Meta-Analysis of Pharmacotherapies for Treating Irritability, Agitation and Aggression in ASD

Friday, May 15, 2015: 11:30 AM-1:30 PM
Imperial Ballroom (Grand America Hotel)
L. K. Fung1, R. Mahajan2, A. A. Nozzolillo3, P. Bernal4, A. Krasner5, B. Jo6, D. L. Coury7, A. Whitaker8, J. Veenstra-Vander Weele9 and A. Y. Hardan10, (1)Stanford University, Palo Alto, CA, (2)Psychiatry, Kennedy Krieger Institute/Johns Hopkins University SOM, Baltimore, MD, (3)Massachusetts General Hospital, Boston, MA, (4)Psychiatry, Children Health Council, Palo Alto, CA, (5)Columbia University, New York, NY, (6)Psychiatry, Stanford University, Stanford, CA, (7)Nationwide Children's Hospital, Columbus, OH, (8)Psychiatry & Behavioral Sciences, Columbia University, New York, NY, (9)Psychiatry, Columbia University / New York State Psychiatric Institute, New York, NY, (10)Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA

Children with ASD have core deficits in social communication and reciprocity as well as restricted and repetitive behaviors. They often experience irritability, which may manifest as temper tantrums, and aggression toward others or to self. These symptoms cause significant distress to the children themselves, and may be a burden on their families and others involved in their care. Risperidone and aripiprazole are, perhaps, the most commonly used medications for the treatment of IAA in individuals with ASD. A wide range of other pharmacologic agents spanning different classes, targeting various mechanisms of action, with many potential adverse events, have also been studied for the reduction of IAA. Therefore, there is a compelling need to systematically analyze these studies to identify agents that may be most effective and safe in reducing these symptoms in children with ASD.


(1) To systematically review and quantitatively analyze the evidence for the efficacy of pharmacologic treatments used to target irritability, agitation and aggression (IAA) in children and adolescents with autism spectrum disorder (ASD). (2) To examine the safety of these compounds in the treatment of IAA in ASD.


Systematic search was performed from MEDLINE/PubMed, Embase, and PsycINFO from inception to September 2013. Eligibility of studies included: randomized controlled trials (RCTs), study population of ASD, mean age of participants <18 years, sample size >10, and written in English. Only studies employing aberrant behavioral checklist – irritability subscale (ABC-I) were included in the meta-analysis. Effect sizes (Cohen’s d) for efficacy were calculated from the means and standard deviations at the end of treatment (placebo and medication) reported in the manuscripts.


A total of 36 RCTs with 1686 participants were identified. Twenty-six of these employed ABC-I to assess IAA and were included in the meta-analysis. These trials represented 19 compounds, with risperidone being the most studied (5 trials). Compared to placebo, 11 compounds [risperidone, aripiprazole, methylphenidate, valproate (1 of 2 studies), citalopram, clonidine, haloperidol, NAC, naltrexone, tianeptine, and venlafaxine] were shown to result in significant improvement in ABC-I at the end of treatment. Seven of them showed a moderate to large effect size [risperidone (d=0.9), aripiprazole (d=0.8), N-acetylcysteine (d=0.7), clonidine (d=0.6), methylphenidate (d=0.6), and tianeptine (d=0.5)]. Among the 26 RCTs, 18 of them were non-crossover studies representing 11 compounds. Haloperidol, risperidone, amantadine, and aripiprazole were found to cause somnolence/sedation. Risperidone, haloperidol, and aripiprazole were shown to cause EPS. Finally, compared to placebo, aripiprazole (d=3.1), risperidone (d=0.8), and valproate (d=0.3) were found to cause the most weight gain.


Current literature suggests that risperidone and aripiprazole have the strongest evidence for reducing IAA in children and adolescents with ASD. However, these compounds have potential adverse events including somnolence/sedation, weight gain and EPS. Methylphenidate may be a useful agent to treatment IAA when inattention, hyperactivity, and/or impulsivity are co-morbid symptoms.  Other medications such as NAC, clonidine, and tianeptine may be potentially effective agents to reduce IAA with fewer adverse events, but replication of these findings is warranted.