A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders
BMC Psychiatry
A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders
Ahmad Ghanizadeh 0 1 2
Ebrahim Moghimi-Sarani 0 2
0 Department of Psychiatry, Shiraz University of Medical Sciences, School of Medicine , Shiraz , Iran
1 Research Center for Psychiatry and Behavioral Sciences, Shiraz University of Medical Sciences, School of Medicine , Shiraz , Iran
2 Keyword: Autism, Clinical trial, Randomized, Therapy , N-acetylcysteine, Oxidative stress
Background: This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD). Method: Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200 mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked. Results: The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect. Conclusions: Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well. Trial registration: This trial was registered at http://www.irct.ir. The registration number of this trial was IRCT201106103930N6
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Background
Autism spectrum disorders (ASD) are characterized by the
three main symptoms of: a) significant impairments in
social relationships, b) language and communication deficits,
and c) restricted interests. Although, autistic disorders
are not very common, their current rates are higher than
that of the previously reported rates [1]. About 1.9% of
school aged children obtain screening cutoff score for
probable autistic disorder [2]. The rate for typical autism
in five-year-old children is 6.26 per 10,000 [3]. In addition,
the global prevalence of autism spectrum disorders is
62/10 000 [4].
The neurobiology and etiology of autism are not clearly
known [5]. However, genetic [6], neurologic, metabolic,
and immunologic factors are suggested to be involved. It
is proposed that there is an imbalance of oxidative stress
and anti-oxidative defenses in children with autism [7,8].
The deficit in antioxidant system is specific in autism [9]
and it mediates the association of some behavioral
symptoms and immunity function [10]. While plasma
antioxidant capacity is decreased [11], the plasma oxidative stress
indicators, such as nitric oxide (NO) and malondialdehyde
(MDA), are increased [12]. In addition, lipid peroxidation
is increased in autism [13]. Oxidative stress markers in
urine may represent oxidative stress index in autistic
patients and some of them are suggested as the biomarkers
of autism [14]. The levels of superoxide dismutase (SOD)
and glutathione peroxidase, as antioxidant enzymes, are
lower in autism than that of the controls [15].
Oxidative stress negatively affects mitochondrion through
respiratory chain [16]. Therefore, oxidative stress is
suggested as a target for treating autism [7,17]. In addition,
animal models of autism revealed that targeting oxidative
markers was effective for treating autism [18].
Glutathione plays a significant role in defense against
oxidative stress in autism [7,19]. The level of glutathione
in the cerebellum and temporal cortex of patients with
autism are markedly decreased (34.2% and 44.6%,
respectively) [20]. The levels of both reduced glutathione
and total glutathione are lowered in autistic patients
than that of the controls [21]. Moreover, glutathione
pathway gene variation increases the risk of autistic
disorders [22].
Glutathione, which is the most important intracellular
defense against oxidative stress, consists of glutamate,
glycine, and cysteine [7]. The pathways of methionine
cycle, transsulfuration pathway, and GSH-synthesis
pathway produce glutathione [23]. The role of cysteine for
the production of glutathione is very important because
cysteine has a rate-limiting role [7]. Recently, an eight-week,
open-label trial showed that glutathione supplementation
increased the reduced-form of glutathione in plasma in
children with autism spectrum disorders [24]. This
supplementation also incre (...truncated)