A Multiple-Center, Randomized, Double-Blind, Placebo-Controlled Study of Oral Aripiprazole for Treatment of Adolescents with Schizophrenia

Background: Aripiprazole is a dopamine partial agonist that has been shown to be efficacious in the treatment of positive and negative symptoms in acute and long-term treatment of schizophrenia in adults. Adolescent-onset schizophrenia is not uncommon and safe and effective treatments are needed.

Objective: The purpose of this study was to determine if aripiprazole would be superior to placebo in ameliorating symptoms of psychosis in adolescents and if aripiprazole would be generally well tolerated in this population.

Methods: This was a 6-week, randomized, placebo-controlled, multicenter study. It was conducted in 101 centers in the United States, Europe, South America, South Africa, Asia, and the Caribbean. The raters at each site had identical instructions for administering the PANSS (Positive and Negative Syndrome Scale) and each site was required to demonstrate interrater reliability to ensure consistency among sites. 302 patients were enrolled and randomized to receive placebo (N=100), aripiprazole 10 mg (N=100), or aripiprazole 30 mg (N=102) for the 6 week duration of the study. Patients were included in the study if they were 13-17 years old, had a DSM-IV axis I primary diagnosis of schizophrenia confirmed at screening, and if they had a PANSS score greater than 70 at baseline. Patients were excluded if they had any current psychiatric comorbidity requiring pharmacotherapy, any evidence of suicide risk, history of mental retardation, major depressive episodes, or severe head trauma. Patients were also excluded if their illness was resistant to antipsychotics, if they were pregnant or breast feeding, or they would not agree to abstinence or birth control. Subjects could participate on an outpatient, partial hospitalization, or full inpatient basis. The participants were measured at baseline and then at weekly visit through day 42. The primary outcome measure was the mean change from baseline for the total score on the PANSS.  The secondary outcome measures included the mean change in PANSS subscale score from baseline, the Clinical Global Impression improvement and severity scales, and the Children’s Global Assessment Scale. The study presumably used a modified intent-to-treat approach. The power of the study was estimated to be >85% if 255 or more subjects were enrolled using a two-sided alpha of 0.025.

Results: Both doses of aripiprazole showed significant improvement over placebo between baseline and the end of treatment on the PANSS score total, the PANSS positive subscale, the CGI severity measure, the CGI improvement measure, and the Children’s Global Assessment Scale. The 10 mg aripiprazole also showed significantly improved results to placebo on the PANSS negative subscale. CGI improvement scores showed progressive improvement in both the 10 mg and 30mg groups over placebo p<0.05 for most weeks. The mean change from baseline in the Children’s Global Assessment score at week 6 was statistically significant for both treatment groups over placebo. Treatment with both doses of aripiprazole resulted in significantly higher rates of remission at week 6 than placebo. The remission rates were 54% in the 10mg group, 58% in the 30mg group and 36% in the placebo group with p values less than 0.02.

Strengths: The study had a good rationale and enrolled a sufficient number of patients. They used multiple assessments for the primary and secondary outcomes and to address adverse events. The study was double-blinded and placebo controlled.

Weaknesses: The study lasted only 6 weeks, compliance was not addressed, and the patients were enrolled from many centers from a large variety of areas. The results were reported using standard error which could lead to misinterpretation. The adverse event reporting was confusing. The success of blinding was never mentioned and there was potential for unblinding due to the increased likelihood of adverse event, especially extrapyridamal symptoms, with the treatment groups. The patients were allowed to take concomitant rescue medications if deemed necessary by their physician; however, this was never quantified by the authors. The study was funded by the manufacturer of the treatment medication and the company employed some of the authors.

Conclusion: Aripiprazole was shown to be more effective than placebo in both strengths studied. The two treatment doses were not evaluated against each other so a conclusion cannot be made as to what strength is most appropriate for adolescents. A placebo effect was notable in this trial. At this time, there are few treatment options for the study population and aripiprazole did show efficacy and reasonable tolerability. This study was filled with limitations. Future studies should include a longer duration, head to head trial of a typical antipsychotic v. aripiprazole, and better result reporting. The future studies should address potential for unblinding and address compliance.

Findling, RL, Robb A, Nyilas M, Forbes RA, Jin N, Ivanova S, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. American Journal of Psychiatry. 2008. p. 1-10.

Kari E. McDonald, Pharm.D. Candidate