Aripiprazole and Acute Extrapyramidal Symptoms in Children and Adolescents: A Meta-Analysis.

Background: Both the US FDA and the European Medicines Agency (EMA) have approved aripiprazole for use in adolescents for specific indications. Given the assumed favorable side-effect profile of aripiprazole, its use in children and adolescents has increased for both official and off-label indications (anxiety disorders, eating disorders, personality disorders). However, several cases of children and adolescents with new-onset extrapyramidal symptoms (EPS) after commencing treatment with aripiprazole have been reported, and a more systematic appraisal of this possible risk is lacking.
Objective: We conducted a systematic review and a meta-analysis to assess the evidence for acute EPS (acute dystonia, akathisia, Parkinsonism) associated with the use of aripiprazole in children and adolescents.
Method: We searched the MEDLINE and Embase databases (2003-10 April 2016) for clinical trials in pediatric patients (aged 0-18 years) using the keywords 'aripiprazole' (regardless of the formulation) and 'extrapyramidal symptoms'. We evaluated the abstracts of papers using the following exclusion criteria: (1) study design: case report, letter to the editor, editorial, or poster presentation data; (2) unrelated PICOS (population, intervention, comparators, outcomes, study) structure. We performed a meta-analysis, in which we used effect sizes with 95 % confidence intervals (CIs). To examine the homogeneity of the effect size distribution, we used a Q-statistic. When we observed heterogeneity in effect sizes, we assessed the possible influence of moderator variables (age and sex, mean dose, study duration, and method of measuring EPS incidence) and evaluated the suitability of either a fixed or a random model. Finally, we assessed the incidence of EPS in children and adolescents treated with aripiprazole compared with placebo.
Results: An initial search via PubMed and Embase yielded 328 hits. A manual search of the reference lists of review papers revealed seven additional relevant articles. We included 41 studies, with 2114 pediatric patients, in the meta-analysis. For the analysis of the mean incidence of EPS, data were provided by 24 studies, with a total of 1446 pediatric patients. Meta-analysis revealed a mean EPS incidence of 17.1 % (95 % CI 0.128-0.223). In terms of the incidence of various extrapyramidal side effects, overall, no significant effects of age, sex, mean dose, study duration, or measuring method could be demonstrated. The side effects 'EPS', 'parkinsonism', and 'tremor' were significantly more common in children and adolescents treated with aripiprazole than in those treated with placebo.
Conclusion: Our meta-analysis provides evidence for a non-negligible incidence of acute EPS in children and adolescents treated with aripiprazole. Although the study has several limitations and further investigation is needed, these findings may help clinicians make more balanced treatment choices and more closely monitor the use of this drug in youth.
Competing Interests: Compliance with Ethical Standards Funding UPC KU Leuven funded the open access fee. Conflict of interest Professor Marc De Hert has been a consultant for, received grant and/or research support and honoraria from, and participated on the speakers’ bureaus and/or advisory boards of the following companies: Janssen-Cilag, Lundbeck, Otsuka, and Takeda. Professor Marina Danckaerts has received research support from Janssen-Cilag and Shire, has been a member of the advisory board of Shire and Neurotech Solutions, and has participated on the speakers’ bureaus of Shire, Novartis, and Medice. Dr. Chiara Bernagie, MD/Ph.D.-student, and Martien Wampers, Ph.D., have no financial ties or conflicts of interest to disclose.