Relationship between the Polymorphism of the AKT1 Gene and the Consumption of Cannabis in the Appearance of Psychosis

Round 1

Reviewer 1 Report (New Reviewer)

Good work

Author Response

Dear reviewer,
Thank you very much for your appreciation and dedication.

Reviewer 2 Report (New Reviewer)

The aim of the review is to provide data concerning the relationship between Cannabis-induced psychosis and the polymorphism of the AKT1 gene that is known to have an impact on psychosis. The review is restricted to only 34 papers, and should be more comprehensive. The text is clear and only moderate English styling is required.

When I looked for papers using the words "Cannabis psychosis Akt1 " I got 27 papers in PubMed – and the following papers should be addressed: 1. doi: 10.1016/j.phrs.2022.106258; 2. doi: 10.3390/brainsci11091240; 3. doi: 10.1111/eip.13082; 4. doi: 10.3390/brainsci10020097; 5. doi: 10.1016/j.psychres.2019.112500.

Using the following search "cannabis psychosis genetics" – 364 articles appear in PubMed. Some of these manuscripts are of relevance to this review (e.g., DOI: 10.1016/j.psychres.2022.114453; DOI: 10.1017/S0033291721005559; DOI: 10.3390/genes12121850).

Their methodology is restricted to papers that they found by direct search using selected search words, but this can miss out several other papers that are cited within these papers such as doi: 10.1590/1516-4446-2016-1969. The "year" restriction leads to the omission of earlier papers that can contribute to the manuscript including doi: 10.1016/j.biopsych.2009.09.024.

Abstract: The conclusion should include the relationship to Cannabis usages.

Line 36: The following percentages do not seem to be logical: "presented by 50% of children" and "75% of young adults develop it". Please correct the sentences. Also, double check the other percentages in the text. Many seems to be quite high.

Line 50: Please define EMG.

Table 2 seems to be a copy (there is a half asterix and a half number 71). Below Table 2 there is a note, where it is written Table 1, instead of Table 2.

The Cannabinoid receptors are written without a hyphen – CB1 and CB2.

Line 190: what do you mean with "a conditioning factor 12"?

Line 193: What do you mean with "(METE LA NEW REFERENCE I HAVE CALLED A IN THIS PARENTHESES)" and what is the intention of 21 in the following sentence: "the debut of mental illness 21"?

Line 198: What do you mean with ") 10, 11, 12"

Line 200: The "25" is not clear.

Line 210 start with "various studies" but the sentence end with one reference. Please add more references.

Line 241 – Should 18 be a reference in brackets?

Lines 267-268 – It says that the MOA is shown below, but there is no illustration for that. I would suggest preparing a Figure illustrating the text in Section 3.2. I would also suggest illustrating the other interactions of cannabinoids described in Sections 3.2.1 and 3.2.2.

Why are there slashes in Table 5? The column showing the conclusions should be the main part of the Table, and the reference should be provided by a number in brackets. This will make the Table more compact and readable. (3 columns instead of 5 columns). Also keep to the Journal style.

In the Table it says: "THC increases dopamine release and decreases dopamine release." – Please correct the text. The following sentence is incomplete: "AKT1 functionality."

Correct: "he rs2494732" to "the rs2494732".

 

 

 

Comments for author File: Comments.pdf

Author Response

Dear reviewer,
We appreciate your recommendations and considerations. We proceed to answer:
1) The language has been reviewed by the University's language department.
2) The recommended articles have been incorporated and inserted into the text of the paper, providing greater knowledge and richness to the manuscript.
3) We appreciate the suggestion of the year. You are right that the fact of putting a filter for example "the last ten years" leaves out articles that may be relevant. The reason for this filter is to limit the most recent articles that show up-to-date knowledge of the topic, although it is true that there are articles that are prior to that year filter and are relevant. Filtering articles with inclusion and exclusion criteria is part of the bibliographic search methodology itself. We incorporate the reference that the reviewer makes us so rightly and that balances the literature in this regard.
4) Summary: The conclusion must include the relationship with the uses of cannabis. The relationship with the uses of cannabis has been included. 

5) Line 36: The following percentages do not seem logical: "presented by 50% of children" and "75% of young adults develop it". Please correct the sentences. Also, check the other percentages in the text. Many seem to be quite high: The term mental illness is rectified by mental health problems, since it is a broader term and includes not only mental illnesses, but also conditions that affect the way you think, feel and behave. The percentages have been suppressed since, as indicated by the reviewer, they are not correct. The percentage of the data for Spain for 2018 has also been modified since the correct percentage is 21% and not the 25% that appeared previously.
6) Line 50: Please define EMG: Severe Mental illness.
7) Table 2 seems to be a copy (there is half Asterix and half number 71). Below Table 2 there is a note, where Table 1 is written, instead of Table 2: Fixed.
8) Cannabinoid receptors are written without a hyphen: CB1 and CB2: Fixed.
9) Line 190: what do you mean by "a conditioning factor 12"?: We have corrected the term conditioning factor to triggering factor.
10) Line 193: What do you mean by "(INSERT THE NEW REFERENCE I HAVE CALLED IN THIS PARENTHESES)" and what is the intention of 21 in the following sentence: "the debut of mental illness 21"?: It has been replaced the term by onset of mental illness.
11) Line 198: What do you mean by ") 10, 11, 12": with the numbers of the bibliographical references.
12) Line 200: The "25" is not clear. Line 210 begins with "several studies", but the sentence ends with a reference. Please add more references: References have been added.
13) Line 241 – Should the 18 be a parenthetical reference?: Fixed.
14) Lines 267-268 – It says that the MOA is shown below, but there is no illustration for that. I suggest that a figure be prepared illustrating the text of section 3.2. I would also suggest illustrating the other cannabinoid interactions described in sections 3.2.1 and 3.2.2.: The word show has been changed to describe since the intention of these authors is to describe the interactions.
15) Why are there bars in Table 5? The column showing the conclusions should be the main part of the table, and the reference should be provided by a number in parentheses. This will make the table more compact and readable. (3 columns instead of 5 columns). Also keep to the Journal style: The table has been modified incorporating the references by means of a number in parentheses and has been reduced to 3 columns. The font size has been increased to 8 following the style standards of the journal.
16) On the chart it says: "THC increases dopamine release and decreases dopamine release." – Please correct the text. The following sentence is incomplete: "AKT1 functionality": Corrected text.
17) Correct: "he rs2494732" to "the rs2494732": Fixed.

Reviewer 3 Report (New Reviewer)

The authors review evidence for psychosis vulnerability arising from AKT1 and cannabis. This is an interesting topic that has been extensively addressed. A review is welcome however I have many concerns concerning the depth of discussion and the quality of presentation. 

 

Given that the article hangs on AKT1/Akt1 there is an inadequate amount of detail describing these and their mechanisms. While there are details of diseases-specific mechanisms later, there really needs to be an overall discussion of AKT1 early on to ground the reader in its basic functions which are diverse and span cell survival, cell communication, etc etc. Then the disease-specific changes will make more sense and also the authors will help the reader identify potential areas of inadequate research.

On the other hand, the use of * and ! is lengthy and might be shortened. Most readers should understand the general process.

Under exclusion criteria – articles cannot have patients – only physicians can. Again, a professional language edit is absolutely required.

Criteria are not specific enough – for instance “use of other drugs” is not constrained. Did the authors exclude individuals who use acetaminophen? Why were only articles from 2010 included?

Is this a systematic review or not? It is written like one but if it is, it should be noted and proper presentation criteria should be referenced.

Did the authors also search review references? What kind of papers were included? Case studies? Reviews? This is not provided.

Although this is more appropriate for a systematic review, how many individuals did the search? How did you ensure correct identification of the papers/data?

Extensive English language corrections are required. There are multiple instances of grammatical errors and improper use of language throughout. I strongly suggest that the authors employ a professional editing service before resubmission.

Please make sure to define all abbreviations. What is an EMG in that context?

Why is the Results section showing corrections? (in red)

There is inadequate analysis of the methodology of the included studies. Are they good? Why or why not? What models were used – this is at least as important as the findings. A review really needs to be more critical and analytical. This is the case throughout. The authors need to clearly identify rodent vs human, in vitro vs in vivo, and what models are used. Otherwise the information is of uncertain quality. The quality of studies is assessed in a 3 sentence paragraph. This is inadequate.

 

The authors present a review about AKT1 but then also discuss COMT and DAT1 but it is not clear why. Please address.

References do not include all cited papers – e.g. Hindocha.

Author Response

Dear reviewer,
We appreciate your recommendations and considerations. We proceed to answer:
1) Since the article hangs on AKT1/Akt1, there is an inadequate amount of detail describing these and their mechanisms. While there are details of disease-specific mechanisms below, there really should be a general discussion of AKT1 from the beginning to ground the reader in its basic functions, which are diverse and encompass cell survival, cell communication, etc. etc. Then the disease-specific changes will make more sense and also the authors will help the reader to identify potential areas of inadequate research: The rationale has been completed by providing data to support the basic functions of AKT1.
2) On the other hand, the use of * and ! it is long and could be shortened. Most readers should understand the general process: It has been fixed.
3) Under exclusion criteria – articles cannot have patients – only doctors can. Once again, a professional language edit is absolutely necessary: ​​Corrected and replaced the word patient with subject.
4) The criteria are not specific enough, eg "use of other drugs" is not restricted. Did the authors exclude people who use acetaminophen? Why were only articles from 2010 included?: The criterion has been removed. “use of other drugs”
5) The authors excluded studies with subjects who consumed another substance because the objective of the review is to study the relationship of the AKT1 gene with the consumption of cannabis in the appearance of episodes of psychosis: The reason for this filter is to limit the articles more recent that show an updated knowledge of the subject, although it is true that there are articles that are prior to that year filter and are relevant. Filtering articles with inclusion and exclusion criteria is part of the bibliographic search methodology itself. There is a general tendency to recommend articles from the last 10 years.

6) Is this a systematic review or not? It is written as one, but if it is, it should be taken into account and reference should be made to the appropriate presentation criteria: This work is not a systematic review, it is a narrative review and is prepared following the characteristics of this type of study.
7) Did the authors also search review references? What kind of documents were included? Study cases? Comments?: Table 5 shows a sample of articles and their types of study.
8) Although this is more appropriate for a systematic review, how many individuals did the search? How was the correct identification of the papers/data ensured?: The search and selection of the bibliographical references was carried out by three researchers and they were supported by the University library service, which made it easier for us to identify and obtain the required articles.
9) The language is reviewed by the University's language department.
10) Please make sure you define all abbreviations. What is an EMG in this context?: EMG: Serious Mental Illness.
11) Why does the Results section show corrections? (in red): These authors regret the error and apologize for it. It was an error in the final review of the article and they thank this reviewer for observing it.
12) There is no adequate analysis of the methodology of the included studies. Are good? Why or why not? What models were used: This is at least as important as the findings. A review really needs to be more critical and analytical. This is the case at all times. Authors need to clearly identify rodent vs. human, in vitro vs. in vivo, and which models are used. Otherwise, the information is of uncertain quality. The quality of the studies is evaluated in a paragraph of 3 sentences. This is inappropriate: These authors have based their work on the most current evidence found in scientific journals that publish original or review papers continuously and have carried out a critical and exhaustive reading and analysis of each article, taking into account that the instruments used in them were validated, responded to our objectives and minimized the possibility of bias. For this, a reflexive and critical analysis was carried out, contextualizing the topic addressed, allowing a clear and broad perspective of the topic.
13) The authors present a review on AKT1, but then they also discuss COMT and DAT1, but it is not clear why: Some studies show that genetic variations COMT AND DAT1 may also be involved and these authors felt that mentioning them could complete knowledge on the subject, reaffirming that there is a more than solid relationship between the AKT1 gene and cannabis use in the appearance of psychotic episodes.
14) The references do not include all the articles cited, for example, Hindocha: The bibliography has been reviewed and the author Hindocha has been included.

Round 2

Reviewer 2 Report (New Reviewer)

The authors have complied all requests.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The manuscript applsci-1698153 has several flaws in its elaboration. The authors do not know the distinction between the original article and a review, there is no scientific method developed or questions to be clarified. There is no correct framing of the theme and the conclusions are scarce and inaccurate.

The authors need to do a very large and complete restructuring of all this to be reviewed at a later stage.

Particular attention in the use of data already published and in the construction of Tables.

Author Response

Dear reviewer,
We appreciate your assessment of the manuscript and we highly value major and minor suggestions to enrich it.
Regarding the main points:
The article is a narrative review that aims to know the scientific evidence about the "Relationship between the AKT gene polymorphism and cannabis use in the onset of psychosis". These authors apologize to the reviewer for the error and appreciate their observation. .
Regarding the fact that there is no developed scientific method or questions to clarify: Scientific method: Once again we thank the reviewer for his correct observation because the methodology corresponds to a narrative review format and not an original article. In the methodology of this narrative review, we have followed the highest methodological rigor in the search and analysis of the articles. We do not start from a research question as such nor from hypotheses to contrast, since we do not apply experimental conditions nor is it an experimental investigation, since the objective is to know the possible relationship between the polymorphism of the AKT1 gene and the consumption of cannabis in the appearance of psychosis from the analysis of scientific evidence.
To do this, the following methodological process was followed, which is reflected in the methodology section of this narrative review to follow the methodological rigor typical of this type of literature review, addressing the following aspects: Search period: from November 2021 to March 2022 .
Keywords following the criteria of the “MeSH” terminology: “psychosis”, “phychotic disordered”, “schizophrenia”, “severely mental disorder”, “AKT1”, “cannabis”, “THC”, “cannabinoid”, “marijuana”.
These words were appended returning the following definitive search string: (psychosis or "phychotic disorder*" or schizophrenia or "sever* mental disorder") AND AKT1 AND (cannabinoid or cannabis or THC or marijuana).
This search string has been introduced in all databases to avoid bias: Scopus, Wos, Cochrane Library, Trip Database, PubPsych and Pubmed. Likewise, clinical practice guidelines and databases were consulted that, after being explored with the same search string, did not yield results such as CMA Infobase, Guía Salud, CUIDEN, ISOC, CINAHL, EMBASE, Sociedad Española de Psiquiatría, PsicINFO, PsyeBITE, Psicodoc , Dialnet, National Guideline Clearinghouse and Virtual Health Library Spain. The application of the Boolean operators used to form the search string is also explained. The databases consulted appear in a table of our own elaboration, where the screening of the articles appears by applying the filters of duplicate articles, languages ​​other than English and Spanish, title of the paper and abstract. Also included are the selection criteria of the articles, defining the inclusion and exclusion criteria that allow following the methodological rigor required in their selection, finally giving rise to a total of 22 articles that make up this narrative review.
Regarding that there is no correct framing of the subject and the conclusions are few and inaccurate.
Correct framing of the topic: we thank the reviewer for the observation on the framing of the work. These authors have contextualized the theme of the work following the design of a narrative review, framing the theme to place the reader in the objective of the work, which is to know the scientific evidence on the relationship between the polymorphism of the AKT gene and the consumption of cannabis in the occurrence of psychosis.
Conclusions: We complete the conclusions and put them more in line with the objective of the narrative review, which is to know the scientific evidence about the "Relationship between the AKT gene polymorphism and cannabis use in the onset of psychosis".

Reviewer 2 Report

In the article, entitled “Relationship Between The Polymorphism Of The AKT1 Gene 2 And The Consumption Of Cannabis In The Appearance Of 3 Psychosis” Zabala-Baños and collaborators aim to investigate the relation between some gene polymorphisms (in particular the AKT1 rs2494732), THC consumption and psychotic disorders. In particular, authors conclude that the probability of acquiring the psychotic disorder in the context of cannabis use occurs mainly in the presence of the “C” allele of the rs2494732 polymorphism of the AKT1.

The article is interesting and of scientific soundness, however the main concern regards the type of article. According, the article structure is not clear if it is a narrative review or systematic review. Authors should clarify in the aim. If the aim is a systematic review authors should write the results section reporting the data of literature without further discussion. Furthermore, the methodology and the statistical analysis is clearly discuss.

Author Response

Dear reviewer,
We appreciate your assessment of the manuscript and we highly value major and minor suggestions to enrich it.
Regarding the main points:
1) We clarify as requested by the reviewer that it is a work based on the design of a narrative review that aims to know the scientific evidence about the "Relationship between the polymorphism of the AKT gene and the consumption of cannabis in the appearance of psychosis ”.
2) This observation is incorporated into the objective.
We have proceeded to review it completely and in detail. We hope it is of your consideration.
Very thankful.

Reviewer 3 Report

Investigating the relationship between AKT1 polymorphism, cannabis consumption and the appearance of psychosis is an interesting subject, taking into account we are witnessing an increase in both cannabis use and psychosis prevalence.

The “Introduction” section was well-structured and the information was useful for giving the reader a general idea on the matter.

However, there are major problems with the article – e.g. articles on the subject not included in the analysis, lack of results in the “Results” section, etc.

Also, after reading the manuscript, I am not sure what the topic was – do you want to talk only about AKT polymorphism? Do you want to include other genes in the study? At this point, you talked a lot about AKT, you wrote five lines on COMT and DAT. Either you focus only on AKT, or you give complete information on COMT and DAT polymorphisms. Why don’t you include other genetic polymorphisms associated with cannabis-induced psychosis? e.g. BDNF. These things should be clearly stated in the manuscript.

One other problem is the language. The manuscript needs extensive editing. There are grammar, punctuation, meaning issues. I strongly suggest a thorough review of the manuscript from that point of view.

 

Comments for author File: Comments.docx

Author Response

Dear reviewer,
We appreciate your assessment of the manuscript and we highly value major and minor suggestions to enrich it.
Regarding the main points:
1) The main objective of the work is to know the scientific evidence about the "Relationship between the polymorphism of the AKT gene and the consumption of cannabis in the appearance of psychosis". The scientific evidence reveals that in the appearance of pathologies such as psychosis, the cannabis is a conditioning factor 12, but the existence of genetic vulnerability is decisive.Thus, several genotypes, involved in dopaminergic function such as the AKT kinase in the first of the three serine/threonine-protein kinases (AKT1), are especially involved in making possible debut of mental illness 21.
Likewise, in carrying out this work, the findings in the results also lead to taking into account other genetic variations such as the polymorphism of the enzyme catechol-O-methyltransferase (COMT) and alterations in the gene that codes for the dopamine transporter (DAT1). ) 10, 11, 12 that could contribute to the increased risk of developing psychosis after interaction with cannabis, so in this section of results we present some data succinctly regarding whether or not they confer said vulnerability 25, constituting a very interesting aspect to investigate, since Chandni Hindocha (2020) found that AKT1, COMT or FAAH did not modulate the specific psychotomimetic response to cannabis, contrary to previous research.
Likewise, we update the results and incorporate two more updated studies that complete the work.

We have proceeded to review it completely and in detail. We hope it is of your consideration.
Very thankful.

Round 2

Reviewer 1 Report

The manuscript still needs to be improved in the articulation of contents.

 

There are many errors in the writing of the manuscript. What are the criteria of the Tables? Because the errors in the elaboration continue (Table 2). The most serious thing is that this work is a Review (poorly constructed) and is presented with Article. The authors do not know the difference between these two formats of scientific work. In either case, the formulation of a question (beginning of the work) must be accompanied by specific data that prove it or guide the reader. None of this was achieved... because the type of article to be considered is not defined.

"Therefore, a review of the literature is necessary to allow shed light on the possible causal link between both factors. The objective of this study is to analyze the scientific evidence that reflects the relationship between the AKT1 gene polymorphism and cannabis use in the onset of psychosis. "

Serious flaws in the use of the Template remain. Authors should be careful in the final document that will be sent to the reviewers:

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Funding: Please add: “This research received no external funding” or “This research was funded 417 by NAME OF FUNDER, grant number XXX” and “The APC was funded by XXX”. Check carefully 418 that the details given are accurate and use the standard spelling of funding agency names at 419 https://search.crossref.org/funding. Any errors may affect your future funding. 420 Institutional Review Board Statement: In this section, you should add the Institutional Review 421 Board Statement and approval number, if relevant to your study. You might choose to exclude this 422 statement if the study did not require ethical approval. Please note that the Editorial Office might 423 ask you for further information. Please add “The study was conducted in accordance with the 424 Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of 425 NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving humans. 426 OR “The animal study protocol was approved by the Institutional Review Board (or Ethics Com- 427 mittee) of NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving 428 animals. OR “Ethical review and approval were waived for this study due to REASON (please 429 provide a detailed justification).” OR “Not applicable” for studies not involving humans or ani- 430 mals. 431 Informed Consent Statement: Any research article describing a study involving humans should 432 contain this statement. Please add “Informed consent was obtained from all subjects involved in 433 the study.” OR “Patient consent was waived due to REASON (please provide a detailed justifica- 434 tion).” OR “Not applicable.” for studies not involving humans. You might also choose to exclude 435 this statement if the study did not involve humans. 436 Written informed consent for publication must be obtained from participating patients who 437 can be identified (including by the patients themselves). Please state “Written informed consent has 438 been obtained from the patient(s) to publish this paper” if applicable. 439 Data Availability Statement: In this section, please provide details regarding where data sup- 440 porting reported results can be found, including links to publicly archived datasets analyzed or 441 generated during the study. Please refer to suggested Data Availability Statements in section 442 “MDPI Research Data Policies” at https://www.mdpi.com/ethics. If the study did not report any 443 data, you might add “Not applicable” here. 444 Acknowledgments: In this section, you can acknowledge any support given which is not covered 445 by the author contribution or funding sections. This may include administrative and technical 446 support, or donations in kind (e.g., materials used for experiments). 447 Conflicts of Interest: Declare conflicts of interest or state “The authors declare no conflict of inter- 448 est.” Authors must identify and declare any personal circumstances or interest that may be per- 449 ceived as inappropriately influencing the representation or interpretation of reported research re- 450 sults. Any role of the funders in the design of the study; in the collection, analyses or interpretation 451 of data; in the writing of the manuscript, or in the decision to publish the results must be declared 452 in this section. If there is no role, please state “The funders had no role in the design of the study; in 453 the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision 454 to publish the results”.

Author Response

Dear reviewer,
We greatly appreciate your assessment. The document has been modified from article to review.
In the same way, all the guidelines that he indicated have been changed and incorporated.

Reviewer 2 Report

Authors replay to reviewer questions. To date the manuscript is available for publication

Author Response

Dear reviewer,
Thank you very much for his contributions. We hope again that the article is of your consideration.

Reviewer 3 Report

Dear authors,

I don't consider the manuscript has been greatly improved. The same issues need to be addressed. 

Best regards.