NAC Improves Irritability and Repetitive Behaviors in Children with Autism
The antioxidant N-acetylcysteine (NAC), which can be found in health food stores, seems to be effective for irritability and repetitive behaviors in children with autism. In a small controlled study that was published by Hardan et al. in the journal Biological Psychiatry in 2012, 33 mostly male children with autism (aged 3-12 years) received either placebo or NAC at doses of 900mg daily for 4 weeks, followed by 900mg twice daily for 4 weeks, then 900mg three times a day for 4 weeks. Beginning in week 4, the children receiving NAC showed significantly improved irritability scores, and a trend for improvement in repetitive behaviors.
Social responsiveness did not improve significantly, but the children receiving NAC did show some improvement in some areas of social behavior, such as social cognition and autism mannerisms.
There were few side effects associated with NAC. The most significant were gastrointestinal side effects, but these were mild, especially when compared with the side effects associated with FDA-approved treatments for autism, such as the atypical antipsychotics risperidone and aripiprazole.
The authors of the study plan to expand their research in a study of more than 100 children with autism.
Editor’s Note: It should we previously summarized this study in the BNN based on research presented by Fung et al. at a meeting of the American Academy of Child and Adolescent Psychiatry two years ago. The study has now been published.
Arbaclofen May Improve Social Behavior in Fragile X Syndrome and Irritability in Autism
Fragile X syndrome is a genetic condition that is the most common single-gene cause of autism and inherited cause of intellectual disability. In addition to mental disabilities it is also characterized by certain physical characteristics (elongated face, protruding ears, and large testes in boys), stereotypic movements such as hand-flapping, and social anxiety.
When autism is associated with Fragile X, a mutation in the Fragile X gene is responsible for the autism. (It is also possible to have autism without Fragile X, or to have Fragile X without autism.) Fragile X is a genetic disorder like Downs Syndrome, while autism is a complex behavioral disorder, likely involving multiple genetic and environmental vulnerabilities.
A new drug called arbaclofen seems to improve social avoidance and problem behaviors in adults and children with Fragile X. Researchers hypothesize that normal social stimuli overwhelm a Fragile X patient because of a defect in inhibition, and arbaclofen acting on presynaptic GABA-B receptors reduces glutamate release, thereby reducing the overactive signaling associated with this defect.
In a 6-week placebo-controlled study of arbaclofen among 63 patients with Fragile X ranging in age from 6 to 39, patients 11 years old and younger received 10mg twice a day and patients 12 and up received 10mg three times a day. The drug was well-tolerated, with only a few reports of sedation or headache. While problem social behaviors and neurobehavioral function improved, irritability did not. The study considered irritability because that is the aspect of autism most often improved by other Federal Drug Administration-approved drugs for autism, such as risperidone and aripiprazole. In another study of arbaclofen in autism spectrum disorders, it did improve irritability and agitation.
Editor’s Note: The GABA-B agonist arbaclofen has previously shown positive effects in motor spasticity. The positive effects noted here in the social domain of autism spectrum disorders and Fragile X are very promising.
N-acetylcysteine Improved the Irritability Associated with Autism
At the 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in October 2010, Lawrence Fung of Stanford University reported that N-acetylcysteine (NAC), a compound sold over-the-counter in health food stores, improved irritability and other symptoms of autism in children aged 8 to 17. In this double-blind, randomized study of NAC compared with placebo, the children who received NAC were treated with 900mg once a day for four weeks, then 900mg BID (twice a day) for four weeks, and finally 900mg TID (three times a day) for the last four weeks of this three-month study. These doses significantly improved irritability and stereotypy (repetitive behaviors) compared with placebo. Side effects were minimal.
Editor’s note: The potential for a safe compound such as N-acetylcysteine to show efficacy in autism is striking. Currently only risperidone and aripiprazole are FDA-approved for effectiveness treating irritability in autism. There has also been a positive study of valproate compared with placebo in autism, although it is not FDA-approved for this purpose.
Most double-blind, placebo controlled clinical trials of NAC have been in adults, so this is the first report that suggests NAC can safely be used in children.
NAC’s ability to improve irritability in autism raises the possibility that this drug may be useful in the treatment of irritability and repetitive behaviors in bipolar disorder, particularly since N-acetylcysteine has also been reported to improve mood, especially depression, in adults with bipolar disorder in the studies of Mike Berk and colleagues published in Biological Psychiatry in 2008.
This study adds to the evidence that suggests N-acetylcysteine may reset the brain’s habit system in the ventral striatum (also called the nucleus accumbens), which is involved in the assessment of the reward value of a variety of substances of abuse and behaviors (as described in BNN Volume 14, Issue 1 from 2010). NAC improves a number of habit-related syndromes including cocaine, heroin, and gambling addictions, trichotillomania (compulsive hair-pulling), and now the irritability and stereotypic behaviors of autism.
In light of NAC’s profile of efficacy and safety, systematic exploration of the drug in childhood-onset bipolar illness is indicated. We are aware of at least one group that is planning such a study.
