Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta-analysis
Introduction
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5 (2013)], autism spectrum disorder (ASD) are neurodevelopmental conditions characterized by two principal "core symptoms" including 1) persistent deficits in social communication and social interaction, and 2) restricted, repetitive patterns of behavior, interests, or activities. Social communication and interaction deficits include difficulties in social-emotional reciprocity, nonverbal communicative behaviors in social interaction (e.g. avoidance of eye contact), solitary behavior, difficulties in comprehending other’s feelings, or difficulties talking about their own feelings. Characteristic problems faced by subjects diagnosed with ASD include restricted, repetitive patterns of behaviors, interests, and activities, such as repeating certain movements or speech, difficulties with changes in schedule or routine, laughs or cries without apparent reason, and unusual ways of playing or no play at all. Individuals with ASD may also present difficulties in other aspects such as anxiety, learning disabilities, and eating problems [DSM-5 (2013)]. It is estimated that one out of 150 children today has some form of ASD, including Asperger's syndrome, Childhood Disintegrative Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS).
Despite a large number of clinical trials, there is no cure for autism. Current treatments for ASD is mainly focused on helping children improve their areas of weaknesses and behavioral problems using treatments such as Applied Behavior Analysis (ABA), and Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) (Reichow, 2012; Virues-Ortega et al., 2013). Since we currently lack a clearly identified pathogenesis of ASD, there is yet no effective pharmacological interventions for the disorder and finding drugs to effectively target the “core symptoms” has been challenging (Posey et al., 2008). But there are medicines that can alleviate other conditions that an autistic patient might have. For instance, when behavioral problems are so disruptive that they prevent learning, medication, such as antipsychotics and antidepressants, can be used to alleviate these disruptive behaviors to improve learning ability (Deb, 2006). However, these medications are unable to address the root of the problem. Hence, the current view is that ASD is a neurodevelopmental disorder with great potential for crucially needed treatment improvement coupled with the realization that at present there is minimum anticipation for a "cure".
Recent animal and human studies have shown that oxytocin (OT), a neuropeptide, plays an important role in modulating social-communicative behaviors (Ebstein et al., 2009; Heinrichs et al., 2009). For example, a large number of studies using animal models have indicated that oxytocin promotes social behaviors such as social memory, pair-bonding, and maternal behavior (Drago et al., 1986; Olazabal and Young, 2006). Evidence from human research further suggested that oxytocin plays a role in social cognition and prosocial behaviors (Bartz et al., 2011), such as trusting (Kosfeld et al., 2005; Mikolajczak et al., 2010), conformity (Huang et al., 2015; Xu et al., 2019a), intention-based moral judgment (Scheele et al., 2014a; Shang et al., 2017), generosity (Israel et al., 2008, 2009; Zak et al., 2007) and cooperation (De Dreu et al., 2010; Declerck et al., 2010). Such promising findings generate considerable excitement about the therapeutic use of oxytocin to ameliorate social functioning deficits in ASD patients. In addition, some studies have reported altered oxytocin levels in individuals with ASD (LoParo and Waldman, 2015; Modahl et al., 1998). These studies indicate that disturbances in oxytocin levels lead to social and communicative dysfunction in ASD patients, and therefore suggest that exogenous oxytocin administration may effectively ameliorate symptoms of ASD. A considerable number of clinical trials have been conducted to understand the effects of oxytocin administration on individuals with ASD. However, meta-analyses and reviews suggest that findings that oxytocin administration improves core symptoms of ASD are mixed and controversial (Alvares et al., 2017; Goel et al., 2018; Guastella and Hickie, 2016; Lee et al., 2015; Okamoto et al., 2016; Ooi et al., 2017). Given the limited number of clinical trials included in these meta-analyses and reviews, e.g. 12 studies in the meta-analyses conducted by Ooi et al. (2017), further validation of the effects of oxytocin on ASD are still needed. In the current meta-analysis, we further separately assessed the effect of OT treatment on the two types of core symptoms: deficits in social functioning and non-social domain functioning, including repetitive movements, restrictive interests, and mood-related symptoms.
Furthermore, research showed that factors such as age, gender, and duration of clinical trials, likely influence the effect of OT treatments in ASD patients. Importantly, previous ASD research has suggested that early diagnosis at young ages coupled with behavioral interventions is more likely to have significant long-term positive effects on improving symptoms and social skills in later years (Helt et al., 2008; Reichow and Wolery, 2009; Rogers and Lewis, 1989). Studies involving healthy participants also found the effects of oxytocin were moderated by gender (Feng et al., 2015; Xu et al., 2017). A majority of subjects in most of the oxytocin trials were male ASD patients. One reason might be the overrepresentation of males in ASD. Another reason could be to exclude potential confounding effects due to variable hormonal cycles in female subjects. Additionally, it should be considered that single-dose challenge and repeated daily administrations probably play a role in the effect of OT treatment on ASD. In the current meta-analysis, we perspicaciously tested how these moderators influence the effects of oxytocin on individuals with ASD. Moreover, to assess whether the recent publications produce different findings from the previous controversial ones, the year of publication was also included as a moderator.
Section snippets
Literature searches and inclusion criteria
We first compiled 21 articles from two prior meta-analysis and review papers on the effects of intranasal oxytocin on autism (Alvares et al., 2017; Ooi et al., 2017). Articles from subsequent years (between 27th Oct. 2015 and 1st Apr. 2019) were searched using the Web of Science (http://www.webofknowledge.com) and PubMed (https://www.ncbi.nlm.nih.gov/pubmed) database with the keywords “oxytocin” AND “intranasal” OR “administration” AND “autism”. The search yielded 322 articles from both
Study characteristics
Across all 28 studies, 745 individuals with ASD were randomized into experimental groups, including between-subject/crossover or single-arm, non-randomized and uncontrolled design. Dosages of OT per treatment ranged between 8 and 24 IU and sample sizes ranged from 8 to 106 ASD patients. The mean age was 32.93 ± 8.87 years and 96.11 % of the patients were male. Detailed study characteristics can be found in Table 1.
Multilevel meta-analysis
The obtained outcomes for non-social domain improvement and social functioning
Discussion
The present study provides meta-analytical estimates of the OT effects on non-social domain improvement and social functioning in autism spectrum disorder. We used a three-level meta-analytic model to determine that OT does not reliably improve clinical symptoms in the non-social domain, but may have beneficial effects on social functioning. Moreover, none of the selected modulators explained a significant amount of between-study variance, suggesting that the overall enhancing effects of OT on
Declaration of Competing Interest
The authors have no conflicts of interest to declare.
Acknowledgements
This work is supported by the Lam Woo Research Fund – Individual Grant, 185605, Lingnan University, Hong Kong, China.
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