Pharmacologic Treatment of Autism
Autism spectrum disorder (ASD) is characterized by deficits in social communication and interactions, as well as restricted and stereotypic behaviors. In addition to these core symptoms, children and adolescents with ASD often suffer from problem behaviors, such as symptoms of irritability and aggression (IA), which may manifest as tantrums, self-injury, and aggressive behaviors toward others. Child neurologists /pediatric neurologists are a first liners in treatment of autism.
Formal definition of irritability is scarce in the literature. Irritability is defined as a “feeling state characterized by reduced control over temper which usually results in irascible verbal or behavioral outbursts,” although this mood state may be present without observed manifestation. The developmental literature and studies suggest that irritability can be defined as “an excessive response to stimuli.”Irritability is also a consequence of emotion dysregulation (a dysfunction of evidenced neurobiologic processes), which can lead to change in mood state and aggression (a behavior).Emotion regulation may be defined as “the process of initiating, avoiding, inhibiting, maintaining, or modulating the occurrence, form, intensity, or duration of internal feeling states, emotion-related physiological, attentional processes, motivational states, and/or the behavioral concomitants of emotion in the service of accomplishing affect-related biological or social adaptation or achieving individual goals.”Emotion dysregulation, therefore, is the inability to regulate such process effectively.Aggression is defined as hostile, injurious, or destructive behavior often caused by frustration. Aggression may be divided into 2 categories: impulsive and premeditated. Impulsive aggression has been shown as a possible consequence of emotion dysregulation. Impulsive aggression and its domains have been described by other terms in the literature. For example, “agitation” has been used to describe impulsive aggression, “self-injurious behaviors” describes inwardly driven aggression, and “temper outbursts/tantrums” is used to describe outwardly driven aggression that may be disruptive to the environment or may involve destruction of property. Neurobiologically, emotion dysregulation may be considered as a common pathologic process underlying IA. The 2 major components of emotion regulation are top-down inhibition and bottom-up drive. Generally, the prefrontal cortex (PFC) and anterior cingulate cortex are thought to be the neural substrate for top-down inhibition, whereas the amygdala and insula are often associated with bottom-up drive. When these regions are dysfunctional, affected people may exhibit more severe irritability and impulsivity. In typically developing people, cognitive control has been shown to be associated with optimal functional connectivity between dorsolateral PFC and parietal cortex. In contrast, in ASD cognitive control has been shown to be controlled by the ventrolateral PFC and anterior cingulate cortex. Furthermore, recent evidence has shown that alterations of the GABAergic system in ASD were also present in some of the same areas responsible for top-down inhibition and bottom-up drive. Although evidence is emerging, additional research is needed to increase our understanding of the neurobiology of IA to allow the development of more effective interventions.
Approximately 20% of people with ASD exhibit IA at moderate to severe levels,with >50% exhibiting significant emotion dysregulation.These symptoms often cause significant challenges to people with ASD and their families and affect treatment implementation and long-term outcomes.In an ideal setting, medications for IA in ASD are typically considered after medical problems and comorbid psychiatric disorders have been addressed and behavioral interventions have been unsuccessful or only partially effective. Clinical judgment may override these conditions in the event of emergencies involving severe agitation or aggression to self or others. Once the clinical situation is more stable, however, the clinician may revisit these conditions before committing to longer-term treatment with medication. Clinicians have used a wide variety of medications to treat IA, mostly on an off-label basis. In 2006, the US Food and Drug Administration (FDA) approved risperidone to treat irritability associated with ASD. The agency included the target behaviors (ie, aggression, deliberate self-injury, and temper tantrums) under the general heading of “irritability” based on 28-week, placebo-controlled trials of risperidone in 156 patients aged 5 to 16 years. Subsequently, aripiprazole was also approved for this purpose, with evidence from 2 randomized controlled trials (RCTs) supporting its efficacy and safety in the treatment of IA. Currently, risperidone and aripiprazole are the only medications approved by the FDA for the treatment of IA in people with ASD. Various RCTs of other pharmacologic agents have also been conducted for IA symptoms in ASD.