Initial research with antipsychotics for aggressive children with ASD involved the use of haloperidol which demonstrated positive effects that were significantly better than placebo (Campbell et al. 1978; Mandell et al. 2008). Aggressive Behavior was improved along with such issues as negativity, lability of affect, and angry affect. Haloperidol is a classic antipsychotic with a high degree of negative effects including unacceptable sedation along with one-third developing dystonias and withdrawal dyskinesias. Use of these older (first generation) antipsychotics has been replaced by use of the newer (second generation) atypical antipsychotics which may have a lower incidence of tardive dyskinesia (Anderson et al. 1984; Campbell et al. 1997; Posey et al. 2008; Caccia 2013). Research has mainly focused on aripiprazole and risperidone (Nazeer 2011).

Regarding aripiprazole, one controlled study of patients 6 to 17 years of age with ASD noted that severe aggression and irritability were significantly improved over placebo using three doses: 5, 10, and 15 mg per day (Marcus et al. 2009). Another research study of this same age and diagnosis cohort also found improvement over 8 weeks that reached a gradually increasing dose with a mean of 8.6 mg per day at the end of an eight week study (Owen et al. 2009). Both studies noted adverse effects of sedation as well as weight gain and the 8 week study also noted the presence of extrapyramidal symptoms (Owen et al. 2009). In 2009 the US Food and Drug Administration (FDA) approved the use of aripiprazole for those with ASD who are 6 to 17 years of age and had considerable irritability. Clinicians generally use a maintenance dose between 5 and 15 mg per day (Kaplan and McCracken 2012).

The United States NIMH RUPP ASD Network studied risperidone and concluded that a mean dose of 2.08 mg/day provided significant reduction in aggression (including self -injury and severe tantrums) in their study of 101 pediatric patients with ASD aged 5 to 17 years of age (McCracken et al. 2002; RUPP^a 2005a). A relapse of these symptoms occurred in most if the medication was stopped at 6 months of age and use of the medication resulted in a significant weight gain of 5.6 kg over 6 months. No evidence of tardive dyskinesia or dystonia was seen in this research. An added benefit of the use of atypical antipsychotics in children with ASD is a significant reduction in hyperactivity (vida infra) (McCracken et al. 2002; Sharma and Shaw 2012).

A meta-analysis of post-2000 RCT studies using risperidone in patients with ASD revealed a large mean-effect size of 1.21 (Sharma and Shaw 2012). In 2006 the US FDA approved it in those with ASD aged 5 to 17 years of age for the management of ASD irritability that includes rapidly changing moods, temper tantrums, deliberate self -injury, and aggression; the maximum daily dose was 3 mg. It is not clear how long to place these children and adolescents on atypical antipsychotics but positive benefits may be seen for 6 to 12 months (Kaplan and McCracken 2012).

Observing for potential side effects (Table 9.9) is important and this includes monitoring each visit for such adverse effects as sedation, lethargy, and weight gain. The clinician should monitor every 6 months for the development of tardive dyskinesia as well as Parkinsonism; also, one should order laboratory studies every 6 months for screening of potential hyperglycemia and hyperlipidemia (Kaplan and McCracken 2012). The Abnormal Involuntary Movement Scale (AIMS) can be used to monitor abnormal movement development (Guy 1976). The clinician can also screen every few visits for symptoms of hyperprolactinemia (i.e., galactorrhea, gynecomastia, menstrual irregularity, sexual dysfunction) and obtain a prolactin level if indicated (Roke et al. 2012). The pharmacokinetics of these agents can be unique and complex for children and adolescents based on individualized factors including demographic variants, phenotype, and drug interactions (Caccia 2013).

Research is limited in the effectiveness of other atypical antipsychotics but there is some early evidence that olanzapine and ziprasidone may be helpful while quetiapine has not been shown to be helpful in ASD children in terms of amelioration of aggression and related symptoms (Potenza et al. 1999; Malone et al. 2007; Martin et al. 1999). Research is seeking novel drugs for management of ASD that have improved drug profiles over atypical antipsychotics (Politte and McDougle 2014). However, antipsychotics remain a commonly used class of psychotropic drugs used in the management of children and adolescents with ASD (Schubart et al. 2013).

In addition to a well-researched role of methylphenidate (MPH) for improvement of hyperactivity and attention span dysfunction in those with ADHD, there is some limited research suggesting that MPH can improve symptoms of aggression in children aged 5 to 11 years with ASD (Handen et al. 2000; Quintana et al. 1995). These studies are small and of limited duration; one noted an increase in unacceptable adverse effects from MPH which included abnormal movement, agitation, and changes of mood (Handen et al. 2000). Thus, the role of MPH is not well established and is considered in selective situations such as when aggression is associated with impulsivity and hyperactivity (Nazeer 2011). There is no research evidence at this time for the use of amphetamines in those with ASD.

There is also limited research on the use of the anticonvulsant divalproex for ASD children or adolescents with aggression. One study has shown modest improvement in use of this mood stabilizer in 55 patients with ASD who were 5 to 17 years of age (Hollander et al. 2010). Limited side effects were recorded in these patients and those with benefit tended to have higher valproate blood levels than those who did not develop improvement in aggression. This chemical has a number of actions including enhancing neurotransmission of gamma-amino-butyric acid (GABA ), blocking voltage-gated sodium channels as well as T-type calcium channels, and also serving as a histone deacetylase inhibitor. Increased appetite, liver dysfunction, and blood dyscrasias can develop with this agent. Divalproex is not approved by the US FDA for this indication. Other mood stabilizers under research include lamotrigine and levetiracetam (Nazeer 2011).

Limited research has noted some positive response in pediatric patients with ASD and aggression who were placed on clonidine (alpha-2 adrenergic agonist) and naltrexone (opioid receptor antagonist) (McCracken et al. 2002; Parikh et al. 2008). These agents are not FDA approved for this indication and more research is needed in this regard.

In addition to revealing benefit in aggressive behavior for children and adolescents with ASD, the United States NIHM RUPP ASD Network also demonstrated some reduction in RRBs with use of risperidone (McDougle et al. 2005). Aripiprazole has also shown an effect on RRBs as well (Marcus et al. 2009; Owen et al. 2009).

The complexity of ASD is indicated by the failure of research studies to show RRBs reduction in patients placed on SSRIs despite the identified serotonin dysfunction found in ASD and despite the known improvement in obsessions as well as compulsions seen in other patients on SSRIs who have anxiety disorders (Kaplan and McCracken 2012). There are anectodal reports of improvement of RRBs in those with ASD on SSRIs and SSRIs are the most common type of psychopharmacologic agents prescribed for these patients (Mandell et al. 2008). One research study of fluoxetine (mean dose of 9.9 mg per day) demonstrated improvement in RRBs over placebo in 39 children aged 5 to 16 years of age (Hollander et al. 2005) while a larger trial of fluoxetine using 158 individuals aged 5 to 17 years of age did not demonstrate improvement (Weblink #3 n. d.).

A study of citalopram (using doses from 2.5 mg per day to a maximum dose of 20 mg per day) did not show reduction in RRBs in 149 patients aged 5 to 17 years of age; also one third developed serotonergic activation-type adverse effects that included insomnia, mood changes, and increased activity (King et al. 2009). An open label study using escitalopram revealed some benefit in RRB reduction (Owley et al. 2005). While some studies found that some ASD patients derive benefit from SSRIs with careful titration and monitoring (Kaplan and McCracken 2012), a RCT meta-analysis concluded the contrary (Williams et al. 2013). Some have suggested the use of mirtazapine which is a noradrenergic and specific serotonergic antidepressant (Nazeer 2011).