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Review
Peer-Review Record

Social Interaction Improved by Oxytocin in the Subclass of Autism with Comorbid Intellectual Disabilities

by Haruhiro Higashida 1,*, Toshio Munesue 1, Hirotaka Kosaka 2, Hidenori Yamasue 3, Shigeru Yokoyama 1 and Mitsuru Kikuchi 1
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Submission received: 18 January 2019 / Revised: 14 February 2019 / Accepted: 15 February 2019 / Published: 22 February 2019
(This article belongs to the Section Neuro-psychiatric Disorders)

Round  1

Reviewer 1 Report

I would like to thank the authors of this paper titled: Social Interaction Improved by Oxytocin in the 3 Subclass of Autism with Comorbid Intellectual 4 Disabilities, for giving me the opportunity to make some comments on this elegant review of the current clinical trials involved in the Autism Spectrum Disorder.

In 2014, Karen J. Parker, Antonio Y. Hardan and colleagues found that levels of oxytocin have a considerable variation in children, and that those with low levels of this hormone have fewer social skills, regardless of whether they suffer from autism or not. The finding suggested the hypothesis that the administration of oxytocin to the autistic patients could improve their condition, but the studies made so far had given mixed results.

In this paper I liked how the authors reviewed the most recent randomized controlled clinical trials (RCT) of OT and I completely agree on their conclusions.  I'm also in favor, accordingly with a recent request of NIH in USA, that the new studies in this field should to involve a more significant sample of autistic individuals and the new research will have to  ascertain also whether the effects of oxytocin are independent of the mode of administration of the substance, with intranasal or sublingual sprays.


Author Response

I would like to thank the authors of this paper titled: Social Interaction Improved by Oxytocin in the 3 Subclass of Autism with Comorbid Intellectual 4 Disabilities, for giving me the opportunity to make some comments on this elegant review of the current clinical trials involved in the Autism Spectrum Disorder.

Thank you very much for these comments.

In 2014, Karen J. Parker, Antonio Y. Hardan and colleagues found that levels of oxytocin have a considerable variation in children, and that those with low levels of this hormone have fewer social skills, regardless of whether they suffer from autism or not. The finding suggested the hypothesis that the administration of oxytocin to the autistic patients could improve their condition, but the studies made so far had given mixed results.

In this paper I liked how the authors reviewed the most recent randomized controlled clinical trials (RCT) of OT and I completely agree on their conclusions.  I'm also in favor, accordingly with a recent request of NIH in USA, that the new studies in this field should to involve a more significant sample of autistic individuals and the new research will have to  ascertain also whether the effects of oxytocin are independent of the mode of administration of the substance, with intranasal or sublingual sprays.

 

We appreciated these valuable comments. I completely agree with these. Therefore, we described these comments and suggestions in future researches in the Conclusion section as follow:

It has been reported that levels of OT have a considerable variation in children and that those with low levels of OT have fewer social skills, regardless of whether they suffer from ASD or not (68). Therefore, it is expected that the administration of OT to the autistic patients could improve their condition. The results of such studies not always showed beneficial effects of OT (Tables 1). However, we found that no conventional measurements could detect the possible effects of OT, but, an alternative means of describing interpersonal events observed in real-life situations (60) or doctors’ impression (CGI; 61) demonstrated favorable effects of OT , and the baseline plasma OT levels predicted the OT-induced behavioral improvements (Supplementary Figure 3). Future studies require a new design to clarify the efficacy of OT under circumstances similar to those faced by individuals with ASD in their daily-lives as members of society.

It is important, accordingly with a recent request of NIH in USA, that the new studies should be planned with a more significant sample of autistic individuals. Future RCTs have to ascertain whether the effects of OT are independent of the mode of administration of the substance, with intranasal or sublingual sprays. On this respect, very recently a report by Yamamoto et al (84) showed that peripheral OT is transported into the brain by receptors for advanced glycation end-products in mice, suggesting that central OT has behavioral effects in humans after intranasal OT administration. This solves the long argument in this field whether or not OT effects are mediated by OT binding to peripheral OT receptors that in turn influence brain activity or directly by central OT receptors after recruitment of OT into the brain.

 


Author Response File: Author Response.docx

Reviewer 2 Report

The work presented is adequate and makes a review of a problem increasingly present as it is ubclass of Autism with Comorbid Intellectual Disabilities

I believe that it is well structured and well founded, I would only ask the authors to eliminate figures 1, 2 and 3 that belong to other studies and that the information contained in these figures be included in the text.

In addition, they should reconsider table 3, I believe that if this text belongs to other works, it should be commented, not expressed literally.

They should include a section of conclusions, after carrying out a review of the publications.


Author Response

The work presented is adequate and makes a review of a problem increasingly present as it is ubclass of Autism with Comorbid Intellectual Disabilities

We appreciated.

I believe that it is well structured and well founded, I would only ask the authors to eliminate figures 1, 2 and 3 that belong to other studies and that the information contained in these figures be included in the text.

We agree with this comment. We deleted from these figures from the text part. However, we would like to help for readers to understand better, we would like to remain as supplementary Figures. In addition, we clearly described that these figures are modified from the report by Munesue et al. (2016), which is reference #60.

In addition, they should reconsider table 3, I believe that if this text belongs to other works, it should be commented, not expressed literally.

According to this comment, we clearly described that it was already reported by Munesue et al., by giving the reference number in new Table 2.

We also combined old Tables1 and 2 into new Table 1, because we thought that it is better when RCTs were listed chronologically.

They should include a section of conclusions, after carrying out a review of the publications.

Thank you very much for the thoughtful comment. We set the independent ‘Conclusion’ chapter. In that section, we mentioned the valuable comments from the reviewer 1. And also we discussed the very recent finding of oxytocin carrier over BBB which possibly gives a clue for the big debate about the action site at peripheral or central oxytocin receptors after intranasal oxytocin administration in humans, as follow:

It has been reported that levels of OT have a considerable variation in children and that those with low levels of OT have fewer social skills, regardless of whether they suffer from ASD or not (68). Therefore, it is expected that the administration of OT to the autistic patients could improve their condition. The results of such studies not always showed beneficial effects of OT (Tables 1). However, we found that no conventional measurements could detect the possible effects of OT, but, an alternative means of describing interpersonal events observed in real-life situations (60) or doctors’ impression (CGI; 61) demonstrated favorable effects of OT , and the baseline plasma OT levels predicted the OT-induced behavioral improvements (Supplementary Figure 3). Future studies require a new design to clarify the efficacy of OT under circumstances similar to those faced by individuals with ASD in their daily-lives as members of society.

It is important, accordingly with a recent request of NIH in USA, that the new studies should be planned with a more significant sample of autistic individuals. Future RCTs have to ascertain whether the effects of OT are independent of the mode of administration of the substance, with intranasal or sublingual sprays. On this respect, very recently a report by Yamamoto et al (84) showed that peripheral OT is transported into the brain by receptors for advanced glycation end-products in mice, suggesting that central OT has behavioral effects in humans after intranasal OT administration. This solves the long argument in this field whether or not OT effects are mediated by OT binding to peripheral OT receptors that in turn influence brain activity or directly by central OT receptors after recruitment of OT into the brain.


Author Response File: Author Response.docx

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