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  • Adonis Sfera 1,2,*,
  • Karina G. Thomas 1 and
  • Zisis Kozlakidis 6
  • et al.

Reviewer 1: Anonymous Reviewer 2: Hiu Chuen Lok

Round 1

Reviewer 1 Report

The manuscript wrote by Sfera A et al., focuses its attention on the investigation of γ-aminobutyric acid (GABA) in the post-pandemic era, related to SARS-CoV-2 virus and angiotensin-converting enzyme-2 (ACE-2), to highlight non-neuronal GABA and summarize potential interventions. Even if the topic is not a complete novelty, the manuscript is well-written, it lists lots of information about the topic, adding many details, which is quite interesting due to the peculiar period of time, and seems to be of help for investigators who would like to approach to this subject. The figures describe in a clear way the related text. It was difficult to revise a submitted manuscript without clearly referred to the lines. The Authors are greatly encouraged to pay attention during the manuscript insertion in the template, where the lines are indicated. Despite this, the manuscript can be published after having addressed several points:

 

 

Please carefully revised the authors’ affiliation:

- indicate the name of the corresponding author/s after the affiliation and indicate it/them with an asterisk as reported in the original template you used for the submission

- indicate the email address of each author.

 

-  Multiple references are indicated in the wrong manner. Please revise and correct.

-  In this sentence “For example, the antiviral and anti-inflammatory properties of GABA were highlighted by recent preclinical studies…”, the GABA the Authors referred to is the nGABA? Please explain.  

-  Please specify what CNS means.

-  From “The SARS-CoV-2” to “[Fig.1]”, please carefully revised this part of the Introduction, complying with the standards of the text (see Author’s guidelines).

-  Figure 1. All the names cited in the figure have to be described in the related figure legends, not only reported as acronyms in the figure.

-  Please change the brackets indicating the figures from square to circular, as you did for Fig.2.

-  Fig.2 needs to be placed after its first citation paragraph. Please move accordingly.

-  What NSP and ORFA mean? Please described them in the text.

 

Author Response

Please carefully revised the authors’ affiliation:

- indicate the name of the corresponding author/s after the affiliation and indicate it/them with an asterisk as reported in the original template you used for the submission.

  1. Correct names, affiliations, and emails:

Adonis Sfera 1,3, Karina G. Thomas 1, Sarvin Sasannia 2, Jonathan J. Anton 1,6 Christina V Andronescu 5, Michael Garcia 3, Dan O. Sfera 1, Michael A. Cummings 1 and Zisis Kozlakidis 4

1    Patton State Hospital, University of California, Riverside

2    Department of Medicine, Shiraz University, Shiraz, Iran

3    University of California, Riverside

4    International Agency For Research On Cancer (IARC), Lyon, France

  1. Stanford University, Medical Anthropology Department

6.California Baptist University

- indicate the email address of each author.

  1. Correct Emails:

adonis.sfera@dsh.ca.gov,

sasannia.sarvin@gmail.com

karinathomas04@gmail.com

candron@stanford.edu

jonathananton4@gmail.com

michael.garcia@dsh.ca.gov

 dan.sfera@gmail.com

cummings.michael@dsh.ca.gov,

kozlakidisz@iarc.fr

 

 

 

 

 

-  Multiple references are indicated in the wrong manner. Please revise and correct.

  1. Corrected

-  In this sentence “For example, the antiviral and anti-inflammatory properties of GABA were highlighted by recent preclinical studies…”, the GABA the Authors referred to is the nGABA? Please explain. 

  1. nGABA =neuronal GABA (corrected)

-  Please specify what CNS means.

  1. Central Nervous System (added)

 

-  From “The SARS-CoV-2” to “[Fig.1]”, please carefully revised this part of the Introduction, complying with the standards of the text (see Author’s guidelines).

  1.  

-  Figure 1. All the names cited in the figure have to be described in the related figure legends, not only reported as acronyms in the figure.

  1. Figure legends added

-  Please change the brackets indicating the figures from square to circular, as you did for Fig.2.

  1. Changed

 

-  Fig.2 needs to be placed after its first citation paragraph. Please move accordingly.

  1. Figure moved

 

-  What NSP and ORFA mean? Please described them in the text.

  1. NSP=nonstructural protein, ORF=Open reading frame (added).

Reviewer 2 Report

In this review, the authors have proposed the psychiatric implications for COVID-19 infections via neuronal and non-neuronal GABA. Considering the profound impart of the COVID-19 pandemic have on all aspects of lives for every corner of the world, any information  on the virulence mechanism to the physiological/psychiatric effect of SARS-CoV-2 virus is critical for the understanding and handling of COVID-19. Thus the subject of this review article of interest.

Overall, the authors have presented a detailed and extensive report on the mechanisms by which the virus depleted GABA2 and its subsequent psychological and physiological consequences, aided by beautifully presented schematic that illustrates the mechanisms.

Overall a few comments:

1) Considering the psychiatric implications for  SARS2-CoV-2 virus infection, are there any actual studies/reports that link COVID-19 to psychological disorders? And if so, were they linked to GABA?

2) Given the controversies/uncertainties surrounding Ivermectin, the sentence "Interestingly, Ivermectin, a potential COVID-19 treatment, binds at the diazepam site..." on page 2 should be removed.

Author Response

Reviewer 2

Overall a few comments:

Q: Considering the psychiatric implications for SARS2-CoV-2 virus infection, are there any actual studies/reports that link COVID-19 to psychological disorders? And if so, were they linked to GABA?

A: yes, not only from our clinical practice, but epidemiological studies reveal that: “COVID-19 infection was associated with higher scores for depression, anxiety, distress, and insomnia was 31.4%, 31.9%, 41.1% and 37.9%, respectively.” (Wu T et al)( Fond G).

Wu T, Jia X, Shi H, Niu J, Yin X, Xie J, Wang X. Prevalence of mental health problems during the COVID-19 pandemic: A systematic review and meta-analysis. J Affect Disord. 2021 Feb 15;281:91-98. doi: 10.1016/j.jad.2020.11.117. Epub 2020 Dec 3. PMID: 33310451; PMCID: PMC7710473.

Fond G, Nemani K, Etchecopar-Etchart D, Loundou A, Goff DC, Lee SW, Lancon C, Auquier P, Baumstarck K, Llorca PM, Yon DK, Boyer L. Association Between Mental Health Disorders and Mortality Among Patients With COVID-19 in 7 Countries: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2021 Nov 1;78(11):1208-1217. doi: 10.1001/jamapsychiatry.2021.2274. PMID: 34313711; PMCID: PMC8317055.

 

COVID-19 associated GABA dysfunction with seizure disorder, chronic fatigue and executive disorder were reported (Versace V)( Nikbakht F).

Versace V, Sebastianelli L, Ferrazzoli D, Romanello R, Ortelli P, Saltuari L, D'Acunto A, Porrazzini F, Ajello V, Oliviero A, Kofler M, Koch G. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol. 2021 May;132(5):1138-1143. doi: 10.1016/j.clinph.2021.03.001. Epub 2021 Mar 13. PMID: 33774378; PMCID: PMC7954785.

Nikbakht F, Mohammadkhanizadeh A, Mohammadi E. How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Mult Scler Relat Disord. 2020;46:102535. doi:10.1016/j.msard.2020.102535

Aside from the scope of this paper, my personal experience as a psychiatrist treating veterans with PTSD, I found that they were more affected by COVID-19 than the general population. Previous studies found low brain GABA in veterans with PTSD:

Meyerhoff DJ, Mon A, Metzler T, Neylan TC. Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep. 2014;37(5):893-900. Published 2014 May 1. doi:10.5665/sleep.3654

Prescot A, Sheth C, Legarreta M, Renshaw PF, McGlade E, Yurgelun-Todd D. Altered Cortical GABA in Female Veterans with Suicidal Behavior: Sex Differences and Clinical Correlates. Chronic Stress (Thousand Oaks). 2018 Jan-Dec;2:2470547018768771. doi: 10.1177/2470547018768771. Epub 2018 Apr 6. PMID: 29756082; PMCID: PMC5947869.

Q: Given the controversies/uncertainties surrounding Ivermectin, the sentence "Interestingly, Ivermectin, a potential COVID-19 treatment, binds at the diazepam site..." on page 2 should be removed.

A: removed

 

Round 2

Reviewer 2 Report

The reviewer would like to thank the authors for the changes and additional information, it's now ready to be published.