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Hamza A Alsayouf,1 Haitham Talo,1 Marisa L Biddappa,1 Mohammad Qasaymeh,2 Shadi Qasem,3 Emily De Los Reyes4 1Kids Neuro Clinic and Rehab Center, Dubai, United Arab Emirates; 2Pediatric Neurology, Dent Neurological Institute, Amherst, NY, USA; 3Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA; 4Pediatric Neurology, Nationwide Children’s Hospital and Ohio State University, Columbus, OH, USACorrespondence: Hamza A AlsayoufKids Neuro Clinic and Rehab Center, Dubai Healthcare City, Dubai, United Arab EmiratesTel +97 145570326Email leeamra1000@gmail.comPurpose: Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with high heterogeneity and no clear common cause. Several drugs, in particular risperidone and aripiprazole, are used to treat comorbid challenging behaviors in children with ASD. Treatment with risperidone and aripiprazole is currently recommended by the Food and Drug Administration (FDA) in the USA for children aged 5 and 6 years and older, respectively. Here, we investigated the use of these medications in younger patients aged 4 years and older.Patients and Methods: This retrospective case series included 18 children (mean age, 5.7 years) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai. These patients began treatment with risperidone or aripiprazole at the age of 4 years and older, and all patients presented with comorbid challenging behaviors that warranted pharmacological intervention with either risperidone or aripiprazole.Results: All 18 children showed objective improvement in their ASD core signs and symptoms. Significant improvement was observed in 44% of the cases, and complete resolution (minimal-to-no-symptoms) was observed in 56% of the cases as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales.Conclusion: Our findings indicate that the chronic administration of antipsychotic medications with or without ADHD medications is well tolerated and efficacious in the treatment of ASD core and comorbid symptoms in younger children when combined with standard supportive therapies. This is the first report to suggest a treatment approach that may completely resolve the core signs and symptoms of ASD. While the reported outcomes indicate significant improvement to complete resolution of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. Furthermore, the findings support the critical need for double-blind, placebo-controlled studies to validate the outcomes.Keywords: risperidone, aripiprazole, antipsychotic, comorbid challenging behaviors