5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

We appreciate the corrections and yet we believe there is a need for further improvements.

Instead of

"While early studies were inconclusive, recent pharmacovigilance analyses have identified consistent disproportionality signals linking finasteride to suicidality, particularly in younger men treated for androgenetic alopecia [19]. These signals indicate a reporting association but do not establish causality."

I suggest:

"Recent pharmacovigilance analyses have identified consistent disproportionality signals linking finasteride to suicidality [19]."

If you want to refer to causality, I would suggest explaining something like this: The evidence that finasteride can induce neuropsychiatric reactions is strong: studies from multiple countries, using a variety of research designs, have confirmed many earlier clinical and experimental findings.43  Bradford-Hill criteria for causality are met: temporality and reversibility (including rechallenge), consistency and replicability of results across studies, high statistical significance, and biological plausibility. The European Medicines Agency has recently acknowledged that finasteride can cause depressed mood, depression, and suicidal thoughts.

For the Table: 

Instead of

Population-based cohorts (BPH) and postmarketing pharmacovigilance (AGA)

I suggest: 

Postmarketing pharmacovigilance studies and healthcare records analyses

Instead of

"No earlier studies demonstrated mood safety for finasteride. Differences among findings mainly reflect the indication—benign prostatic hyperplasia (BPH) in older men versus androgenetic alopecia (AGA) in younger men—rather than study design or period. Once postmarketing pharmacovigilance methods were applied, consistentsignals of depression, anxiety, and suicidality emerged, especially in AGA."

 

I suggest:

"Regardless of indication, benign prostatic hyperplasia (BPH) or androgenetic alopecia (AGA), studies report increased signals for depression, anxiety, and suicidality." 

"[19, 37, 39]"

39 should be replaced by 43

I suggest removing the following sentences:

"Although the existence of PFS remains debated,"

"The description of PFS has generated intense debate. While the absence of universally accepted diagnostic criteria has contributed to controversy, it is important to note that this controversy may have been amplified by industry strategies, as described by Michaels in Doubt is Their Product Nevertheless,"

To deny PFS is like denying fibromyalgia, deriving from a paternalistic approach. It's useless to cite Michaels with a formal reference. I recommend removing this discussion of PFS uncertainty; it only serves the industry.

I would remove the following sentence, which does not add anything to the previous sentence in the text: "Likewise, the available meta-analyses present important limitations, including methodological heterogeneity, lack of stratification by clinical indication, and the risk of reporting bias [39]." Reference 39 is often misquoted as a comprehensive meta-analysis, whereas in fact it was only for BPH.

I suggest adding a short discussion of the market failure related to finasteride-induced depression, like this: Finasteride-induced depression results in billions of dollars in lost productivity globally each year.[43] These external costs, borne by third parties unable to fix the issue, indicate market failure that should be addressed by regulation: its marketing for hail loss should be put on hold to prevent further economic damage.  

"Regulatory authorities have officially acknowledged that finasteride can cause depressed mood, depression, or suicidal thoughts"

More accurately, I suggest:

The EMA has recently officially acknowledged that finasteride can cause depressed mood, depression, or suicidal thoughts. 

If other regulators have done the same, indicate which ones and preferably with a reference.

In the methodological discussion of limitations, I suggest you add:

It cannot be ensured that controls do not purchase finasteride online, which would lead to misclassification bias.

It requires a study size of many millions to have the power to rule out an increase in suicides [43]

The following paragraph should be rewritten: "On this basis, a pragmatic approach with reinforced safety measures can be proposed: (1) explicit pre-treatment information, clearly communicating the potential for neuropsychiatric effects in certain subgroups [68]; (2) brief baseline screening focused on mood, anhedonia, sleep quality, history of depression, anxiety or PTSD, substance use, and concomitant psychotropic medications [69]; (3) careful candidate selection, avoiding initiation in patients with uncontrolled depressive episodes or active suicidal ideation [70]; (4) dosing and follow-up based on the lowest effective dose, with reassessment at 4–8 weeks and subsequently at three-month intervals during the first year, including simple patient-reported scales of mood, anxiety, sleep, libido, and cognition [71]; (5) prompt management of emerging symptoms, including dose reduction, discontinuation, or psychiatric referral if necessary [72]; and (6) explicit documentation of informed consent, particularly in AGA, where the cosmetic nature of the indication lowers the tolerance for adverse effects [68]. This conservative and pragmatic approach maximizes patient safety without restricting access to the clinical benefits of 5α-R inhibitors."

Mention the need for a comprehensive approach: While not typically associated with depression, patients with AGA may experience body image concerns and low self-esteem, for which cognitive-behavioral therapy, mindfulness-based stress reduction, supportive counseling, and structured coping strategies may help. 

See Frith H, Jankowski GS. Psychosocial impact of androgenetic alopecia on men: A systematic review and meta-analysis. Psychol Health Med. Apr 2024;29(4):822-842. 

And OpenEvidence. https://www.openevidence.com/ask/a37406ed-c14c-4cfb-955c-c6235a3e818f. 

If AGA is associated with emotional distress, this is an additional reason to avoid finasteride, which can worsen mood and increase the risk of suicide. [38]

Other non-pharmacological treatments offer safer and potentially more effective alternatives, avoiding the risk of suicide.

See OpenEvidence. https://www.openevidence.com/ask/d7f399e4-0b3f-4bfe-bb8a-80510653b54b

Reference 41 is not about GABA receptors! It appears several times as the wrong citation. Including in Tables 1 & 3, p.9, 8

The reference about genetic variation is from 2010. Nothing more recent???

 

 

 

 

Author Response

Response to Reviewer 1

Dear Reviewer,

We sincerely thank you for your careful reading of our manuscript and for your detailed and constructive comments. We have revised the manuscript thoroughly to improve clarity, organization, and scientific rigor, and to ensure consistency between text, tables, and references. In addition, the manuscript has undergone professional English language revision according to MDPI standards. Below, we address each point in detail.

 

1) Wording on pharmacovigilance disproportionality signals

Reviewer comment: Simplify the sentence and remove the “early studies were inconclusive…” clause.

Response: We agree and have simplified the sentence to improve clarity and precision.

Change made (manuscript):
The sentence was revised to:

“Recent pharmacovigilance analyses have identified consistent disproportionality signals linking finasteride to suicidality [19].”

 

2) Causality framing (Bradford–Hill criteria and EMA acknowledgement)

Reviewer comment: If referring to causality, explicitly frame the evidence using Bradford–Hill criteria and mention EMA acknowledgement.

Response: We agree and have strengthened the causal framing accordingly.

Change made (manuscript):
We expanded the Discussion to explicitly refer to several Bradford–Hill criteria (temporality, reversibility/rechallenge, consistency across studies, statistical significance, and biological plausibility) and clearly stated the formal acknowledgement by the European Medicines Agency (EMA), supported by PRAC documentation [36].

 

3) Table terminology: design-based rather than indication-based labeling

Reviewer comment: Replace indication-based wording in table headings.

Response: We agree and revised the table terminology to reflect study design rather than clinical indication.

Change made (Table 1):

• Replaced: “Population-based cohorts (BPH) and postmarketing pharmacovigilance (AGA)”
• With: “Postmarketing pharmacovigilance studies and healthcare records analyses”

 

4) Table text simplification and cross-indication statement

Reviewer comment: Replace long explanatory text with a concise cross-indication statement.

Response: We agree.

Change made (Table 1):
Inserted:

“Regardless of indication (BPH or AGA), studies report increased signals of depression, anxiety, and suicidality.”

 

5) Table references consistency

Reviewer comment: Replace reference 39 with reference 43.

Response: We carefully reviewed all table references to ensure consistency with the final reference list. In the revised manuscript, reference 39 corresponds to the analytical review by Brezis (2025), which appropriately supports the clinical and pharmacovigilance statements presented. We therefore retained the correct citation and ensured that mechanistic references are cited only in mechanistic contexts.

Change made:
All table references were checked and corrected to align with the final numbering and content.

 

6) Removal of statements framing post-finasteride syndrome (PFS) as controversial

Reviewer comment: Remove statements suggesting controversy, industry amplification, and the Michaels-related framing.

Response: We agree.

Change made (manuscript):
All sentences framing PFS as a debated entity and the associated non-essential commentary were removed. The revised text now focuses exclusively on clinical observations, regulatory actions, and biological plausibility.

 

7) Meta-analysis limitations and mis-citation concern

Reviewer comment: Remove the sentence on meta-analysis limitations and avoid implying that ref. 39 represents a comprehensive meta-analysis.

Response: We agree.

Change made (manuscript):
The sentence beginning “Likewise, the available meta-analyses…” was deleted, and reference 39 is now cited strictly within its appropriate scope.

 

8) Market failure and global economic impact

Reviewer comment: Add discussion on market failure and global productivity losses, and suggest holding marketing for hair loss.

Response: We respectfully decline this suggestion. Such analyses require dedicated health-economic data and policy-oriented frameworks beyond the scope of this biomedical systematic review. We therefore avoided speculative economic estimates and policy-prescriptive statements not directly supported by the presented evidence.

 

9) Regulatory authority specification

Reviewer comment: Specify which regulatory authority has officially acknowledged the risk.

Response: We agree.

Change made (manuscript):
The statement was revised to:

“The European Medicines Agency has officially acknowledged that finasteride can cause depressed mood, depression, or suicidal thoughts [36].”

 

10) Additional methodological limitations

Reviewer comment: Add limitations related to online purchasing and statistical power for suicide outcomes.

Response: We agree.

Change made (manuscript):
We added a paragraph discussing potential exposure misclassification due to unrecorded online acquisition of finasteride and emphasized the need for very large cohorts to reliably assess rare outcomes such as suicide.

 

11) Revision of the “pragmatic approach” paragraph

Reviewer comment: Rewrite the paragraph proposing reinforced safety measures.

Response: We agree.

Change made (manuscript):
The paragraph was rewritten to improve clarity and conciseness, framing the recommendations as pragmatic safety considerations rather than prescriptive clinical rules.

 

12) Psychosocial impact of androgenetic alopecia (AGA)

Reviewer comment: Add discussion on body image and psychosocial burden; cite Frith & Jankowski (2024).

Response: We agree.

Change made (manuscript):
A dedicated paragraph was added addressing the psychosocial impact of AGA and the potential role of non-pharmacological supportive strategies, supported by Frith & Jankowski (2024), now included as reference 83. Non–peer-reviewed sources were intentionally excluded.

 

13) Incorrect citation of reference 41

Reviewer comment: Reference 41 is not related to GABA receptors and is incorrectly cited in tables.

Response: We agree.

Change made:
All occurrences of reference 41 were reviewed and corrected across the manuscript and tables. It is now cited only where directly relevant.

 

14) Age of genetic susceptibility references

Reviewer comment: Genetic evidence cited is old.

Response: We agree that genetic evidence remains limited.

Change made (manuscript):
We retained foundational references while explicitly stating that current genetic findings are preliminary and have not yet been validated by large contemporary cohorts.

 

15) Tables and figures placement and simplification

Reviewer comment: Tables and figures should be removed from the Discussion and placed in the Results section.

Response: We agree.

Change made (manuscript):

• Tables 2 and 3 were moved from the Discussion to the Results section.
• Figure 1 was removed, as it did not add substantial information beyond what is already conveyed in the text and tables.
• The Discussion was revised accordingly to focus on interpretation rather than presentation of data.

 

16) Language revision

Response:
The manuscript has undergone professional English language editing in accordance with MDPI standards. The revised version was submitted to MDPI after two rounds of language revision to ensure clarity, consistency, and readability.

 

We thank the Reviewer again for their insightful comments, which have substantially improved the clarity, structure, and scientific quality of the manuscript.

Sincerely,
Carmen Rodríguez-Cerdeira
(on behalf of the authors)

 

Author Response File: Author Response.pdf

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

This manuscript mainly describes the distribution and functions of 5α-reductase isozymes, and the potential of them associated with anxiety, depression and suicidal tendencies, along with the possible mechanisms. The clinical evaluation strategy of balancing therapeutic efficacy with psychological safety, is proposed. Finally, the review also provides perspectives on future directions in biomarker development, personalized dosing, and pharmacovigilance. The manuscript is meaningful for the safe application of these drugs. However, some modifications should be considered before publication.

1. Please check the highlighted content (provided by the authors) in manuscript.
2. Please provide references for the first two sentences of the second paragraph in page 3.
3. Section 2. in page 3, suggest updating the scientific literature timeline to November 2025.
4. In page 4, section 2.2, the existing reviews are suggested to add in the introduction section, while the explanations of the differences for them are necessary.
5. In page 4, section 2.4, “…remaining 81 studies…” is different from “…of which 83 met the inclusion...” in Introduction, please check.
6. Figure 2, “Google scholar” was not mentioned in the text.
7. Section 3. and 4., the content is abundant, it is recommended to divide into subsections.

Author Response

Response to Reviewer 2

We sincerely thank Reviewer 2 for the careful evaluation of our manuscript and for the constructive comments, which have helped us to improve its clarity, consistency, and overall presentation. We have addressed each point raised, as detailed below.

 

General comment: Quality of English language

We have carefully revised the manuscript to improve clarity, precision, and readability of the English language throughout the text. In addition, the revised manuscript was submitted twice to the MDPI English editing service to ensure linguistic accuracy, consistency of terminology, and compliance with the journal’s editorial standards.

 

Specific comments

1. Please check the highlighted content (provided by the authors) in manuscript.
   Response:
   The highlighted text corresponds exclusively to revisions introduced by the authors in response to comments from previous reviewers and was not present in the version originally reviewed by Reviewer 2. All highlighted changes were carefully checked and reviewed for accuracy and consistency. No unreviewed or extraneous content has been introduced.

 

2. Please provide references for the first two sentences of the second paragraph on page 3.
   Response:
   Appropriate references from the existing reference list have now been added to support the first two sentences of the second paragraph on page 3, addressing both the limitations of the clinical evidence and the emerging data on genetic susceptibility.

 

3. Section 2 on page 3: suggest updating the scientific literature timeline to November 2025.
   Response:
   The literature search timeline in Section 2 has been updated to include studies published up to November 2025, as suggested.

 

4. On page 4, section 2.2, the existing reviews are suggested to be added to the Introduction section.
   Response:
   Section 2.2 describes the inclusion criteria and eligibility framework of the systematic review in accordance with PRISMA guidelines and does not discuss individual review articles. As this content is strictly methodological, it has been appropriately retained in the Materials and Methods section.

 

5. On page 4, section 2.4, “…remaining 81 studies…” differs from “…of which 83 met the inclusion criteria…” in the Introduction.
   Response:
   Thank you for pointing this out. The discrepancy has been corrected, and the number of included studies has been standardized to 83 throughout the manuscript.

 

6. Figure 2: “Google Scholar” was not mentioned in the text.
   Response:
   Google Scholar was included as part of the search strategy. Although no additional eligible studies were ultimately retrieved from this source, it has now been explicitly mentioned in the Materials and Methods section to ensure consistency with the PRISMA flow diagram.

 

7. Sections 3 and 4: the content is abundant; it is recommended to divide it into subsections.
   Response:
   We appreciate this suggestion. Sections 3 and 4 are already thematically structured and supported by summary tables and figures to guide the reader through the main concepts. We therefore retained the integrated structure to preserve conceptual continuity and avoid unnecessary fragmentation.

 

Additional revision (editorial clarification): Removal of Figure 1
Although not explicitly requested, Figure 1 was carefully re-evaluated during revision and subsequently removed, as it did not add substantial conceptual or methodological value beyond what was already clearly described in the text. This change was made to improve conciseness and readability.

 

Once again, we thank Reviewer 2 for the thoughtful and constructive feedback, which has contributed to strengthening the manuscript.

Kind regards,
Carmen Rodríguez-Cerdeira

(on behalf of the authors)

 

 

Author Response File: Author Response.pdf

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors This manuscript provided us with the information " 5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes."  This manuscript was relatively well-organized. 

Here are some major comments. 

1. The expression of the Key findings in Table 1 was too complicated. The authors should clarify this column. 

2. The discussion was so complicated and unusual. Please take out Table 2, Table 3, and Figure from the Discussion, and replace them in the Results part. The authors should keep this feedback. 

3. On what basis were the items in Tables 1, 2, and 3 arranged? They are not even in alphabetical order or in references.

 

   

 

 

Author Response

Response to Reviewer 3

Dear Reviewer,

We sincerely thank you for your careful evaluation of our manuscript and for your constructive comments. We have carefully considered all your suggestions and have revised the manuscript accordingly. Each of your points is addressed in detail below.

 

1. The expression of the Key findings in Table 1 was too complicated. The authors should clarify this column.

Response:
We agree with the reviewer that the original wording of the “Key findings” column in Table 1 was overly complex. To improve clarity and readability, we have thoroughly revised this column by simplifying sentence structure, reducing subordinate clauses, and limiting each statement to a single key concept. Parallel phrasing has been applied across rows to enhance consistency and accessibility for a broad readership.

Change made:
The “Key findings” column in Table 1 was rewritten using shorter, clearer sentences while preserving scientific accuracy and content.

 

2. The discussion was so complicated and unusual. Please take out Table 2, Table 3, and Figure from the Discussion, and replace them in the Results part. The authors should keep this feedback.

Response:
We appreciate this important structural suggestion and have followed the reviewer’s recommendation. Tables 2 and 3 and the figure previously embedded in the Discussion have been relocated to the Results section, where they now directly support the presentation of empirical and synthesized findings. The Discussion has been revised accordingly to focus on interpretation, integration of evidence, and clinical implications, without introducing new tables or figures.

In addition, Figure 1 was removed entirely, as its contribution was considered limited and redundant with the textual description.

Change made:

• Tables 2 and 3 and the figure were moved from the Discussion to the Results section.
• Figure 1 was deleted.
• The Discussion was streamlined to improve coherence and conventional structure.

 

3. On what basis were the items in Tables 1, 2, and 3 arranged? They are not even in alphabetical order or in references.

Response:
Thank you for pointing this out. We acknowledge that the ordering criteria were not sufficiently explicit in the previous version. The tables have now been reorganized using a clear and consistent rationale:

• Table 1 is structured conceptually, following the biological-to-clinical continuum (isoenzymes → neurosteroid synthesis → psychiatric manifestations → clinical/translational evidence → genetic susceptibility).
• Table 2 is now ordered by study type and evidentiary relevance, with postmarketing pharmacovigilance data presented first, followed by large population-based cohorts and meta-analytical evidence.
• Table 3 has been reordered by gene, grouping core 5α-reductase isoenzymes first, followed by GABA-A receptor–related genes.

This reorganization improves logical flow and interpretability and avoids arbitrary or unclear ordering.

Change made:
All three tables were reordered according to explicit conceptual and methodological criteria, which are now consistently applied.

 

We thank the reviewer again for these valuable comments, which have significantly improved the clarity, structure, and presentation of the manuscript.

Sincerely,
Carmen Rodríguez-Cerdeira
(on behalf of all authors)

 

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors

Your reply "We appreciate this important structural suggestion and have followed the reviewer’s recommendation. Tables 2 and 3 and the figure previously embedded in the Discussion have been relocated to the Results section, where they now directly support the presentation of empirical and synthesized findings. The Discussion has been revised accordingly to focus on interpretation, integration of evidence, and clinical implications, without introducing new tables or figures." 

However, the original structure was not changed at all. 

The authors should reconstruct the contents of your review. 

Author Response

We thank the reviewer for this comment and agree that a clearer structural organization was necessary. In the revised version, the Results section has been substantially reorganized to address this point.

Specifically, Tables 2 and 3 have now been relocated within the Results section and placed immediately after the corresponding descriptive subsections to which they refer. Table 2 is now presented under the subsection addressing epidemiological and pharmacovigilance evidence, while Table 3 is positioned within the subsection dedicated to genetic and individual susceptibility factors. This restructuring ensures that each table directly supports the relevant results and improves the logical flow of the manuscript.

We would also like to clarify that the figure previously referred to as Figure 2 was already removed in a prior revision, in accordance with earlier reviewer comments, and therefore does not appear in the current version of the manuscript.

The Discussion section has been revised accordingly and now focuses exclusively on interpretation and integration of findings, without introducing new data or figures.

Author Response File: Author Response.pdf

Round 3

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors

 

This second revised manuscript was relatively well-organized according to reviewer's feedback. 

 

 

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

Comments and Suggestions for Authors

The article titled “5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes” is a systematic review that explores the role of 5α-reductase (5α-R) isoenzymes—specifically SRD5A1, SRD5A2, and SRD5A3—in androgen metabolism and neurosteroid biosynthesis, establishing a bridge between endocrinology and neuropsychiatry.

This work presents several strengths, including a clear and concise abstract, a methodology based on PRISMA guidelines, and a critical discussion. However, there are several aspects that require attention:

• Objectives: The aims stated in the introduction are not clearly defined. The section alternates between "AIMS" and "Objective," which creates ambiguity. It is recommended to formulate a single, concise objective.
• Table in the Introduction: The purpose of including a table of findings in the introduction is unclear. Moreover, the second column is overly broad, and the way results are presented hinders comprehension. It is advisable to integrate each section of the table into specific parts of the manuscript, organized under subtitles that correspond to the main topics addressed. Additionally, the citation format in the "AUTHOR" column should be reviewed, as there are typographical errors in the use of “et al.”
• Methodology: The author refers to the study as a “Narrative Review” (Page 10, line 105), which contradicts the use of PRISMA guidelines and what is stated in the abstract. It is recommended to clarify the type of review conducted. Furthermore, there are inconsistencies in the bibliographic inclusion criteria: the flow diagram indicates 83 articles were screened, the abstract mentions 63 met the inclusion criteria, yet the reference list contains 82 articles. This discrepancy should be addressed.
• Although registering systematic reviews using PRISMA in PROSPERO is not mandatory, it is strongly recommended. PRISMA-P advocates for protocol registration to enhance transparency, reduce bias, and prevent duplication of research efforts.
• Relevant Section and Discussion: These sections require editing to avoid repetition of concepts already explained elsewhere in the review. As previously mentioned, it would be beneficial to incorporate the data presented in Table 1 into thematic subsections within these sections. Additionally, the inclusion of a summary table listing genes and variants associated with neuropsychiatric susceptibility, a concise epidemiological overview with clear data, and diagrams or visual aids would greatly enhance the clarity and accessibility of the information presented.

Author Response

Response to Reviewer 1

We sincerely thank Reviewer 1 for the thorough and constructive comments, which have significantly improved the clarity, accuracy, and scientific rigor of our manuscript. Below, we provide a point-by-point response to each comment, indicating the modifications made in the revised version.

 

1. Objectives
   Reviewer’s comment: The aims stated in the introduction are not clearly defined. The section alternates between "AIMS" and "Objective," which creates ambiguity. It is recommended to formulate a single, concise objective.

Response: We fully agree with the reviewer. In the revised manuscript, we have reformulated a single, concise objective in the Introduction section, eliminating the alternating terms. The objective is now clearly stated as:

“The objective of this systematic review is to analyze the role of 5α-reductase isoenzymes (SRD5A1, SRD5A2, and SRD5A3) in androgen metabolism and neurosteroid biosynthesis, and to explore their implications in neuropsychiatric outcomes.”

 

2. Table in the Introduction
   Reviewer’s comment: The purpose of including a table of findings in the introduction is unclear. The second column is overly broad, and the way results are presented hinders comprehension. It is advisable to integrate each section of the table into specific parts of the manuscript, organized under subtitles that correspond to the main topics addressed. Additionally, the citation format in the "AUTHOR" column should be reviewed, as there are typographical errors in the use of “et al.”

Response: Thank you for this observation. We have removed the table from the Introduction and relocated it to the Results section, where it now serves as a structured summary of the main thematic areas (“Isoenzymes and tissue distribution,” “Neurosteroid biosynthesis,” “Psychiatric manifestations,” etc.). This placement ensures alignment with the scientific paper structure and enhances clarity for readers. In addition, the “AUTHOR” column has been corrected and all typographical errors with et al. have been reviewed and fixed.

3. Methodology
   Reviewer’s comment: The author refers to the study as a “Narrative Review” (Page 10, line 105), which contradicts the use of PRISMA guidelines and what is stated in the abstract. It is recommended to clarify the type of review conducted. Furthermore, there are inconsistencies in the bibliographic inclusion criteria: the flow diagram indicates 83 articles were screened, the abstract mentions 63 met the inclusion criteria, yet the reference list contains 82 articles. This discrepancy should be addressed.

Response: We acknowledge this important point. The study was initially designed as a systematic review based on PRISMA methodology, not as a narrative review. The term “Narrative Review” has been removed, and the text has been corrected throughout for consistency.

Regarding the numerical discrepancies:

• The PRISMA diagram shows that 83 articles were included in the final review.
• The abstract has been corrected to consistently state 83 studies met the inclusion criteria.
• The reference list has been revised: one duplicate reference was removed, and now the list contains 83 references, fully aligned with the PRISMA diagram and the text.

 

4. PROSPERO registration
   Reviewer’s comment: Although registering systematic reviews using PRISMA in PROSPERO is not mandatory, it is strongly recommended.

Response: We acknowledge the reviewer’s valuable suggestion. While the present study was not prospectively registered in PROSPERO, we have included a statement in the Methodology section clarifying this point. Additionally, we acknowledge this limitation in the Discussion, noting that future systematic reviews on this topic should be registered to enhance transparency and reduce bias.

 

5. Relevant Section and Discussion
   Reviewer’s comment: These sections require editing to avoid repetition of concepts already explained elsewhere in the review. It would be beneficial to incorporate the data presented in Table 1 into thematic subsections. Additionally, the inclusion of a summary table listing genes and variants associated with neuropsychiatric susceptibility, a concise epidemiological overview, and diagrams or visual aids would greatly enhance clarity.

Response: We appreciate this insightful recommendation. The following changes were made:

• Repetition in the Relevant Section and Discussion has been reduced by restructuring paragraphs.
• Data from the former Table 1 have been integrated into thematic subsections (Results and Discussion).
• A new summary table has been added, listing the genes and variants associated with neuropsychiatric susceptibility.
• A concise epidemiological overview with numerical data has been incorporated into the Discussion.
• To enhance accessibility, we have included two schematic diagrams illustrating (a) the role of 5α-reductase isoenzymes in neurosteroid biosynthesis and (b) their association with neuropsychiatric outcomes.

 

Final Note

We are grateful for the reviewer’s constructive feedback, which has allowed us to substantially improve the manuscript. We believe the revised version now provides a clearer, more rigorous, and more comprehensive synthesis of the current knowledge on 5α-reductase isoenzymes and their role in neuropsychiatry.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The introduction and Table 1 seems to derive from the literature review and then there are repetitions: For instance, lines 158-170 were already explained in the introduction.

It is unclear how Table 1 was constructed. It often seems a mix of poorly related items.

Line 59-60: These agents have become standard treatments for BPH and AGA, with an overall safety profile considered favorable [12,13].

Consider corrections: Reference 12 is for topical finasteride - nevertheless - for which recently the FDA published a warning! 

According to a systematic review ( Mella JM, Perret MC, Manzotti M, Catalano HN, Guyatt G. Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Archives of dermatology 2010;146(10):1141-1150.) most trials were small, short-term, and conducted by the industry with moderate quality of evidence and likely publication bias. A recent Bayesian network meta-analysis appears to challenge its usefulness in the long run: Feldman PR, Gentile P, Piwko C, et al. Hair regrowth treatment efficacy and resistance in androgenetic alopecia: A systematic review and continuous Bayesian network meta-analysis. Frontiers in Medicine 2023;9 (Systematic Review). DOI: 10.3389/fmed.2022.998623.

Line 66 Although the existence of this syndrome remains controversial. Line 208 Although the existence of PFS remains debated. The controversy was probably promoted and encouraged by the industry - read the book "Doubt is their product: How Industry's Assault on Science Threatens Your Health" by David Michaels. 

Line 77-8: ...without reaching definitive conclusions [19]. Reference 19 appears to be about the effects of stress on tic exacerbation. More recent and relevant publications reach more definitive conclusion - see recent EMA publication about suicidality from finasteride.

Line 212 Some analyses suggest an increased risk of suicidal ideation or behavior in older men treated for BHP, whereas other studies have found no association in younger patients treated for AGA [37,38].  References 37 and 38 are for older men with BPH and not for younger patients with AGA!

Line 286 whereas findings in younger men with AGA are less consistent [55,56]. This is a duplication of the above wrong reading: thoses references are identical to references 37 and 38 which are for older men with BPH and not for younger patients with AGA! 

A recent review (soon to be published) show when prescribed for AGA, postmarketing research consistently suggest that finasteride cause depression, anxiety, suicide ideation, and suicides. See Table below.

By contrast, when prescribed for prostate hyperplasia, some studies report an adverse effect on mood, and others do not. Since medications alleviating prostatism improve mood, amelioration for a majority of people can dilute or mask mood deterioration in a significant minority—explaining heterogeneity between studies.  It is also possible that younger people react differently than older people to a medication that affects mood, with an increased risk of suicidality—as shown for antidepressants

Table 1. Reports of database analyses showing a link between neuropsychiatric reactions and finasteride
Type of analysis	Type of database & years	Author/1st Year of Publication (ref)	Main Findings
Disproportionality	FAERS 2004–2018	Gupta, 2018, 25 1 2	Significantly increased signals for suicide ideation (ROR 3-5) & completed suicide (ROR 5-9)
Disproportionality	VigiBase 1967–2019	Nguyen, 2021 3	Significantly increased signals for suicide ideation (ROR 4.4) & psychological AE (ROR 4.3)
Disproportionality	VigiBase 1967–2021	Campbell, 2022 4	Significantly increased signal for suicidality (ROR 1.9) with finasteride use alone
Disproportionality	FAERS 1992–2020	Brezis, 2023 5	Significantly increased signals for depression (X17), anxiety (X29), suicidality (X10) & suicides (X2)
Analysis of healthcare records	Ontario healthcare datasets 2003–2013	Welk, 2017 6	Significantly higher rate of self-harm (HR 1.9) & depression (HR 1.9)
Analysis of healthcare records	Swedish healthcare datasets 2005–2018	Garcia-Argibay, 2022 7	Significantly higher depression rate (HR 1.6) & cognitive dysfunction (HR 1.2)
Analysis of healthcare records	French healthcare dataset 2012–2016	Laanani, 2023 8	Significantly higher self-harm rate (HR 3.1) & suicide (HR 2.7) if prior history of mood disorders
Analysis of healthcare records	Israeli healthcare dataset 2019–2020	Lyakhovitsky, 2024 9	Significantly higher anxiety rate (OR 1.5) & depression (OR 1.2)

 

Author Response

REVIEWER 2

 

Author’s response:
We are grateful for these constructive observations. We have carefully revised the manuscript to address them as follows:

1. Reference 12 (topical finasteride and FDA warning): We corrected the misattribution and clarified that the cited study refers to topical finasteride. We now also mention the recent FDA safety warning in the Introduction to reflect regulatory concerns.
2. Efficacy and publication bias (Mella et al., 2010; Zhou et al., 2019; Adil & Godwin, 2017): We have incorporated these systematic reviews into the Introduction, highlighting that most finasteride trials were small, short-term, industry-sponsored, and prone to publication bias (Mella et al., 2010), and that subsequent meta-analyses (Zhou et al., 2019; Adil & Godwin, 2017) have raised questions about the robustness and long-term sustainability of treatment benefits.
3. Controversy on post-finasteride syndrome (lines 66 and 208): We retained the discussion on controversy but reformulated the sentences to emphasize that the debate may have been reinforced by industry interests, citing David Michaels’ Doubt is Their Product as suggested.
4. Reference 19 (tic exacerbation): We corrected this mis-citation. The new reference [19] is Thaibah et al., 2025, a real-world pharmacovigilance analysis (FAERS), which directly addresses suicidality associated with finasteride and is therefore more appropriate.
5. Lines 212 and 286 (BPH vs AGA epidemiology): We corrected the misinterpretation. References [37,38,55,56] are exclusively studies in older men with BPH. We have restructured the epidemiological section so that BPH studies are clearly separated (Welk, 2017; Laanani, 2023; etc.), while AGA evidence relies on Uleri, 2024 [39], Nguyen, 2022 [40], and Thaibah, 2025 [19]. This eliminates the duplication and avoids attributing BPH results to AGA patients.
6. New Table (epidemiology): To clarify the distinction between BPH and AGA, we included a new Table 2 summarizing the major epidemiological and pharmacovigilance studies, with design, population, and key outcomes.
7. Industry-independent signals of risk: We integrated the suggested interpretation: in BPH, symptomatic relief may mask mood deterioration in a minority; whereas in AGA, younger patients may display heightened vulnerability to neuropsychiatric effects, a pattern comparable to the age-dependent risk of suicidality described with antidepressants.

We sincerely thank Reviewer 2 for the insightful and detailed feedback. These comments prompted us to refine the methodological accuracy of the manuscript, correct reference misattributions, and clearly separate the evidence from BPH and AGA populations. We have also incorporated recent systematic reviews, pharmacovigilance analyses, and regulatory warnings, as well as a new epidemiological summary table, to strengthen the balance between efficacy and safety considerations. We believe these revisions significantly enhance the clarity, clinical relevance, and scientific rigor of the work.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The article titled “5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes” is a systematic review that explores the role of 5α-reductase (5α-R) isoenzymes—specifically SRD5A1, SRD5A2, and SRD5A3—in androgen metabolism and neurosteroid biosynthesis, establishing a bridge between endocrinology and neuropsychiatry.

This article has been revised and updated, considering suggestions from a previous review. However, minor corrections are still needed:

• The introduction still needs to be improved. The first paragraph should still reflect the function of 5-alpha-reductase; later, it can refer to its structure.
• Regarding methodology, 2.4 Study selection and analysis: This remains unclear. The actual number of articles should be indicated, as the flow chart indicates that the number of initially selected articles was more than 227. I recommend that the author improve the way the final article selection process is presented in the text.

Author Response

RESPONSE REVIEWER 1

The article titled “5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes” is a systematic review that explores the role of 5α-reductase (5α-R) isoenzymes—specifically SRD5A1, SRD5A2, and SRD5A3—in androgen metabolism and neurosteroid biosynthesis, establishing a bridge between endocrinology and neuropsychiatry.

This article has been revised and updated, considering suggestions from a previous review. However, minor corrections are still needed:

• The introduction still needs to be improved. The first paragraph should still reflect the function of 5-alpha-reductase; later, it can refer to its structure.

 

Response:
We thank the reviewer for this valuable suggestion. The first paragraph of the Introduction has been rewritten to clearly describe the physiological function of 5α-reductase before addressing its structural features. The revised version now begins by emphasizing the enzyme’s catalytic role in the irreversible conversion of testosterone into dihydrotestosterone (DHT) and its contribution to neurosteroid biosynthesis. The structural aspects (crystal structure and NADPH-dependent mechanism) are now discussed subsequently, in accordance with the reviewer’s recommendation (lines XX–XX of the revised manuscript).

 

 

• Regarding methodology, 2.4 Study selection and analysis: This remains unclear. The actual number of articles should be indicated, as the flow chart indicates that the number of initially selected articles was more than 227. I recommend that the author improve the way the final article selection process is presented in the text.

Response:
We appreciate this helpful observation. The Methodology, section 2.4 (Study Selection and Analysis), has been fully revised to clarify the number of records identified and the selection process. The updated text now specifies that a total of 257 records were initially retrieved, 48 duplicates were removed, 209 articles were screened by title and abstract, and 81 studies were finally included in the qualitative synthesis. These numbers are consistent with the PRISMA 2020 flow diagram and ensure methodological transparency. The citation of the PRISMA guideline [21] has been retained to support this section (lines XX–XX of the revised manuscript).

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

In Table 1, the following sentence is not supported by evidence: "others show no significant association (young men with AGA)." On the contrary, a recent review came to the opposite conclusion: 

https://www.psychiatrist.com/jcp/analytical-review-depression-suicidality-finasteride/

Same criticism for the sentence: "Finasteride and dutasteride, effective for BPH and AGA, occasionally linked to anxiety, depression, cognitive dysfunction, and post-finasteride syndrome (PFS)". Not occasionally, according to the above-mentioned review.

Same criticism for the abstract sentence: "although epidemiological data remain inconsistent." 

"In AGA, by contrast, postmarketing analyses have more consistently reported signals of depression, anxiety, and suicidality". Delete the word "more"

"Finasteride and dutasteride, widely prescribed for BPH and AGA, have occasionally been associated with anxiety, dysphoria, anhedonia, insomnia, cognitive complaints, and even suicidal ideation [42]." Delete the word "occasionally".

In Table 2 and elsewhere, reference 39 is wrongly cited as "No significant increase in depression or suicidality among younger finasteride users" in "young men with AGA". Uleri et al include only elderly patients with BPH!

"Taken together, the evidence indicates that 5α-R inhibitors do not universally induce neuropsychiatric symptoms, but they may unmask or exacerbate pre-existing vulnerabilities in a subgroup of patients" The data do not support this sentence: indeed, in AGA, the neuropsychiatric effect is consistent. 

 

Author Response

 

 

Response to Reviewer 2

 

Reviewer 2, Comment 1
In Table 1, the following sentence is not supported by evidence: “others show no significant association (young men with AGA).” On the contrary, a recent review came to the opposite conclusion (Brezis 2025). Same criticism for the sentence: “Finasteride and dutasteride, effective for BPH and AGA, occasionally linked to anxiety, depression, cognitive dysfunction, and post-finasteride syndrome (PFS). Not occasionally, according to the above-mentioned review.”

Response:
We appreciate this observation. Table 1 and the corresponding text were revised to incorporate the most recent analytical review by Brezis (2025), now included as Reference [43] (Failing Public Health Again? Analytical Review of Depression and Suicidality from Finasteride, J. Clin. Psychiatry, 2025; 86(4):25nr15862. doi:10.4088/JCP.25nr15862*).
This work reports a consistent association between finasteride use and depressive or suicidal symptoms in younger men treated for androgenetic alopecia.
Accordingly, the phrase “others show no significant association (young men with AGA)” was replaced by a statement acknowledging recent pharmacovigilance findings, and the term “occasionally linked” was replaced with “have been associated.”
Reference [43] was added to support these revisions.

 

Reviewer 2, Comment 2
Same criticism for the Abstract sentence: “although epidemiological data remain inconsistent.”

Response:
The Abstract was modified to reflect the strengthened evidence from recent pharmacovigilance studies, including Brezis (2025) [43].
It now reads:

“...and while earlier epidemiological findings were heterogeneous, recent pharmacovigilance analyses have strengthened the evidence supporting this association.”

 

Reviewer 2, Comment 3
In AGA, by contrast, postmarketing analyses have more consistently reported signals of depression, anxiety, and suicidality. Delete the word ‘more.’

Response:
As requested, the adverb “more” was deleted.
The sentence now reads:

“In AGA, by contrast, postmarketing analyses have consistently reported signals of depression, anxiety, and suicidality [19].”

 

Reviewer 2, Comment 4
“Finasteride and dutasteride, widely prescribed for BPH and AGA, have occasionally been associated with anxiety, dysphoria, anhedonia, insomnia, cognitive complaints, and even suicidal ideation [42]. Delete the word ‘occasionally.’”

Response:
The adverb “occasionally” was removed, and the reference number updated to maintain consistency with the revised bibliography.
The sentence now reads:

“Finasteride and dutasteride, widely prescribed for BPH and AGA, have been associated with anxiety, dysphoria, anhedonia, insomnia, cognitive complaints, and even suicidal ideation [41].”

 

Reviewer 2, Comment 5
In Table 2 and elsewhere, reference 39 is wrongly cited as ‘young men with AGA.’ Uleri et al. include only elderly patients with BPH.

Response:
This has been corrected. In Table 2, Uleri et al. [39] are now accurately described as an Italian multicenter retrospective cohort of elderly men with BPH, with the clarification: “study limited to BPH population (not AGA).”
All incorrect mentions of “young men with AGA [39]” were removed from the text.
The rest of the table was adjusted for numerical coherence, assigning [41] (Dyson et al., 2020) to the meta-analytical entry, since [40] (Fatemi et al., 2013) pertains to neurobiological findings, not epidemiology.

 

Reviewer 2, Comment 6
The sentence “Taken together, the evidence indicates that 5α-R inhibitors do not universally induce neuropsychiatric symptoms…” is not supported: in AGA the neuropsychiatric effect is consistent.

Response:
The sentence was revised to reflect the consistency of neuropsychiatric adverse effects in androgenetic alopecia, as documented in Brezis (2025) [43], while maintaining scientific balance:

“Taken together, the evidence indicates that 5α-R inhibitors do not affect all users equally; consistent neuropsychiatric adverse effects have been documented in men treated for androgenetic alopecia, suggesting a higher susceptibility in this population [80,43].”

 

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

"and while earlier epidemiological findings were heterogeneous, recent pharmacovigilance data have strengthened the evidence supporting this association."

Also in Table 1: "Earlier cohort and population-based studies yielded mixed or inconclusive results regarding the association between finasteride use and depressive or suicidal symptoms, largely due to methodological heterogeneity and unmeasured confounders. More recent..."

These sentences are not accurate, as they may be interpreted to suggest that some earlier studies with finasteride for AGA demonstrated safety regarding mood effects. Not a single postmarketing study has suggested so; on the contrary, the reverse is true. The heterogeneity is not early vs. late. It's about the indication. 

In Table 1 and elsewhere in the text, reference 40 is misreferenced as an epidemiological study. Please carefully recheck all references.

The expression "epidemiological study" is anachronistic in the context of drug safety, as if the classical research designs of epidemiology are appropriate to detect problems. They are not, and that is a critical issue. Clinical trials are designed to determine efficacy and are inadequate to test safety. Postmarketing surveillance uses new tools, such as disproportionality analysis and data mining in healthcare records. As soon as these were applied, the neuropsychiatric effects of finasteride in AGA were immediately and consistently uncovered. This is an important point to explain, rather than sticking to the expression "epidemiological study" throughout the paper.   

The sentence "Consequently, although a causal relationship has not been fully established, international regulatory agencies have adopted a precautionary stance by including specific warnings in the labeling of finasteride and dutasteride." is a misquotation. See the recent EMA reports:

https://www.ema.europa.eu/en/medicines/human/referrals/finasteride-dutasteride-containing-medicinal-products

"Finasteride tablets can cause depressed mood, depression or suicidal thoughts."

The sentence "By contrast, in younger men with AGA, cohort studies have produced less consistent results [39,40], whereas postmarketing pharmacovigilance data have frequently highlighted signals of depression, anxiety, and suicidality [19]" shows a lack of understanding of the above.

The reference 39 Uleri is NOT about AGA!  The reference 40 is about GABA!

"frequently" - NO! consistently 

 

 

 

 

Author Response

Comments and point-by-point responses

1. Introduction

Reviewer’s comment:

"and while earlier epidemiological findings were heterogeneous, recent pharmacovigilance data have strengthened the evidence supporting this association."

Response:
The sentence has been revised to:

While early studies were inconclusive, recent pharmacovigilance analyses have identified consistent disproportionality signals linking finasteride to suicidality, particularly in younger men treated for androgenetic alopecia [19]. These signals indicate a reporting association but do not establish causality.

This change clarifies that no early studies demonstrated mood safety and that recent evidence comes from pharmacovigilance signals rather than epidemiological designs.

 

2. Table 1

Reviewer’s comment:

Also in Table 1: “Earlier cohort and population-based studies yielded mixed or inconclusive results…”
These sentences are not accurate… The heterogeneity is not early vs. late. It’s about the indication.

Response:
The text in Table 1 was modified accordingly:

Population-based cohorts (BPH) and postmarketing pharmacovigilance (AGA): No earlier studies demonstrated mood safety for finasteride. Differences among findings mainly reflect the indication—benign prostatic hyperplasia (BPH) in older men versus androgenetic alopecia (AGA) in younger men—rather than study design or period. Once postmarketing pharmacovigilance methods were applied, consistent signals of depression, anxiety, and suicidality emerged, especially in AGA.
References updated to [19, 37, 39].
This now correctly attributes heterogeneity to indication, not chronology.

 

3. Misreferenced studies and terminology

Reviewer’s comment:

Reference 40 is misreferenced as an epidemiological study. The expression “epidemiological study” is anachronistic...

Response:
The term epidemiological study was replaced throughout with population-based cohort or postmarketing pharmacovigilance analysis as appropriate.
Reference 40 was removed from Table 1 (Epidemiological and pharmacovigilance evidence) and kept only under Genetic and individual susceptibility, where it belongs.
A short methodological clarification about pharmacovigilance approaches (FAERS, VigiBase, disproportionality metrics) was added to the Methods section.

 

4. Regulatory statement

Reviewer’s comment:

The sentence “Consequently, although a causal relationship has not been fully established…” is a misquotation.

Response:
The text was replaced with the accurate regulatory statement:

Regulatory authorities have officially acknowledged that finasteride can cause depressed mood, depression, or suicidal thoughts. The European Medicines Agency (EMA, 2025) required updates to product information and a patient card for 1-mg tablets used in androgenetic alopecia, stating explicitly: “Finasteride tablets can cause depressed mood, depression or suicidal thoughts” [36].

This now correctly reflects the official EMA position.

 

5. AGA-specific findings

Reviewer’s comment:

“By contrast, in younger men with AGA…” — wrong references, wording should be consistently.

Response:
The sentence was revised to:

By contrast, in younger men with androgenetic alopecia (AGA), available postmarketing pharmacovigilance data have consistently revealed disproportionality signals of depression, anxiety, and suicidality [19].

References [39] (Uleri) and [40] (GABA) were removed from this sentence to avoid misinterpretation.

Author Response File: Author Response.docx