Divalproex for Managing Aggression and Irritability in Children with Autism Spectrum Disorder: A Systematic Review

Background: Aggression and irritability are common challenges in children with autism spectrum disorder (ASD), often requiring pharmacological management. Divalproex, an anticonvulsant and mood stabilizer, is used off-label for these symptoms, but its effectiveness remains unclear. This systematic review evaluates the efficacy and safety of divalproex in managing aggression and irritability in children with ASD. Methods: A systematic review was conducted following PRISMA guidelines, registered with PROSPERO (CRD420251029754). Searches were performed in PubMed, Embase, PsycINFO, and Web of Science, identifying studies involving children with ASD treated with divalproex, valproic acid, or valproate sodium. Data were extracted on study design, sample size, intervention details, outcomes, and adverse effects. Results: Ten studies met inclusion criteria, comprising three randomized controlled trials, one open-label trial, and six case reports. Intravenous (IV) divalproex demonstrated rapid reductions in aggression, suggesting potential for acute stabilization. However, oral divalproex produced inconsistent results for chronic aggression and irritability. Adverse effects included weight gain, sedation, and behavioral activation, with toxicity risks in polypharmacy settings. Discussion/Conclusion: Divalproex may offer value for acute management of aggression in children with ASD when administered intravenously. Its role in chronic management is less clear, with inconsistent outcomes and notable side effects. Clinicians should prioritize regular serum monitoring and consider alternative options for chronic use. Further research is needed to clarify its clinical role, particularly in diverse patient populations.