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After address the issues raised by the reviewers you can submit the manuscript for final decision.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Many thanks for asking me to review this very interesting paper. I am recommending some revisions. If the authors can offer a point-by-point response to each of my queries and address the issues raised, the manuscript may potentially be acceptable for publication.

Detailed comments:

Introduction:

-It would be helpful if the authors could highlight if any previous studies have investigated MetS in drug naïve patients BD. This would help demonstrate the potential value of their study by identifying gaps in the literature, that their study could potentially address i.e. please include a strong rationale for conducting the current study.

-Please include a hypothesis at the end of the introduction after the aims.

Methods:

-Were patients recruited prospectively, or was data recruited retrospectively from the patient medical records?

-Please have an operational definition for “initial-treatment and drug-naïve”, especially for “initial treatment. What would be the cut-off for initial treatment? This is very important, as metabolic side effects of psychotropics can appear as early as a few weeks after initiating treatment.

-What is the value of quantifying MetS severity? Patients either meet the criteria for MetS or not. This mathematical calculation is not a standard method, and would recommend it be removed all together (unless the authors can provide a very strong rationale and explanation for including it, which is currently lacking). MetS can be investigated as a dichotomous outcome. There is no need to investigate it as a continuous variable.

-Was data collected for physical health problems associated with MetS like DM and HTN? Or were these excluded?

-When was the study conducted?

-Were patients with schizoaffective disorders included or excluded?

-Please specify in your methods, exactly what parameters were of each test were collected (eg specific parameters of lipid profile).

-Why were prolactin and thyroid functions investigated? These are not necessary to diagnose MetS.

-Please provide references for all the rating scales used in this study.

-As per my comment above about no need to measure MetS severity, there is no need to include the linear regression looking at MetS severity as a continuous variable.

Results:

-There is no need to include figure 2. The data can be reported as text in the manuscript.

-For table 1, in the heading, do not use “t/ x2“. Just write “test”, and mention whether it’s a t-test or chi-square in the relevant test section for each parameter.

-In table 1, say “Illness duration” not “Disease duration”.

-In table 1, what is meant by “MetS scores”? It would be better to remove this if it is related to severity.

-I am not sure what is the value of including non-metabolic parameters in table 1, other than to rule out abnormalities in these parameters, which can be mentioned in the methods sections. They make for confusing reading. It would be worth mentioning how many subjects had abnormal non-metabolic parameters like TFTs and prolactin and whether these were included in the final or not.

-In table 1, it should be “PANSS” and not “PSS”.

-In table 2, I don’t know what is the value of including creatinine and TFTs. Any subjects with abnormalities in these parameters should have been excluded before any analysis, as these are potential confounders.

-Unless a very strong rationale can be made, I would recommend removing the whole section 3.4 and table 3.

Discussion:

-The discussion section needs to be considerably expanded. For example, the authors need to provide possible explanations for the significantly lower rates of MetS in their sample compared to other studies. The other main findings of the study also need to be discussed in the context of what is currently existing in the literature, especially recent studies on MetS. For example, there are two recent studies (both published in 2024) that investaigted MetS in bipolar: “Mohd Ahmed et al. (2024): Prevalence and risk factors for metabolic syndrome in schizophrenia, schizoaffective, and bipolar disorder. International journal of psychiatry in clinical practice, 28(1), 35–44.” and “Aziz et al. (2024): Metabolic syndrome and its relation to antipsychotic polypharmacy in schizophrenia, schizoaffective and bipolar disorders. International clinical psychopharmacology, 39(4), 257–266”.

Reviewer #2: Thank you very much for this opportunity to review the manuscript. This is a clinical study to discuss metabolic syndrome in patients with BD. Logistic regression identified age, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), free tetraiodothyronine (FT4), and psychotic symptoms as significant predictors of MetS development. Mets is a hot issue among people with mental disorders. This study has certain innovative and clinical significance. After reviewing the manuscript, I put forward the following suggestions on the content of the article:

Q1: The inclusion criteria for participants: 4. A score of ≥7 on the 17-item Hamilton Depression Scale (HAMD-17) and/or a score of ≥6 on the Young Mania Rating Scale (YMRS).

The author is asked to supplement the references and briefly explain why the score line is set.

Q2: The age range of the subjects included by the researchers was 18-60 years old. It can be imagined that in order to avoid the confounding effect brought by age, the author should explain and supplement relevant evidence in the preface or methodological part.

Q3: Diagnostic Criteria for MetS. In this article, the diagnostic criteria for MetS were accorded to the standards tailored for the Chinese population by the Chinese Diabetes Society [22]. The latest version of the guidelines for the prevention and treatment of type 2 diabetes in China is the 2020 edition, while the author's reference version is still the 2017 edition. Are there any differences between the two versions of the standards? Why do the authors prefer to use the historical version?

Q4: This study was a survey conducted by two research centers. 841 patients were included in the study. Please describe briefly in the methodological section how the total sample size of patients was calculated.

Q5: Table 1 presents a comparison between the subgroups with and without co-morbid MetS, focusing on demographic data and general clinical information. The statistical effect size of the included study variables can be supplemented in Table 1.

Q6: The researchers discussed the innovation of the paper in the discussion. The second paragraph states that “Our study reported a MetS prevalence of 17.84% in ITDN BD patients based on a much larger sample size, overlapping with the scope of known reported prevalence.” We can understand the limitations of innovation in cross-sectional surveys. However, it is suggested that the author highlight the necessity and scientific innovation of this study in the first or second paragraph of the discussion.

Q7: In the third paragraph of the discussion, the author writes: “Unsurprisingly, disturbed thyroid function also reasonably and incidentally affects metabolic levels in BD patients [32], thereby increasing the risk of MetS.” The authors' discussion of the link between thyroid function and MetS in BD patients is too simplistic, please discuss in further detail.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes:  Karim Abdel Aziz

Reviewer #2: Yes:  Zhiwei Liu

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Prevalence and correlates of metabolic syndrome in patients with initial-treatment and drug-naïve bipolar disorder: a large sample cross-sectional study

PONE-D-24-34269R1

Dear Dr. Lin Zhang

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

Kind regards,

Dirceu Henrique Paulo Mabunda, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: This study aimed to determine the prevalence of MetS and its clinical correlates among initial-treatment and drug-naïve (ITDN) BD patients. The results found a MetS prevalence of 17.84% among the study participants. Binary logistic regression identified age, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), free tetraiodothyronine (FT4), and psychotic symptoms as significant predictors of MetS development. Further, multiple linear regression analysis indicated that advanced age was a significant predictor of higher MetS scores. Mets is a hot issue among people with mental disorders. This study has certain innovative and clinical significance. The authors have made careful revisions in accordance with the comments of the reviewers. This research has considerable significance and application prospect. The results of this article are worth referring to and publishing.

Reviewer #3: 1. My major concern is how could the authors recruit patients not exposed to psychotropics at all from the inpatient setting. Patients with bipolar disord2. er will be exposed to some psychotropics in the outpatient setting or the emergency department. The authors should clearly state - how have they defined drug naive status.

2.The authors should provide more information about MetS score - in terms of its importance and clinical implications.

3. Table -3 the authors should use the variables in different combinations in the multiple regression to descibe what proportion of MetS score is explained by the variables studied.

4. A simple measure of number of criteria of MetS should be considered as an indicator for severity of MetS too. Accordingly the authors should compare the predictors of both the methods, i,e, number of criteria and MetS Score to see what emerges as better predictor.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: No

Reviewer #3: Yes:  Sandeep Grover

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