Title: Associations between serum cytokine levels and postmenopausal depression in
postmenopausal women with and without menopause hormone therapy
Version: 7 Date: 21 Dec 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This study objetive was to investigate the relationship between pro-
inflammatory cytokines (i.e., IL11#, IL-6, IL-18, and TNF-#) and depressive symptoms in
postmenopausal women, considering the impact of menopause hormone therapy (MHT). The
objective is clear, simple and well-defined by the authors, and despite being a recurrent topic
in literature, the specific understanding of menopausal depression symptoms and inflammatory
cues have interest to the community, defining biological interventions and the potential role of
MHT in mitigating those markers and outcome. The study design is observational and considers
an uneven distribution between the POST and the POST+MHT groups (94 vs 42), which can be a
bias when evaluating outcomes, and could be better discussed. The methodological biochemical
assessment is standard and could potentially be applied in the clinic.  In addition, it was not
clear whether the authors would apply to a second cohort to confirm their findings. This work
focus on presenting positive association of IL-18 and TNF-a levels with depression scores in
non-MHT users, and could be considered as markers of depression in postmenopausal woman,
pointing to the inflammation role in postmenopausal depression. Yet, the novelty and further
confirmation could improve their findings.
REQUESTED REVISIONS:
There are some information that would improve the manuscript:
- It was not clear from the methods whether depression pre-menopausal was considered as a
factor.
- Statistical analysis were performed, yet more detailed confounders should be considered
(as mentioned, physical activity, and medical history including pre-menopausal depression
existence and antidepressant use) and were not evaluated in the tables.
- How were those confounders influencing the outcome? With several different values, a model
showing which variables are more likely to influence the POST depression would benefit the
study, and enhance inflammatory claims.
- The study focus on associating POST (and POST+MHT) to depression, and then to cytokine
levels. But all in bulk analysis. However, there is no direct association of having depression and
the cytokine levels, as there is no separate group. How the authors manage those?
- Is there a planned test cohort to test the hypothesis of IL-18 and TNF-a being predictive of
depression? Or whether the use of MHT is favourable?