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

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA.
Biological psychiatry (Impact Factor: 9.47). 02/2012; 71(11):956-61. DOI: 10.1016/j.biopsych.2012.01.014
Source: PubMed

ABSTRACT 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.
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 daily 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 Responsiveness Scale.
Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).
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.

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Available from: Lawrence Fung, Aug 15, 2015
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    • "The nonvesicular glutamate released into the extracellular space stimulates the type 2/3 metabotropic glutamate receptors (mGluR2/3), which, in turn, inhibit the vesicular release of glutamate, thereby resulting in a decrease in glutamatergic neurotransmission (Baker et al., 2002). In clinical trials, administration of NAC or a placebo in a blind fashion to a group of children with autistic disorder supports the potential usefulness of NAC for treating behavioral disturbance in children with autism (Hardan et al., 2012). The purpose of this study was to determine whether NAC normalizes the increased presynaptic transmitter release and decreased social interaction seen in VPA-exposed offspring. "
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    ABSTRACT: Autism-like phenotypes in male valproate (VPA)-exposed offspring have been linked to high glutamatergic neurotransmission in the thalamic-amygdala pathway. Glial cystine/glutamate exchange (system Xc(-)), which exchanges extracellular cystine for intracellular glutamate, plays a significant role in the maintenance of extracellular glutamate. N-acetylcysteine (NAC) is a cystine prodrug that restores extracellular glutamate by stimulating system Xc(-). In this study, we examined the effects of NAC on autism-like phenotypes and neurotransmission in the thalamic-amygdala synapses, as well as the involvement of metabotropic glutamate receptors 2/3 (mGluR2/3). Valproate-treated rats received a single intraperitoneal injection of 500 mg/kg NaVPA on E12.5. On postnatal day 21 (P21), NAC or saline was administered once daily for 10 days. From day 8 to 10, NAC was given 1/2 h prior to behavioral testing. Chronic administration of NAC restored the duration and frequency of social interaction and ameliorated anxiety-like behaviors in VPA-exposed offspring. In amygdala slices, NAC treatment normalized the increased frequency of mEPSCs and decreased the paired pulse facilitation (PPF) induced by VPA exposure. The effects of NAC on social interaction and anxiety-like behavior in the VPA-exposed offspring were blocked after intra-amygdala infusion of mGluR2/3 antagonist LY341495. The expressions of mGluR2/3 protein and mGluR2 mRNA were significantly lower in the VPA-exposed offspring. In contrast, the mGluR3 mRNA level did not differ between the saline- and VPA-exposed offspring. These results provide the first evidence that the disruption of social interaction and enhanced presynaptic excitatory transmission in VPA-exposed offspring could be rescued by NAC, which depends on the activation of mGluR2/3.
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    • "Alternative shuttling of electrons to cytochrome c bypassing complex I/III seems to have a role for neuroprotection through enhancing the production of ATP and lowering the production of ROS (Wen et al., 2011; Rojas et al., 2011; Ghanizadeh et al., 2013). A potential therapeutic effect of N-Acetyl cysteine has been reported in clinical trials involving children with autism (Ghanizadeh and Derakhshan, 2012; Hardan et al., 2012). Mitochondrial-targeted molecules and nutrients, such as coenzyme Q(10), acetyl-l-carnitine, ␣-lipoic acid, ␣-tocopherol and ascorbic acid, that support mitochondrial functions and reduce OS have been long investigated for treatment of Down syndrome (reviewed in Pagano and Castello, 2012; Lott et al., 2011). "
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    • "Importantly, NAC was well tolerated, as has been the case in children with autism (Hardan et al. 2012), in adolescents with cannabis dependence (Gray et al. 2012), in adults with trichotillomania (Grant et al. 2009), and when used adjunctively with SSRIs, in adults with SSRI-resistant anxiety disorders (Lafleur et al. 2006). Additional, prospective trials are urgently needed to assess the potential role of glutamate modulators, such as NAC, in youth with anxiety disorders, including those who have had partial responses to ''first-line'' psychopharmacologic and psychotherapeutic interventions. "
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