Clinical Use of Valproate and Divalproex in Autism Spectrum Disorder: A Systematic Review of Efficacy and Safety

The aim of this systematic review is to appraise the current evidence on the efficacy and safety of valproate (VPA), including divalproex sodium (DVPX), in managing irritability, aggression, repetitive behaviors, and other associated symptoms, mostly in the pediatric population with autism spectrum disorder (ASD). Major medical literature databases were searched for randomized controlled trials (RCTs), open-label trials, and any other relevant studies or clinical trials reporting on patients with ASD (predominantly children and adolescents) treated with DVPX/VPA for any reason. A total of 654 abstracts were screened, and four clinical trials were selected for inclusion. Out of these four clinical trials, three were RCTs (n = 13, 27, and 30), and one was an open-label trial. Data were extracted using a standardized form focused on study design and validity domains. Two reviewers independently abstracted data, with discrepancies resolved by consensus. Meta-analysis was not performed due to a lack of homogeneity among the three RCTs. Although most of the studies reported improved overall symptoms, they had different outcome measures. The quality of evidence available is low, and there is a need for higher-powered studies in the future. There is insufficient evidence to make conclusive recommendations on DVPX/VPA for improvement in core symptoms in the pediatric population. However, DVPX/VPA may represent a potential off-label option for selected patients with significant irritability, aggression, and repetitive behaviors associated with ASD.