Depression Events Associated with Proton-Pump Inhibitors in Postmarketing Drug Surveillance Data
Round 1
Reviewer 1 Report
This manuscript aims to identify reports regarding the increase in depression in patients taking PPIs as monotherapy when compared to H2RAs.
Please address the following concern:
In the Methods section, please include the manner in which you identified all the brand names of the analyzed drugs, and if not all the brand names of all the countries that had reports in the database were identified, please include that information in the Study limitations section.
Author Response
Reviewer 1
This manuscript aims to identify reports regarding the increase in depression in patients taking PPIs as monotherapy when compared to H2RAs.
Please address the following concern:
- In the Methods section, please include the manner in which you identified all the brand names of the analyzed drugs, and if not all the brand names of all the countries that had reports in the database were identified, please include that information in the Study limitations section.
Thank you for the comment. We expanded the Methods and the Study Limitation sections to address this issue
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Dear Authors,
The article is remarkable for its scope, it analyzes a significant number of FAERS reports over such a large period of time.
In the introduction section, I suggest the authors to mention more recent articles as references to highlight both the pathology associated with PPI use and the mechanisms of action: as examples are citations from 1989, 1991 and even 1986.
Mention of additional post-marketing adverse reactions also requires support through citations to argue these reactions, apart from the neurological disorders supported by the citations presented [17, 18].
In the discussion section, the authors specify that this is the first study on the relationship between PPIs / H2 receptor antagonists for histamine and depression. Therefore, for a better support of this study, given that the results highlight a rather low number of cases of depression, the authors should mention why this study focused on PPIs or H2 inhibitors and depression, considering that there are other categories of drugs used in the mentioned pathologies. Also at the end of the section it is mentioned "increased risk of depression observed when using PPIs" which contradicts the previous finding in the same section: "the number of depression reports was relatively low". These contradictory statements require clarification.
Author Response
Reviewer 2
Dear Authors,
The article is remarkable for its scope, it analyzes a significant number of FAERS reports over such a large period of time.
- In the introduction section, I suggest the authors to mention more recent articles as references to highlight both the pathology associated with PPI use and the mechanisms of action: as examples are citations from 1989, 1991 and even 1986.
Thank you for the suggestion. We added studies on more recently approved PPI pivotal trials, describing the AE profiles, and the mechanism of action. Additionally, included studies on neuropsychiatric pathophysiologic mechanisms.
- Mention of additional post-marketing adverse reactions also requires support through citations to argue these reactions, apart from the neurological disorders supported by the citations presented [17, 18].
Thank you for the suggestion, additional citations on this topic covering other neurological disorder association with PPI use.
- In the discussion section, the authors specify that this is the first study on the relationship between PPIs / H2 receptor antagonists for histamine and depression. Therefore, for a better support of this study, given that the results highlight a rather low number of cases of depression, the authors should mention why this study focused on PPIs or H2 inhibitors and depression, considering that there are other categories of drugs used in the mentioned pathologies.
Thank you for raising an interesting point. We were interested in the PPIs due to growing evidence on neuropsychiatric pathology. The number of reports was sufficient for the analysis, but we needed a control group. The H2RAs were selected as a control group due to the identical indication and sufficient number of reports required for reliable confidence interval evaluations. Indeed, there are other drugs in the mentioned pathologies, but the number of submitted monotherapy reports was not sufficient for reliable statistical analysis.
- Also at the end of the section it is mentioned "increased risk of depression observed when using PPIs" which contradicts the previous finding in the same section: "the number of depression reports was relatively low". These contradictory statements require clarification.
We agree that language use was not optimal. We corrected the corresponding sections to avoid false impression of contradiction. The absolute numbers were actually high, however, the fraction of depression reports to the total number was relatively low. But still statistically higher than the control level.
Author Response File: Author Response.pdf
Reviewer 3 Report
This is an interesting and very well-written manuscript. Commendation to authors for evaluating such a large number of ADR reports to determine association of proton pump inhibitors (PPIs) with depression. The findings of this study can be helpful for healthcare providers while prescribing PPIs to people suffering from depression or those who are at high risk of depression. I recommend minor revisions for this manuscript.
1. Section 2.2: “Legal representatives” is mentioned twice. Please correct it.
2. Please mention “Figure 1” in the text.
3. It would be better to add the overall prevalence of depression in the result section.
4. It would be more useful to add the demographic analysis in the manuscript rather than providing it as supplement data.
5. Did the duration of PPI use had any impact of the incidence of depression?
6. Add implications for practice and the future research.
Author Response
Reviewer 3
This is an interesting and very well-written manuscript. Commendation to authors for evaluating such a large number of ADR reports to determine association of proton pump inhibitors (PPIs) with depression. The findings of this study can be helpful for healthcare providers while prescribing PPIs to people suffering from depression or those who are at high risk of depression. I recommend minor revisions for this manuscript.
- Section 2.2: “Legal representatives” is mentioned twice. Please correct it.
Thank you for catching this error, it has been corrected.
- Please mention “Figure 1” in the text.
Referenced Figure 1 added to the Results section.
- It would be better to add the overall prevalence of depression in the result section.
Thank you for the suggestion, the overall reported frequency has been added to the results.
- It would be more useful to add the demographic analysis in the manuscript rather than providing it as supplement data.
The demographic analyses tables have been moved from the Supplement to the main manuscript.
- Did the duration of PPI use had any impact of the incidence of depression?
Unfortunately, neither the duration of use nor the case narratives were available through FAERS.
- Add implications for practice and the future research.
Thank you for the recommendation. The following statement was added to the Conclusion section:
“Prescribers should be aware of this potential risk and educate the patients to avoid deviations on recommended dose, frequency, and use duration.Further studies are needed to evaluate the neurologic adverse events of PPIs in a controlled setting, identify at risk populations and identify the molecular mechanisms associated with the PPIs’ neuropsychiatric adverse events.”
Author Response File: Author Response.pdf
