Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorder

Abstract

Previous versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) did not allow the possibility of diagnosing attention-deficit/hyperactivity disorder (ADHD) in individuals with autism spectrum disorder (ASD). However, this veto has been removed in the current version of the DSM (DSM-5), highlighting the need for screening and appropriately managing, when present, symptoms of ADHD (i.e., inattention and/or hyperactivity/impulsivity) in individuals with ASD. Evidence from neuroimaging and genetic studies points to shared but also specific neurobiological underpinnings across the two disorders. While there is a large body of research on the pharmacological and non-pharmacological treatments of ADHD, evidence on the management of ADHD symptoms in individuals with ASD needs further investigation. Future studies should explore pathophysiologically based, rather than symptomatic, intervention strategies for ADHD associated with ASD.

Appendix. Management of Disruptive Behaviors (Other Than ADHD) in Children and Adolescents with ASD

In a sizable portion of patients with ASD referred to child and adolescent mental health services, the main concerns include not only typical ADHD core symptoms (i.e., hyperactivity, inattention, and impulsivity) but also related disruptive behaviors such as physical aggressiveness, temper outbursts, or irritability, the latter being defined as an abnormal disposition to uncontrolled anger or aggression (Elbe and Lalani 2012). Although the prevalence of such maladaptive behaviors has not systematically been evaluated in children/adolescents with ASD, individual studies show that they are frequent and impairing in this population. For example, a study in a sample of 487 young people with pervasive developmental disorder (PDD) showed that up to 30 % of them presented with symptoms of irritability, including aggression (24.5 %), severe tantrums (30.2 %), and deliberate self-injurious behavior (16 %) (Lecavalier 2006).

Empirical evidence is available for both pharmacological and non-pharmacological strategies aimed to manage such impairing behaviors. Non-pharmacological interventions are grounded on behavioral techniques such as stimulus-based procedures (e.g., altering antecedent events), instruction-based procedures (e.g., instruction of appropriate behaviors), extinction-based procedures (e.g., withholding or minimizing presumed reinforcers), reinforcement-based procedures (e.g., increasing desired behaviors), punishment-based procedures (e.g., reducing behavior by delivering a contingent event), and systems change procedures (e.g., altering structural features of environment) (Horner et al. 2002). Although no formal meta-analyses have been published on the efficacy (and safety) of these behavioral interventions, a comprehensive research synthesis concluded that (1) disruption/tantrum was the most likely behavior targeted by such interventions, with aggression being the second most likely; (2) early use of behavioral interventions results in reductions of problem behaviors by 80–90 %; (3) interventions based on functional assessment are more likely to reduce the severity and frequency of disruptive behaviors (Horner et al. 2002).

Another promising and relatively novel intervention is based on Social Stories, originally developed to teach children with autistic spectrum disorders how to play games while increasing their ability to interact with others in a socially appropriate way (Gray 1993). Such stories are written to reflect a situation that the child with ASD finds difficult and provide information on what is happening, why, and which are the desirable responses in that specific social situation. A systematic review of case series reported so far concluded that across all seven research articles retrieved, 13 of 15 participants demonstrated a decrease in the frequency of disruptive behavior, with only two participants recording no change in behavior following the Social Story intervention (Rhodes 2014). It is worthy to point out that a rigorous meta-analysis of the efficacy/effectiveness of non-pharmacological interventions for disruptive behaviors in children with ASD, taking into account the level of blinding of raters, for example, a recent meta-analysis on non-pharmacological interventions for ADHD (Sonuga-Barke et al. 2013), is currently lacking in the field.

With regard to pharmacological treatments, although, as pointed out in the main chapter, no medication is currently approved to treat the core symptoms of ASD, there is an extensive practice, and an increasing evidence base, for the use of several agents to reduce the intensity and frequency of disruptive behaviors associated with ASD. Most of the evidence pertains to antipsychotics, in particular risperidone. The body of research on risperidone for disruptive behaviors has been recently meta-analytically reviewed pooling data from 16 open-label studies and 6 placebo-controlled trials (Sharma and Shaw 2012). This meta-analysis concluded that the sample weighted mean effect size for risperidone was 1.13 for open-label studies and 1.21 for placebo-controlled studies, thus indicating, in both cases, high efficacy of risperidone on ASD-related disruptive behavioral, according to the Cohen’s classification of effect size (Cohen 1992). In terms of tolerability and safety, the most common adverse events (AEs) reported in trials of risperidone for ASD included excessive weight gain [e.g., in the Research Units on Pediatric Psychopharmacology (RUPP) study (McDougle et al. 2005): 2.7 ± 2.9 kg vs. 0.8 ± 2.2 kg in the control group], increased appetite, fatigue, drowsiness, dizziness, and drooling. Follow-up data indicate that after 6 months of treatment, risperidone leads to a mean weight gain of about 5 kg, which exceeds developmentally expected norms (Martin et al. 2004). Prolactin levels tend to increase significantly: for instance, after 8 weeks, a fourfold increase has been observed, with a slight decrease after 6 months. Of note, prolactin levels were not associated with any adverse events (Anderson et al. 2007).

Another agent that has been increasingly investigated over the past years is aripiprazole. Two published placebo-controlled randomized trials (Owen et al. 2009; Marcus et al. 2009) assessing the effects of this drug for disruptive behaviors in children with ASD reported a statistically significant reduction of disruptive symptoms favoring aripiprazole (dose: 5–15 mg/day). In the first trial (Owen et al. 2009), discontinuation rates due to adverse events (AEs) were 10.6 % for aripiprazole and 5.9 % for placebo. Extrapyramidal symptom-related AE rates were 14.9 % for aripiprazole and 8.0 % for placebo. Mean weight gain was 2.0 kg with aripiprazole and 0.8 kg with placebo at week 8. No serious AEs were reported. In the second study (Marcus et al. 2009), sedation was the most common AE leading to discontinuation. Presyncope (at the dose of 5 mg/day) and aggression (at 10 mg/day) were the two severe AEs reported during the study. At week 8, mean weight change was +0.3 kg on placebo, +1.3 kg on aripiprazole 5 mg/day, +1.3 kg on aripiprazole 10 mg/day, and 1.5 kg on aripiprazole 15 mg/day.

This body of evidence has led the Food and Drug Administration to approve first risperidone (www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108759.htm) and, more recently, aripiprazole (www.online.lexi.com) for the treatment of irritability associated with autism spectrum disorder in children aged 6–17 years, and by contrast, in Europe, the European Medicines Agency has approved risperidone for the short-term treatment of aggressive or disruptive behaviors in children with subaverage intellectual level and disruptive behavior from the age of 5 years (www.medicines.org.uk/emc/medicine/12818/SPC/).

Other agents that have been assessed for the management of ASD-related disruptive behaviors include typical antipsychotic such as haloperidol [e.g., (Cohen et al. 1980)], although their possible side effects, including sedation, acute dystonia, and withdrawal dyskinesias, do not make this class as first-line option. Research on other drugs, such as antiepileptic (lamotrigine and levetiracetam), amantadine, and carnitine, has not shown so far clear beneficial effects of these agents on disruptive behaviors in children with ASD (Kirino 2014).

With regard to the sequencing of treatments (pharmacological and non-pharmacological), the National Institute for Health and Care Excellence (NICE) guidelines recommended using medication for behavioral problems in ASD only if environmental, psychosocial, or other interventions have been insufficient or cannot be delivered because of the severity of the behavior (https://www.nice.org.uk/guidance/qs51). Many experts in the field [e.g., (Dinnissen et al. 2015; Scahill et al. 2009)] concur with the view that pharmacological treatments should be considered only as short-term option when there is a history of behavioral symptoms that occur in multiple settings and that do not respond to behavioral interventions.