, liver enzymes, or glucose were observed. A mean prolongation of QTcF of 8.8 milliseconds occurred with ziprasidone, compared with 3.5 milliseconds with placebo. One ziprasidone recipient experienced QTc prolongation that exceeded 460 milliseconds.
In the 26-week open-label extension, 5 participants experienced adverse cardiac events (tachycardia in 2, palpitations in 2, and atrial fibrillation in 1). No change in BMI, lipid values, or levels of liver enzymes or glucose was clinically significant. Wang characterized ziprasidone for type I bipolar disorder in this age-group as “safe and generally well-tolerated,” and indicated that the findings confirm metabolic safety.
Two studies of aripiprazole(Drug information on aripiprazole) (Abilify) for the same indication and agegroup were reported by Margaretta Nyilas, MD, of Otsuka Pharmaceutical Development. In a 3-arm, 4-week, controlled trial, 300 youths received placebo or aripiprazole 10 or 20 mg daily. Both dosages of aripiprazole were associated with greater improvement in symptoms than placebo on several efficacy measures, including the YMRS, and at all scheduled evaluations.
In the 26-week continuation phase, Nyilas indicated, “most adverse events were mild to moderate in severity.” The most commonly reported events were dose-related somnolence and extrapyramidal effects. Nyilas indicated that there was no clinically significant weight gain associated with aripiprazole over the duration of treatment.
To assess risk and benefit of maintaining antipsychotic therapy along with lithium(Drug information on lithium) after its initial use to treat psychotic features and/or severe aggression in youth with bipolar I disorder, Vivian Kafantaris, MD, and colleagues at Zucker Hillside Hospital, Glen Oaks, NY, provided open-label combination treatment to 68 patients for at least 6 months. Those who attained remission were randomized to a 48-week, double-blind design of either lithium and placebo, or lithium with olanzapine (Zyprexa). Switching to either risperidone(Drug information on risperidone) (Risperdal) or quetiapine(Drug information on quetiapine) (Seroquel) was permitted for possible improved response or tolerability.
Kafantaris reported that in the open stabilization period, “weight gain and dyslipidemias remained problematic, despite switches to the other 2 permitted second-generation antipsychotics (SGAs).” In the 48-week trial, Kafantaris reported only an 11% difference between the antipsychotic/lithium combination and the lithium/placebo groups in maintaining remission: 33% (4 of 12) of those taking the active combination and 22% (2 of 9) taking lithium/placebo. “The benefit of continuing SGA treatment was smaller than expected and did not clearly outweigh the risks,” Kafantaris reported. A trend favoring the combination treatment 12 weeks after randomization, however, suggested the need for further study of short-term adjunctive antipsychotic treatment.
Scrutinizing safety across antipsychotics
Ginger Nicol, MD, of the Washington University School of Medicine, St. Louis, reported preliminary results from the Metabolic Effects of Antipsychotics in Children (MEAC) study. Nicol and colleagues employed sensitive measures to monitor changes in antipsychotic-naive patients aged 7 to 18 years whose targeted symptoms were treated for 12 weeks with aripiprazole, olanzapine(Drug information on olanzapine), or risperidone. Treatment-related changes in adiposity and insulin sensitivity were detected and monitored with an array of technologies, including dual-energy x-ray absorptiometry (DXA), abdominal MRI, and stable isotopomer tracing during hyperinsulinemic-euglycemic clamps.
Nicol reported that in the first 35 patients to complete therapy, antipsychotic treatment was associated with a significant increase in total body fat and a decrease in whole body insulin sensitivity. She cautioned, “antipsychotic treatment in children requires careful attention to the balance of potential risks and benefits.”
Seeking to distinguish among antipsychotics for the likelihood of diabetes-related adverse effects, researchers at Bristol-Myers Squibb and Otsuka America Pharmaceutical reviewed these reported events in an FDA database. Andrei Pikalov, MD, PhD, reported their analysis, stratified by patient age, for SGAs and haloperidol(Drug information on haloperidol) (Haldol). In patients 18 years or younger, the relative ratio of reported diabetes mellitus emergence was aripiprazole, 1.69; clozapine(Drug information on clozapine), 4.10; olanzapine, 3.83; quetiapine, 2.42; risperidone, 2.45; ziprasidone, 1.31; and haloperidol, 1.31.
Pikalov elaborated, “the potential for an association between diabetes mellitus and haloperidol or aripiprazole was low in both pediatric and adult populations. In contrast, potential associations . . . were observed between diabetes mellitus and olanzapine or clozapine in both populations. Potential associations were observed for risperidone, quetiapine, and ziprasidone in adults.”
In the workshop panel on ethics applications in child psychopharmacology research and practice, Julie Zito, PhD, University of Maryland, Baltimore, considered the limited data available to guide psychopharmacotherapy in children. Even when randomized clinical trials have been conducted, Zito pointed out, the limited inclusion criteria limit generalizing the findings.
Zito advocated an increase in postmarketing research, “to address the uncertainties of off-label prescription drug use.” She called for additional studies of comparative effectiveness and better established clinical monitoring, along with “better infrastructure to assess the incidence of adverse events associated with medication use in community populations.”