Risperidone and aripiprazole, followed by N-acetylcysteine, appear most effective in treating irritability and aggression in youth with autism spectrum disorders (ASD), according to a systematic review and meta-analysis published in the February issue of Pediatrics.
“Although risperidone and aripiprazole have the strongest evidence for reducing ABC-I [Aberrant Behavioral Checklist–Irritability] in youth with autism spectrum disorders, they also have evidence for significant adverse events for a subset of patients,” reported Dr. Lawrence K. Fung of Stanford (Calif) University, and his associates (Pediatrics. 2016 Feb.;137[Suppl 2]:S124-35).
More than half of autistic individuals show significant emotion dysregulation, and about 20% have irritability or aggression at moderate to severe levels.
©Enterline Design Services LLC/thinkstockphotos.com
The authors combed Medline, PsychINFO, Embase, and review articles to identify randomized placebo-controlled trials evaluating medications to treat irritability and aggression in ASD youth, aged 2-17 years. The researchers used Aberrant Behavioral Checklist–Irritability scores as the primary endpoint in assessing effect size for improvement of emotional and behavioral symptoms in individuals with ASD.
Of 35 randomized controlled trials involving 1,673 participants included in the systematic review, 25 trials used the ABC-I, with 11 targeting irritability as the primary outcome and the other 14 targeting a different primary outcome. Five of the 11 trials targeting irritability tested the effectiveness of risperidone, while 2 tested aripiprazole, 2 tested valproate, 1 tested N-acetylcysteine, and 1 tested amantadine. Risperidone, aripiprazole, and N-acetylcysteine showed improvement in ABC-I scores with a moderate to large effect size. Valproate showed significant improvement to a lesser extent, but amantadine did not.
Among medications tested in the other 14 trials using the ABC-I, clonidine, methylphenidate, and tianeptine showed improvement with moderate effect sizes ,while venlafaxine and naltrexone showed improvement with a small effect size. Other medications tested included atomoxetine, citalopram, dextromethorphan, levetiracetam, mecamylamine, omega-3 fatty acid, and secretin. Hyperactivity and impulsivity improved in trials testing atomoxetine and dextromethorphan.
In trials using assessments other than ABC-I, risperidone and haloperidol showed effectiveness, compared with placebos, although risperidone beat haloperidol in a head-to-head trial. Some improvement in irritability also occurred with clomipramine, naltrexone, and a supplement with 19 vitamins and 9 minerals, compared with placebo.
The researchers calculated a number needed to treat (NNT) of two for risperidone at a dose between 1.2 and 1.9 mg, but the number needed to harm (NNH) for sedation from risperidone was also two. Risperidone’s NNH for extrapyramidal symptoms was six to seven. Flexible dosing with aripiprazole yielded an NNT of three, but fixed dosing led to an NNT of five to seven. The NNH for sedation with aripiprazole was 16, and the NNH for extrapyramidal symptoms was 20.
Sedation also occurred with haloperidol (NNH = 1) and amantadine (NNH = 10), and haloperidol caused extrapyramidal symptoms (NNH = 10). Weight gain occurred with risperidone, aripiprazole, and valproate.
“The reason for more compounds failing to show efficacy is not clear, but some of the negative studies had small sample sizes,” the authors noted. “Therefore, it is possible that some of these negative studies may represent false negatives,” and some of the studies used baseline ABC-I scores below the typical cutoff of at least 18 for inclusion.
The research was conducted through the Autism Speaks Autism Treatment Network and was supported by the U.S. Department of Health and Human Services, and the maternal and child health research program at Massachusetts General Hospital. Dr. Daniel Coury has received research funding from Autism Speaks, SynapDx, and Neuren Pharmaceuticals; has consulted for Cognoa; and is a speaker for Abbott/Innovative Biopharma. Dr. Jeremy Veenstra-VanderWeele has received research funding from Seaside Therapeutics, Roche Pharmaceuticals, Novartis, Forest, Sunovion, and SynapDx and has consulted for or advised Roche Pharmaceuticals, SynapDx, and Novartis.