A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder.

Logan K Wink,Zemin Wang,Christopher J Mcdougle,Craig A Erickson,Ryan Adams,James E Klaunig,David J Posey,Martin H Plawecki

doi:10.1186/s13229-016-0088-6

Abstract

BackgroundSocial impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD.MethodsThis study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing ≥15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1:1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12.ResultsThirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16).ConclusionsThe results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.Trial registrationClinicaltrails.gov NCT00453180

Highlights

Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments
For the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale [23] (SRS), Vineland Adaptive Behavior Scales 2nd Edition [24] (VABS-II), and oxidative stress biomarkers, differences between the groups for change in each outcome measure over the course of the study were tested using multi-level modeling
Three participants were lost to follow-up after week 4, and three withdrew due to irritability (NAC), diarrhea and encopresis, and defiant and self-injurious behavior, respectively

Summary

Introduction

Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. Growing neurobiologic understanding of ASD has identified glutamatergic neurotransmission and metabolic pathways impacting oxidative stress levels as potential targets of drug development in this complex disorder [4]. Glutamatergic dysfunction appears to play a significant role in ASD pathology, as studies have identified abnormal peripheral glutamate levels, aberrant glutamate expression in the postmortem brain, and genetic abnormalities in glutamate signaling genes in individuals with ASD [5]. Evidence of oxidative stress in the postmortem brain, and abnormalities in genes encoding for antioxidant enzymes have been reported in individuals with ASD [4, 6, 7]

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