Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

he manuscript “A Case-Control Study of the Association between Hypocholesterolemia and Depressive Symptoms in a Mexican Population from Los Altos Sur, Jalisco” is a well-conducted and clearly written study addressing an important and timely question in biological psychiatry: the relationship between serum lipid levels and depressive symptoms. The design is methodologically sound, the psychometric tools are appropriate, and the biochemical procedures are described in adequate detail. The results are consistent and show that participants with depressive symptoms present lower total cholesterol, LDL-C, and VLDL-C compared to controls, while frequent physical activity emerges as a protective factor against depression and anxiety.

The discussion is coherent and integrates several plausible neurobiological explanations, including serotonergic mechanisms, inflammation, oxidative stress, and HPA-axis activation. However, the paper could be strengthened by expanding this framework to include the emerging perspective that links lipid metabolism to energy metabolism and mitochondrial function, which represent a unifying biological substrate for mood disorders. This integrative approach is increasingly supported by recent literature showing that metabolic dysfunction, mitochondrial inefficiency, and altered lipid homeostasis jointly contribute to mood regulation and stress vulnerability.

Please consider to cite:

Socci, V., Fagnani, L., Barlattani, T., Celenza, G., Rossi, A., & Pacitti, F. (2025). Future research perspectives on energy metabolism and mood disorders: a brief narrative review on metabolic status, mitochondrial hypothesis and potential biomarkers: Energy metabolism and mood disorders. Italian Journal of Psychiatry.

This review offers a concise yet comprehensive synthesis of how mitochondrial dysfunction and altered energy metabolism intersect with lipid biology, inflammation, and neurotrophin signaling in mood disorders. It also discusses the role of physical exercise in restoring metabolic balance through mitochondrial biogenesis and improved oxidative regulation—concepts that fit well with the present findings.

 

Incorporating this reference would give the manuscript greater theoretical depth, situating the reported associations within the broader framework of metabolic psychiatry. Lipid abnormalities, rather than being isolated markers, could then be understood as part of a systemic bioenergetic imbalance influencing both neurobiological function and emotional regulation. This addition would also strengthen the discussion of physical activity as a protective factor by linking it to mechanisms of mitochondrial resilience.

Aside from this conceptual enhancement, a few minor linguistic and editorial adjustments would improve precision and flow—for example, replacing “significative” with “significant,” standardizing lipid abbreviations (HDL-C, LDL-C, VLDL-C), and clarifying that HDL-C was measured directly while LDL-C was calculated via the Friedewald equation.

Overall, this is a solid and valuable contribution to the study of metabolic correlates of depression.

Author Response

To the comment: "Please consider to cite: Socci, V., Fagnani, L., Barlattani, T., Celenza, G., Rossi, A., & Pacitti, F. (2025)..."

We considered using this work for our study; it is cited in the introduction and discussion.

To the comment about a "few minor linguistic and editorial adjustments".

We replaced “significative” with “significant”, aldo stadarized abbreviations to "HDL, LDL, VLDL" to simplify. A grammatical check was done for all the document.

To the comment: "clarifying that HDL-C was measured directly while LDL-C was calculated via the Friedewald equation".

We added a simple clarification on the "Lipid profile assay" method, stating that HDL was calculated directly; this implies that other measurements were calculated or estimated, as stated in this section.

On actual template changes for all reviewers were performed and highlighted (in yellow could found changes for your observations).

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript, Pérez-Sandoval and colleagues present a case–control study investigating the association between serum lipid profiles and the presence of depressive symptoms. They compare 42 cases, identified by BDI-II scores, with 84 matched controls from the Los Altos Sur region of Jalisco, Mexico.Using psychometric assessments and serum lipid assays, the study’s principal finding is a significant association between hypocholesterolemia and elevated depressive symptoms.Overall, this manuscript addresses a complex and highly relevant topic at the intersection of metabolic health and psychiatry. The focus on a specific, previously understudied population in Mexico represents a valuable contribution to a literature base often dominated by European and North American cohorts. Although preliminary, the findings are intriguing and merit further consideration.However, the reviewer has several major concerns regarding the interpretation of the results that need to be addressed. The following comments are provided for the authors’ consideration:

1. In the abstract, the authors state: “This study highlights the importance of serum lipid levels in mental health, suggesting that cholesterol levels may increase vulnerability to depression symptoms and hopelessness” (lines 27–29). This phrasing strongly implies a directional, causal relationship. In a case–control study, the results can only establish an association or correlation between variables at a single point in time. The reviewer recommends revising this sentence to remove any language suggesting causality, which may otherwise mislead readers.
2. All participants were recruited from the Los Altos Sur region of Jalisco, Mexico. However, the manuscript provides no demographic, cultural, or biomedical context for this region. In the discussion section, the authors mention factors such as genetics and environmental factors that may affect both lipid metabolism and mental health and may explain divergent findings across populations.Without contextual information, it is difficult for readers to evaluate how local characteristics may affect the results or their generalizability. The reviewer suggests adding a paragraph to the discussion section that provides relevant background on the study population, including any known genetic, lifestyle, or environmental characteristics of the Los Altos Sur region that may be pertinent to the study variables.The authors should also explicitly address how recruitment from a single region may limit the broader applicability of their findings.
3. In Table 3, the authors state that a Mann–Whitney test was used and report p > 0.05. However, the table lists p values of p = 0.000, which typically indicates high statistical significance rather than nonsignificance.The reviewer recommends carefully rechecking the p values for accuracy and consistency.
4. The abbreviation for the Plutchik Suicide Risk Scale is inconsistent. The Abbreviations list on page 9 defines it as SHS, while the Methods section and Table 3 refer to it as SRS. Table 2 further complicates matters by labeling BHS and SHS scores. The reviewer recommends standardizing the abbreviation across the entire manuscript—including the abbreviations list, methods section, tables, and maintext, to ensure clarity and consistency.

Author Response

To the comment: 

1. In the abstract, the authors state: “This study highlights the importance of serum lipid levels in mental health, suggesting that cholesterol levels may increase vulnerability to depression symptoms and hopelessness” (lines 27–29). This phrasing strongly implies a directional, causal relationship. In a case–control study, the results can only establish an association or correlation between variables at a single point in time. The reviewer recommends revising this sentence to remove any language suggesting causality, which may otherwise mislead readers.

We changed phrasing to associations or relations, not suggesting causality.

To the comment: 

1. All participants were recruited from the Los Altos Sur region of Jalisco, Mexico. However, the manuscript provides no demographic, cultural, or biomedical context for this region. In the discussion section, the authors mention factors such as genetics and environmental factors that may affect both lipid metabolism and mental health and may explain divergent findings across populations.Without contextual information, it is difficult for readers to evaluate how local characteristics may affect the results or their generalizability. The reviewer suggests adding a paragraph to the discussion section that provides relevant background on the study population, including any known genetic, lifestyle, or environmental characteristics of the Los Altos Sur region that may be pertinent to the study variables.The authors should also explicitly address how recruitment from a single region may limit the broader applicability of their findings.

We add a brief description of suicide rate from the region and national rate. No specific cultural background could be provided due to the lack of research.

To the comment: 

1. In Table 3, the authors state that a Mann–Whitney test was used and report p > 0.05. However, the table lists p values of p = 0.000, which typically indicates high statistical significance rather than nonsignificance.The reviewer recommends carefully rechecking the p values for accuracy and consistency.

Correction have been done on table foot.

To the comment: 

1. The abbreviation for the Plutchik Suicide Risk Scale is inconsistent. The Abbreviations list on page 9 defines it as SHS, while the Methods section and Table 3 refer to it as SRS. Table 2 further complicates matters by labeling BHS and SHS scores. The reviewer recommends standardizing the abbreviation across the entire manuscript—including the abbreviations list, methods section, tables, and maintext, to ensure clarity and consistency.

A major standarization was done to ensure homogenity of terms.

On the actual template, changes related to your comments are green-highlighted. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present a case-control study on the relationship between hypocholesterolemia and depressive symptoms in the Mexican population of Los Altos Sur, Jalisco.

The authors raise the important issue of the rapid increase in mental disorders worldwide in recent decades. It is estimated that depression affects over 280 million people.
The authors emphasize that mental disorders are phenomena rooted in social and cultural factors, and in recent years, they have been linked to genetic, neurophysiological, and biochemical factors, such as depression and suicidal behavior. These factors include lipid concentrations in both serum and brain tissue, particularly hypocholesterolemia.

The paper cites several important studies examining the potential relationship between hypocholesterolemia and psychological vulnerability. According to other cited studies, the prevalence of hypocholesterolemia was analyzed in individuals with a history of suicidal ideation or suicide attempts.

The aim of this study was to compare serum lipid levels and depressive symptoms in symptomatic and asymptomatic individuals. The association between lipid levels and anxiety severity and suicide risk was also examined in the case-control group.

The main finding of this case-control study is that individuals with depressive symptoms from the Los Altos Sur region of Mexico demonstrate a distinct serum lipid profile, characterized by significantly lower levels of total cholesterol, LDL-c, and VLDL-c compared to a control group without previous psychiatric disorders.

The authors aptly referred to the work of others regarding the association of hypocholesterolemia with major depression, reinforcing the notion that lipid metabolism may be a significant biological factor in the pathophysiology of depression in this specific population.
The strength of this study is that it is the first report describing such a link in this particular region of Mexico.

It is important to deepen our understanding of the biological factors that influence symptoms and personality traits in individuals at risk of suicide, which could pave the way for more effective preventive and therapeutic methods.

The references cited in this manuscript appropriate and relevant to this research

Please add the conclusions section

Author Response

To the comment: Please add the conclusions section.

The section was added and is red-highlighed.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have thoroughly addressed all of my comments, and I recommend the manuscript for acceptance. The study provides valuable insights into the association between serum lipid levels and mental health conditions, suggesting that cholesterol levels may be linked to increased vulnerability to depression and hopelessness. These findings enhance our understanding of the relationship between serum lipids and psychiatric disorders. Congratulations to the authors, I am pleased to support the manuscript’s progression toward publication.