A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

Abstract

Background An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant in the treatment of behavioral disturbance in children with autism. Methods This is a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice-daily for 4 weeks and 900 mg three-times-daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist – Irritability subscale) and safety measures were performed at baseline, 4, 8, and 12 weeks. Secondary measures included the ABC-Stereotypy subscale, Repetitive Behavior Scale – Revised (RBS-R), and Social Responsiveness Scale (SRS). Results Thirty-three subjects (31 males, 2 females; aged 3.2–10.7 years) were randomized in the study. Follow-up data was available on fourteen subjects in the NAC group and fifteen in the placebo group. Oral NAC was well-tolerated with limited side effects. Compared to placebo, NAC resulted in significant improvements on ABC-Irritability subscale (F=6.80; p<.001; d=.96). Conclusions Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted. ClinicalTrials.gov Identifier NCT00627705

Deletion of Fmr1 results in sex‐specific changes in behavior

“…While some have suggested that the female Fmr1 KOs should be included in studies with males based on similarity, here we highlight the marked phenotypic differences, and as such, future research could focus on how these phenotypes could, and should, be treated separately. For instance, repetitive behavior phenotypes are commonly treated using several different types of drugs, including 5‐HT1BR agonists (Ho et al., 2016), 5HT1A partial antagonists (Chugani et al., 2016) and more recently, antioxidants (Hardan et al., 2012). Through the routine exclusion of females from biomedical studies, opportunities are missed to explore potential treatments and how sex may impact the efficacy of such treatments.…”

The Efficacy of AdjunctiveN-Acetylcysteine in Major Depressive Disorder

“…38 N-acetylcysteine has been shown to be potentially efficacious in a bewildering array of divergent disorders, from bipolar disorder 10,15,23 to schizophrenia, 6,14 obsessive-compulsive disorder, 39 nailbiting, 40 autism, 41 attention-deficit/hyperactivity disorder, 42 cocaine and cannabis abuse, 43 smoking, and blast traumatic brain injury, 44 although there are negative studies, including those in bulimia 45 and pediatric trichotillomania, 46 and the methodological quality of trials is highly variable. 4 As N-acetylcysteine has multiple mechanisms of action, it remains to be clarified if it works on common targets across disorders, such as oxidative stress or inflammation, or if some actions, such as glutamate-cysteine exchange, are more important to some disorders than others, such as addictions.…”

Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis

“…26,27,30,38,41 In contrast to risperidone and aripiprazole, NAC, methylphenidate, and tianeptine did not cause significant somnolence, EPSs, or weight gain. 26,27,38,41 However, findings from these studies are limited by the lack of replication because demonstrated efficacy and tolerability generally came from only 1 RCT (exception: methylphenidate). Furthermore, the treatment targets for clonidine, methylphenidate, and tianeptine were not irritability (ie, ABC-I was not indicated as primary endpoint and baseline ABC-I was ≤18).…”

“…12,13,[19][20][21][22][23][25][26][27]29,30,34,35,38,39,41,60 NAC, clonidine, methylphenidate, and tianeptine yielded moderate to large effect sizes. 26,27,30,38,41 In contrast to risperidone and aripiprazole, NAC, methylphenidate, and tianeptine did not cause significant somnolence, EPSs, or weight gain. 26,27,38,41 However, findings from these studies are limited by the lack of replication because demonstrated efficacy and tolerability generally came from only 1 RCT (exception: methylphenidate).…”