Abstract: Risperidone and aripiprazole are approved by the USA Food and Drug Administration for the treatment of irritability and aggression in children from the ages of 5 and 6 years, respectively. However, there are no approved medications for the treatment of autism spectrum disorder (ASD) core signs and symptoms. Nevertheless, early intervention is recognized as key to improving long term outcomes. This retrospective case study included 10 children (mean age, 2 years 10 months) with ASD who presented with persistent irritability and aggression before 4 years of age that was unresponsive to behavioral interventions and sufficiently severe to consider pharmacological intervention with risperidone or aripiprazole combined with standard supportive therapies. Besides ameliorating comorbid behaviors, improvement was observed in ASD core signs and symptoms for all patients, with minimal-to-no symptoms observed in 60% of patients according to the Childhood Autism Rating Scale 2-Standard Test and Clinical Global Impression scales. Excessive weight gain in two patients was the only adverse effect observed that required intervention. This is the first study to suggest that ASD can potentially be treated in very young children (
Keywords: autism spectrum disorder; risperidone; aripiprazole; antipsychotic agents; case study
Autism spectrum disorder (ASD) is a complex and highly heterogeneous neurodevelopmental disorder, with each patient being unique in their presentation . However, there are core symptoms that are universal to all patients, including impaired communication and social interaction, and restricted and repetitive behaviors. ASD is increasing in prevalence, with 1 in 54 children diagnosed in the USA in 2016 compared with 1 in 150 in 2000 . This increase, at least in part, may be due to improved detection methods and increased awareness among parents and clinicians [3,4].
ASD is an umbrella term that has replaced older terminology for autistic disorder, Asperger’s syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified [1,5]. ASD symptoms can appear before 2 years of age but typically become more evident between 2 and 3 years of age [1,6]. Children with ASD experience developmental difficulties with behavior, communication, and socialization to a variable and often debilitating extent. Although core domains can improve with age, several symptom subdomains, including limited interests, social smiling, and emotional expression, may remain unchanged with poor outcomes common in later adulthood [7–10].
The standard recommended treatment of ASD in children involves early intervention with behavioral, occupational, and speech therapies to support healthy development and improve socialization . No medications have yet demonstrated efficacy in clinical trials and been approved by any regulatory agency for the treatment of ASD core signs and symptoms . Instead, medications are prescribed where needed as an adjunct to treat comorbid challenging behaviors so as to support children with their development and social functioning [12–14].
Risperidone and aripiprazole were approved by the USA Food and Drug Administration (FDA) in 2006 and 2009 [15,16] for the treatment of irritability and aggression in children from the age of 5 or 6 years for risperidone or aripiprazole, respectively [17,18], and these remain the only medications approved in the USA for treating any ASD-associated comorbid behavioral problems . Other common challenging comorbid behaviors in children with ASD include self-injury, hyperactivity, and disruptive behavior. Improvements in comorbid behaviors are frequently observed in children treated with risperidone or aripiprazole . However, these drugs are mixed dopamine- and serotonin-receptor antagonists or partial agonists, falling within a class of medications termed atypical antipsychotics . Atypical psychotics can cause adverse effects such as weight gain, hyperprolactinemia, sedation, cardiac symptoms (e.g., tachycardia or a prolonged QTc interval), extrapyramidal symptoms (e.g., dystonia or tardive dyskinesia), and metabolic disturbances (e.g., hyperlipidemia or hyperglycemia) [11,21,22]. Therefore, children treated with these medications require close monitoring with regular follow-up.
Several medications have been prescribed to mitigate medication side effects or help improve symptoms in older children with ASD when medication switch or discontinuation is not an option. For example, metformin may be prescribed to manage weight gain induced by risperidone , whereas methylphenidate, atomoxetine, guanfacine, and bupropion, which are used to treat attention-deficit hyperactivity disorder (ADHD), have been used to alleviate hyperactivity and poor attention in older children with ASD [24–27]. However, the addition of further medications needs to be carefully weighed as these increase the burden of potential adverse effects; ideally, medications causing adverse effects should be discontinued.
ASD is currently considered a non-curable disorder , and no registered clinical trial of risperidone or aripiprazole has provided evidence for their use in treating the core ASD signs and symptoms in children, even though there have been many studies on their use in children aged 5–18 years for the treatment of comorbid challenging behaviors [11,20]. For risperidone, there have also been several reports of the treatment of children with ASD under the age of 4 years [28–37]. Importantly, some of these studies have noted improvements in not only comorbid challenging behaviors but also social relatedness, restricted and repetitive behaviors, and levels of cooperation with developmental activities.
In this report, we therefore present a single-center, retrospective case study describing our experience in treating 10 very young children with ASD and challenging comorbid behaviors. These children initiated treatment between the age of 2 to 4 years with risperidone or aripiprazole to manage persistent comorbid challenging behaviors, either with or without atomoxetine or methylphenidate, and in combination with standard supportive therapies.