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    4 views6 pages

    N Acetylcisteine in Children With Autism

    Uploaded by

    Suzy Dos Reis
    article

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
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    of 6
    Arcuivat REPORT A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism Antonio Y. Hardan, Lawrence K, Fung, Robin A. Libove, Tetyana V. Obukhanych, Surekha Nair, Leonore A. Herzenberg, Thomas W. Frazier, and Rabindra Tirouvanziam Background: An imbalancein the excitatory/inhibitory systems with abnormalities in the glutamatergic pathvrays has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently inked to this disorder. The goal ofthis 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 was 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 daly for 4 weeks. ‘The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Respon siveness Scale. Results: Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized inthe study. Follow-up data was, available on 14subjectsin the NAC group and 15 Inthe placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted insignificant improvements on ABC iitabilty subscale (F = 680; «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. Key Words: Antioxidant, autism, disruptive behaviors, glutamate, glutathione, iritablity tistc disorder is a pervasive developmental disorder char- acterized by impairment in communication and reciprocal social interaction, as well as stereotypic/tepetitive behav- Tors. Causes of autism remain elusive, yet clearly combine genetic, developmental, and environmental factors (1). Several neurobio logical models have recently been proposed including the exis- tence ofa glutamatergic dysfunction (2) and excessive oxidative stress (3), These models have sparked hope forthe development of Targeted therapeutic agents leading to disease-specific interven Increased ratio of excitationnhibition (E) in sensory, mne- monic, social, and emotional systems have been proposed as a ‘model underlying atleast some forms of autistic disorder (2). While glutamatergic pathways modulate excitatory neurotransmission, ‘gamma-aminobutyric acidergic pathways modulate inhibitory neurotransmission predominantly. This hypothesisis supported by evidence of increased glutamatergic transmission from neuro- pathologic and neurobiological studies. Postmortem investiga- tions have reported increases in expression ofthe messenger RNA of several genes associated with glutamatergic pathways, including ‘excitatory amino acid transporter 1 and glutamate receptor ami: rno-3-hydroxy-S-methyl-4-soxazolepropionic acid type 1, two members of the glutamate system (4). Genetic studies have also reported a link between autism and specific glutamate receptor From the Departments of Psychiatry and BehavioraSclencestAVH UKE, RAL, SH, RT) and Genetics (FVO, LAH, Stanfod University, Stanford, Califor ia: nd Center for Pediatrie Behowoal Health (TAF), leveland Cin, ‘leveland, Ohi Address correspondence to Antonio Y. Hardan, MD. Stanford University, Department of Psychiatry and Behavioral Sciences, 401 Quay Row, Stanford, CA 94305; Ema hordanayestanord od, Received ul 25,2011; revsed Jan 11, 2012; accepted Jan 19,2012, 006-5225/836.00 doil0.1016/jbiopssch.2012.01.014 ‘genes (5-8). Glutamic acid decarboxylase, an enzyme that catalyzes this decarboxylation of glutamate to gamma-aminobutyric acid, has also been reported to be reduced in parietal and cerebellar cortices of individuals with autism (2). Finally, increases in gluta ‘mate levels in serum (10,11) and cerebrospinal Mid (12,13) have also been observed in children with autism. ‘Another emerging hypothess in autism suggests that the con- dion s aresult of redoximbalance (3, ie, disequilibrium between ‘oxidants and antioxidantsinthe body, which eads toaccumulation of reactive oxygen species (ROS). Ordinarily, ROS are removed by superoxide dismutase, catalase, and glutathione (GSH; tripeptide slutamyl-cysteiny-alycine) related enzymes, including GSH perox dase and GSH reductase. Accumulation of ROS can cause chemical modifications and functional changes of DNA, RNA, protein, lipid, {and carbohydrate moieties, thereby resulting in cellular dysfunc- tion. The potential involvement of redox imbalance in the patho- ‘genesis of autism has been suggested by neuropathologic (3), ge- ‘etic (14), and clinical studies (15). Differences in allele frequency and/or significant gene interaction between individuals with au tism and typically developing control subjects were found for rele vant genes encoding GSH S-transferases, a key family of enzymes that detoxify pro-oxidative compounds by coupling them to the body's main antioxidant molecule, glutathione (14). Peripheral, decreased levels of antioxidant enzymes, such as erythrocyte GSH. peroxidase and superoxide dismutase (16), and decreased cellular {and mitochondrial GSH (15) were found in several investigations, Decreased plasma Sadenasyl--homacysteine as wells Sadeno- sy-L-methionine, two intermediates in the synthesis of cysteine (4), which is 2 key precursor of GSH, had also been reported, Final, it is suggested that redox imbalance may cause, at least party, the neuronal insult and dysfunction seen in autism (15). ‘N-acetylcysteine (NAC) isan orally bioavailable prodiug of os teine that swell known forts role as an antidote against acetamin- ‘phen overdose induced liver damage by maintaining or restoring hepatic concentrations of cysteine, leading to GSH synthesis (17). ‘Cysteine supplied by NAC treatment can aso be oxidized to cystine, BIOL PSYCHIATRY 2012.44 © 212 Society of Biological Psychiatry 2° BIOL PSYCHIATRY 2012x3008 a substrate for the glutamate-cstine antiporter. This antiporter Slows for the cellular uptake of eystne, which causes the reverse transport of glutamate into the extracellular space. The nonvesi lar glutamate released into the extracelilar space stimulates the type 2/3 metabotropic glutamate receptors, which, tur, inbbit the vesictlr release of glutamate, thereby resulting in decreare in .100), a though interestingly there was. large reduction (d ~ 72)in hyper- activity at week 12 with changes from baseline to end of the tral reaching statistical sigifcance(4 NAC = 10.4 97; placebo. 3.2% 3.3;F(1,22) = 557, p = 028) Differences were less striking between the two groups at elther week 4 [A NAC = ~5.3 > 82: placebo = 5 = 75; (1,23) ~ 349, p ~ 074) or week 8 [A NAC 7.7 + 97:4 placebo ~ 3 * 1039;F(1,22) » 363, ~ 070), Global Improvement was assessed using the CGH subscale. Inthe NAC ‘group, five subjects were judged to be much improved, six were ‘minimally improved, two were no change, and one was much i {b : — 7 Figure 1. Significant improvement with Nacetycytsine (NAC treatment forthe piimary outcome messures Aberrant havior Checks etablty subscale (ABC-tabily F680, p 001; d ~ 96) with improvement being observedinweek and contining tvoughweek andweek 3 Ear bars denote standorddevistons Forciarty postive error bart are shown for the placebo group and negative err bar are shown forthe NAC group www sobp org/journal 4° BIOL PSYCHIATRY 20120cx8% ‘Table2. Treatment Responses of Participants with Autism Assigned to Receive NAC o Mean 50) Range AY. Hardan etal astine Week 2 Placeboin= 15) ___NACIn= 18) __——aceboin= 15) NACIH= 14 =F _ip__Cohen'sd nec ‘ABCieeabty MsGHS41 — 169:79)N-27] —34199)(441} ——-7.2057)(0-48] 680

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