Navigating the Depths of Depression: A Review of Genetic-Guided Treatment Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I must commend the authors on a manuscript with excellent depth and coverage of the major prospects and targeted applications of PGx, particularly for MDDs. The manuscript is well organized, easy to read, and follows a logical flow that critically assesses the current developments in the field, while also exploring opportunities for development. A job well done and a timely output for the field as a whole.

 

While I am happy to recommend this manuscript be published as is, I must highlight one glaring omission - a major limitation of this study is the fact that only one half the "drug metabolism" chain is examined in this review. While some justification for this is given in section 3.2.3 and later on again in subsequent sections, the total absence of drug transporter proteins is an oversight that must be reconsidered. For example, Drug transport proteins, specifically efflux transporters like P-glycoprotein (P-gp/ABCB1 - discussed in brief in this manuscript) and Breast Cancer Resistance Protein (BCRP), are essential to consider alongside cytochrome P450 (CYP450) enzymes in MDD management because they critically dictate brain availability of antidepressants and determine individual treatment responsiveness. Coupled with this are the uptake transporters like the SLC super family which dictate the initial bioavailability. 

 

I am not asking for a revision of the manuscript. I wish simply to bring to the attention of the authors that they have only discussed one half of the chain in sufficient detail, and that they may consider adding a single paragraph explaining the differential effects of these transporters across diverse (particularly African) populations despite them having limited clinical validity - thereby strengthening the argument for inclusion of diverse populations in clinical trials.

 

 

Author Response

Dear Reviewer,

Thank you for your time and effort in evaluating our manuscript. We greatly appreciate your comments and suggestions. In response, we have revised Section 3.2.3 accordingly to address your concerns.

Kind regards,
Gheorghe Pop

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to the Authors

1. There is a major inconsistency between the text and Figure 1 regarding the number of studies included in the final synthesis. The manuscript states that 142 studies were included, whereas Figure 1 reports only 81 studies. The authors must reconcile this discrepancy and ensure that the numbers in the text, figure, and methodology section are fully consistent.

2. The manuscript describes itself as a narrative review, yet the study selection process resembles a systematic review with PRISMA-style reporting. This methodological ambiguity weakens the credibility of the literature synthesis. The authors should clearly state whether the review is narrative or systematic and adjust the methodology section, figure, and reporting structure accordingly.

3. Several statements suggest strong clinical benefits of pharmacogenomic-guided prescribing (e.g., improvements in remission rates up to 1.8-fold), which may overstate the current strength of evidence. The authors should carefully verify the supporting meta-analyses and ensure that the magnitude of effect is accurately contextualized.

4. The manuscript states that pharmacogenomic panels commonly include CYP2D6, CYP2C19, CYP2C9, and CYP3A4, yet the discussion and evidence presented focus almost exclusively on CYP2D6 and CYP2C19. If CYP2C9 and CYP3A4 are mentioned as relevant pharmacokinetic genes, their clinical relevance and evidence base should also be discussed.

5. The manuscript states that certain genetic variants are associated with 1.5-4-fold increased odds of non-response or adverse effects, but the supporting evidence appears to be largely derived from studies focusing on CYP2D6 and CYP2C19. The authors should clarify whether this range applies broadly across pharmacogenomic markers or only to specific gene-drug interactions.

6. Several introductory statements describing major depressive disorder and treatment resistance lack clearly linked references. For example, the claim that up to 30% of patients exhibit inadequate response to initial pharmacotherapy should be explicitly supported by a high-quality epidemiological or clinical study. The authors should ensure that all quantitative claims are accompanied by specific and appropriate references.

7. Statements describing the pharmacokinetic effects of CYP2C19 and CYP2D6 variants on antidepressant metabolism require clear referencing. For example, the discussion of poor and ultra-rapid metabolizers affecting escitalopram exposure should cite authoritative sources such as CPIC or DPWG guidelines or well-established pharmacokinetic studies. Adding these references will strengthen the scientific grounding of the manuscript.

8. Several abbreviations, including PGx, MDD, and POC are defined multiple times throughout the manuscript. Once defined at their first occurrence, abbreviations generally should not be redefined unless a substantial portion of the manuscript separates the sections.

9. Some abbreviations appear before being formally defined, particularly POC (point-of-care) in the early sections of the manuscript. For clarity and adherence to scientific writing conventions, each abbreviation should be introduced with its full term at the first occurrence.

10. The manuscript repeats similar descriptions of the study scope and objectives in multiple sections, particularly when introducing pharmacogenomics and point-of-care technologies. This redundancy disrupts the narrative flow of the paper. The authors should consolidate these statements into a single concise description in the introduction or methodology section.

Based on the issues outlined above, I recommend major revision. The manuscript addresses a relevant topic, but significant methodological clarification, improved referencing, and editorial refinement are required before it can be considered for publication.

Author Response

Dear reviewer, thank you for your time and effort in evaluating our manuscript. We greatly appreciate your comments and suggestions. Please find our answers below.

1. There is a major inconsistency between the text and Figure 1 regarding the number of studies included in the final synthesis. The manuscript states that 142 studies were included, whereas Figure 1 reports only 81 studies. The authors must reconcile this discrepancy and ensure that the numbers in the text, figure, and methodology section are fully consistent.

• Thank you for the observation; the figure had the correct numbers. We updated the text accordingly.

 

2. The manuscript describes itself as a narrative review, yet the study selection process resembles a systematic review with PRISMA-style reporting. This methodological ambiguity weakens the credibility of the literature synthesis. The authors should clearly state whether the review is narrative or systematic and adjust the methodology section, figure, and reporting structure accordingly.

• We have clarified in the Methods section that this is a narrative review and that PRISMA 2020 elements were used solely to enhance transparency, not to indicate a systematic review.

 

3. Several statements suggest strong clinical benefits of pharmacogenomic-guided prescribing (e.g., improvements in remission rates up to 1.8-fold), which may overstate the current strength of evidence. The authors should carefully verify the supporting meta-analyses and ensure that the magnitude of effect is accurately contextualized.

• We agree that the current clinical evidence for PGx-guided prescribing is still evolving and requires nuanced presentation. We have revised the text to more accurately contextualize these findings.

 

4. The manuscript states that pharmacogenomic panels commonly include CYP2D6, CYP2C19, CYP2C9, and CYP3A4, yet the discussion and evidence presented focus almost exclusively on CYP2D6 and CYP2C19. If CYP2C9 and CYP3A4 are mentioned as relevant pharmacokinetic genes, their clinical relevance and evidence base should also be discussed.

• We have clarified in the revised Section 3.1 that while commercial panels include CYP2C9 and CYP3A4, these genes are not the focus of current CPIC or DPWG antidepressant dosing guidelines and play only a minor role in antidepressant metabolism. The sentence now explicitly distinguishes their limited clinical relevance from the primary focus on CYP2D6 and CYP2C19.

   

5. The manuscript states that certain genetic variants are associated with 1.5-4-fold increased odds of non-response or adverse effects, but the supporting evidence appears to be largely derived from studies focusing on CYP2D6 and CYP2C19. The authors should clarify whether this range applies broadly across pharmacogenomic markers or only to specific gene-drug interactions.

• We have revised the third paragraph of Section 3.1 to explicitly state that the 1.5- to 4-fold increased odds apply specifically to CYP2D6 and CYP2C19 variants (not to all pharmacogenomic markers). This change removes any potential ambiguity.

 

6. Several introductory statements describing major depressive disorder and treatment resistance lack clearly linked references. For example, the claim that up to 30% of patients exhibit inadequate response to initial pharmacotherapy should be explicitly supported by a high-quality epidemiological or clinical study. The authors should ensure that all quantitative claims are accompanied by specific and appropriate references.

• Initially, we had all the citations for the introductory paragraph at the end. We moved the citations after each claim for better clarity. The 30% number came from the STAR*D trial.

 

7. Statements describing the pharmacokinetic effects of CYP2C19 and CYP2D6 variants on antidepressant metabolism require clear referencing. For example, the discussion of poor and ultra-rapid metabolizers affecting escitalopram exposure should cite authoritative sources such as CPIC or DPWG guidelines or well-established pharmacokinetic studies. Adding these references will strengthen the scientific grounding of the manuscript.

• We updated the references accordingly.

 

8. Several abbreviations, including PGx, MDD, and POC are defined multiple times throughout the manuscript. Once defined at their first occurrence, abbreviations generally should not be redefined unless a substantial portion of the manuscript separates the sections.

• We have removed all redundant re-definitions (except in the table's legend).

 

9. Some abbreviations appear before being formally defined, particularly POC (point-of-care) in the early sections of the manuscript. For clarity and adherence to scientific writing conventions, each abbreviation should be introduced with its full term at the first occurrence.

• We updated the manuscript accordingly.

 

10. The manuscript repeats similar descriptions of the study scope and objectives in multiple sections, particularly when introducing pharmacogenomics and point-of-care technologies. This redundancy disrupts the narrative flow of the paper. The authors should consolidate these statements into a single concise description in the introduction or methodology section.

• We updated the manuscript accordingly.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

I would like to thank the Editor and the Journal for the opportunity to review this manuscript entitled “Navigating the Depths of Depression: A Review of Genetic-Guided Treatment Approaches.” The topic is timely and relevant. Overall, the manuscript addresses an important and evolving area of precision psychiatry. However, several aspects of the manuscript could be improved to enhance its clarity and scientific rigor, particularly regarding the methodological description, structure of some sections, synthesis of the literature, and reduction of repetitive information. The following comments are intended to help strengthen the manuscript and improve its overall clarity and scientific contribution.

Comments:

1. Abstract; (lines 36–56): Please consider revising the Abstract. It is recommended to provide a structured abstract that clearly presents the Background, Methods, Results, and Conclusions, which would improve clarity and help readers better understand the key aspects of the review.

 

2. Introduction; (lines 61–63): The specific data source and year of the estimate are not clearly indicated in the sentence. Since global prevalence estimates vary depending on the methodology and dataset used (e.g., WHO, IHME/GBD), it would be helpful to clearly clarify the source and year of this estimate to improve accuracy and transparency.

 

3. Introduction; (lines 71–74): The references cited in this paragraph (1–5) mainly address epidemiology and disease burden rather than treatment strategies. It would therefore be helpful to support this statement with references to clinical treatment guidelines or treatment algorithms (e.g., APA, NICE, or CANMAT guidelines) that discuss current antidepressant prescribing practices. In addition, please ensure that reference citations are appropriately distributed and linked to the corresponding statements throughout the Introduction section and the entire manuscript.

 

4. Introduction; (lines 93–100): Please revise this paragraph to clearly state the aim(s) of the review. The paragraph currently presents a research question; however, the aims of the review are not clearly defined. In addition, the subsequent sections of the manuscript are not clearly structured to address this research question. It would improve the clarity and coherence of the manuscript if the Results sections were reorganized to directly address the stated aims or research question.

 

5. Materials and Methods; (lines 104–107): The manuscript describes the study as a narrative review, while stating that elements of the PRISMA framework were adopted. Please clarify the methodological approach to avoid potential confusion. For example “This narrative review incorporated selected elements of PRISMA……”

 

6. Materials and Methods; (lines 108–122): The manuscript reports searching databases. However, the search strategy lacks several important methodological details. The manuscript should clearly specify the search date range, inclusion and exclusion criteria, screening procedures, and the number of reviewers involved in the study selection process.

 

7. Materials and Methods; (lines 123–127): The manuscript states “312 articles were assessed for eligibility; and 142 studies …….. were included in the final synthesis” However, eligibility criteria are not defined.

 

8. Materials and Methods; (PRISMA flow chart); (Figure 1, page 4): The diagram shows inconsistent numbers “81 records included in the review”. However, the text states “142 studies were included in the final synthesis”.

 

9. Manuscript; (lines 130–625): It is recommended to further improve the structure and organization of the manuscript to clearly align the main sections. Currently, the Results and Discussion sections are combined. Separating and strengthening these sections would enhance the clarity, transparency, and reproducibility of the review and help readers, clinicians, and policymakers better interpret and apply the findings in practice.

 

10. Section 3.1; (lines 134–139): This paragraph contains redundant information about pharmacogenomics that has already been discussed in the Introduction section. Please avoid repeating this information to improve the clarity and conciseness of the manuscript.

 

11. Section 3.1; (lines 140–150): This paragraph should clearly differentiate between pharmacokinetic and pharmacodynamic evidence strength. Clinical guidelines strongly support the clinical use of CYP2D6 and CYP2C19, whereas the evidence for SLC6A4 and HTR2A remains inconsistent. It is recommended to clearly separate clinically actionable pharmacokinetic genes from exploratory pharmacodynamic genes in this section.

 

12. Section 3.2; (lines 179–183): Many pharmacogenomics (PGx) implementation challenges arise due to the lack of effective clinical decision support (CDS) integration. Please provide specific examples of CDS systems used in PGx implementation programs to better illustrate how pharmacogenomic data can be translated into clinical prescribing decisions.

 

13. Section 3.2.3; (lines 238–257): The barriers to PGx implementation are well described; however, the discussion is largely qualitative. Where possible, please support these statements with quantitative evidence, such as studies reporting clinician awareness levels, adoption rates of PGx testing, or reimbursement data. Including such data would strengthen the evidence base of this section.

 

14. Table 2; (line 310, pages 8–9): The footnote notation (e.g., the superscript “¹” associated with FDA 510(k)) is not clearly explained, and some formatting elements in the table appear unclear (e.g., “k”). In addition, the cost estimates reported in the note below the table lack supporting references. It is recommended to clarify the footnote notation and provide appropriate references for the reported cost estimates.

 

15. Section 3.4; (lines 343–373): The discussion here mainly emphasizes the positive findings of these trials. It would strengthen the review to also address key criticisms raised in the literature, including the modest absolute effect sizes reported in some trials, the heterogeneity of PGx testing panels, and the ongoing debate regarding the clinical utility of routine PGx testing.

 

16. Section 3.5; (lines 489–578): The manuscript aims to review genetic-guided treatment approaches, but this section shifts the focus toward general treatment strategies. Please either shorten this section or strengthen its connection to pharmacogenomic (PGx) biomarkers, or consider removing it to maintain the integrity, conciseness, and alignment of the manuscript with its aims.

 

17. Limitations; (lines 627–656): The Limitations section mainly discusses the limitations of existing studies and technologies rather than the limitations of the current review itself. Some of these points could be more appropriately addressed earlier within the Discussion where they are contextually relevant. It is recommended that this section clearly describe the limitations of the present study, such as the narrative review design, potential selection bias in the literature search, absence of a formal study quality or risk-of-bias assessment, possible publication bias in the included literature, lack of quantitative evidence synthesis….etc.

 

18. Conclusions; (lines 657–685): The conclusion section is relatively long and reiterates several points already discussed in earlier sections (e.g., clinical trial evidence, implementation challenges, and future perspectives). It would improve the clarity and impact of the manuscript if this section were shortened and focused on the main take-home messages and key conclusions of the review, please avoiding repetition of previously discussed information.

 

19. Plagiarism should be reduced to less than 15%

 

Author Response

Thank you for your time and effort in evaluating our manuscript. We greatly appreciate your comments and suggestions. 

 

1. Abstract; (lines 36–56): Please consider revising the Abstract. It is recommended to provide a structured abstract that clearly presents the Background, Methods, Results, and Conclusions, which would improve clarity and help readers better understand the key aspects of the review.

• We have revised and structured the abstract accordingly to improve clarity and readability.

 

2. Introduction; (lines 61–63): The specific data source and year of the estimate are not clearly indicated in the sentence. Since global prevalence estimates vary depending on the methodology and dataset used (e.g., WHO, IHME/GBD), it would be helpful to clearly clarify the source and year of this estimate to improve accuracy and transparency.

• We have now explicitly stated the source and year of the estimate

 

3. Introduction; (lines 71–74): The references cited in this paragraph (1–5) mainly address epidemiology and disease burden rather than treatment strategies. It would therefore be helpful to support this statement with references to clinical treatment guidelines or treatment algorithms (e.g., APA, NICE, or CANMAT guidelines) that discuss current antidepressant prescribing practices. In addition, please ensure that reference citations are appropriately distributed and linked to the corresponding statements throughout the Introduction section and the entire manuscript.

• We have updated the text to incorporate the clinical practice guidelines.

 

4. Introduction; (lines 93–100): Please revise this paragraph to clearly state the aim(s) of the review. The paragraph currently presents a research question; however, the aims of the review are not clearly defined. In addition, the subsequent sections of the manuscript are not clearly structured to address this research question. It would improve the clarity and coherence of the manuscript if the Results sections were reorganized to directly address the stated aims or research question.

• We have revised the paragraph to clearly articulate the specific aims of the review, while retaining the original research question.

 

5. Materials and Methods; (lines 104–107): The manuscript describes the study as a narrative review, while stating that elements of the PRISMA framework were adopted. Please clarify the methodological approach to avoid potential confusion. For example “This narrative review incorporated selected elements of PRISMA……”

• We have clarified in the Methods section that this is a narrative review and that PRISMA 2020 elements were used solely to enhance transparency, not to indicate a systematic review.

 

6. Materials and Methods; (lines 108–122): The manuscript reports searching databases. However, the search strategy lacks several important methodological details. The manuscript should clearly specify the search date range, inclusion and exclusion criteria, screening procedures, and the number of reviewers involved in the study selection process.

• We have now added the missing methodological details, including the full search date range (January 2000–February 2026), and the inclusion and exclusion criteria.

 

7. Materials and Methods; (lines 123–127): The manuscript states “312 articles were assessed for eligibility; and 142 studies …….. were included in the final synthesis” However, eligibility criteria are not defined.

• We have now added the missing methodological details, including the full search date range (January 2000–February 2026), and the inclusion and exclusion criteria.

 

8. Materials and Methods; (PRISMA flow chart); (Figure 1, page 4): The diagram shows inconsistent numbers “81 records included in the review”. However, the text states “142 studies were included in the final synthesis”.

• The numbers presented in the flowchart were correct; we updated the text accordingly.

 

9. Manuscript; (lines 130–625): It is recommended to further improve the structure and organization of the manuscript to clearly align the main sections. Currently, the Results and Discussion sections are combined. Separating and strengthening these sections would enhance the clarity, transparency, and reproducibility of the review and help readers, clinicians, and policymakers better interpret and apply the findings in practice.

• Thank you for this recommendation. We deliberately designed the manuscript with integrated Results and Interpretation subsections to maintain a clear narrative flow and to avoid forcing the reader to jump between separate Results and Discussion sections for each topic. This structure was chosen to preserve continuity and enhance readability in a narrative review that spans genetics, clinical evidence, technology, and implementation. We therefore respectfully propose to retain the current format, which we believe best serves the aims of the paper. We are happy to discuss any further adjustments if required by the editor.

 

10. Section 3.1; (lines 134–139): This paragraph contains redundant information about pharmacogenomics that has already been discussed in the Introduction section. Please avoid repeating this information to improve the clarity and conciseness of the manuscript.

• Thank you for this observation. We have removed the first paragraph, which repeated information already presented in the Introduction. The subsection now begins directly with the description of current commercial and research panels, thereby eliminating redundancy and improving conciseness.

 

11. Section 3.1; (lines 140–150): This paragraph should clearly differentiate between pharmacokinetic and pharmacodynamic evidence strength. Clinical guidelines strongly support the clinical use of CYP2D6 and CYP2C19, whereas the evidence for SLC6A4 and HTR2A remains inconsistent. It is recommended to clearly separate clinically actionable pharmacokinetic genes from exploratory pharmacodynamic genes in this section.

• We updated the section accordingly.

 

12. Section 3.2; (lines 179–183): Many pharmacogenomics (PGx) implementation challenges arise due to the lack of effective clinical decision support (CDS) integration. Please provide specific examples of CDS systems used in PGx implementation programs to better illustrate how pharmacogenomic data can be translated into clinical prescribing decisions.

• We have added specific examples of CDS systems.

 

13. Section 3.2.3; (lines 238–257): The barriers to PGx implementation are well described; however, the discussion is largely qualitative. Where possible, please support these statements with quantitative evidence, such as studies reporting clinician awareness levels, adoption rates of PGx testing, or reimbursement data. Including such data would strengthen the evidence base of this section.

• We have added quantitative data on clinician confidence levels.

 

14. Table 2; (line 310, pages 8–9): The footnote notation (e.g., the superscript “¹” associated with FDA 510(k)) is not clearly explained, and some formatting elements in the table appear unclear (e.g., “k”). In addition, the cost estimates reported in the note below the table lack supporting references. It is recommended to clarify the footnote notation and provide appropriate references for the reported cost estimates.

• We have removed the unexplained superscript “1”, and added a supporting reference for the cost estimates in the table note. 

 

15. Section 3.4; (lines 343–373): The discussion here mainly emphasizes the positive findings of these trials. It would strengthen the review to also address key criticisms raised in the literature, including the modest absolute effect sizes reported in some trials, the heterogeneity of PGx testing panels, and the ongoing debate regarding the clinical utility of routine PGx testing.

• We updated the section accordingly.

 

16. Section 3.5; (lines 489–578): The manuscript aims to review genetic-guided treatment approaches, but this section shifts the focus toward general treatment strategies. Please either shorten this section or strengthen its connection to pharmacogenomic (PGx) biomarkers, or consider removing it to maintain the integrity, conciseness, and alignment of the manuscript with its aims.

• We retained this section because it provides essential clinical context on next-line treatment options for patients who do not achieve remission even with PGx-guided initial antidepressant selection. Although the focus of the review is on genetic-guided approaches, adjuvant therapies represent a critical component of real-world MDD management and offer future opportunities for PGx biomarkers to help guide augmentation decisions.

 

17. Limitations; (lines 627–656): The Limitations section mainly discusses the limitations of existing studies and technologies rather than the limitations of the current review itself. Some of these points could be more appropriately addressed earlier within the Discussion where they are contextually relevant. It is recommended that this section clearly describe the limitations of the present study, such as the narrative review design, potential selection bias in the literature search, absence of a formal study quality or risk-of-bias assessment, possible publication bias in the included literature, lack of quantitative evidence synthesis….etc.

• We agree that the Limitations section should focus more clearly on the methodological limitations of the present review itself. We have restructured it accordingly, adding a dedicated opening paragraph

 

18. Conclusions; (lines 657–685): The conclusion section is relatively long and reiterates several points already discussed in earlier sections (e.g., clinical trial evidence, implementation challenges, and future perspectives). It would improve the clarity and impact of the manuscript if this section were shortened and focused on the main take-home messages and key conclusions of the review, please avoiding repetition of previously discussed information.

• We have substantially shortened the Conclusion
  
  

19. Plagiarism should be reduced to less than 15%

• As a narrative literature review that synthesizes findings from more than 80 original studies, we have directly copied only the exact numerical results (e.g., effect sizes, confidence intervals, remission rates, odds ratios) as published in the source articles to ensure accuracy and fidelity. All interpretive text, discussion, and conclusions were rephrased and synthesized by the authors from multiple sources rather than copied extensively from any single paper.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to the Authors

The authors have convincingly addressed the key concerns raised in the initial review, resulting in a substantially improved, clearer, and more methodologically consistent manuscript. The revised version is now well-positioned for publication.

Reviewer 3 Report

Comments and Suggestions for Authors

None