Antidepressants and Risk of Sudden Cardiac Death: A Network Meta-Analysis and Systematic Review

Round 1

Reviewer 1 Report

Due to scattered data related to ventricular arrhythmias and sudden cardiac death from antidepressants, in the present paper the Authors performed a network systematic review and meta-analysis to evaluate and analyze the overall likelihood of such risks collectively. The researchers demonstrated that the use of antidepressants in patients with mental disorders was not associated with VA/SCD. TCA has the lowest risk, followed by SNRI and SSRI in comparison with a placebo. They performed a sensitivity analysis as well as meta-regression, and the result was consistent with those before doing sensitivity anal-ysis and meta-regression. The similar outcomes confirmed the low likelihood of VA/SCD from antidepressant use, especially TCA.

Overall, I found the present network systematic review and meta-analysis concise, straightforward, timely, well conducted, very interesting and scientifically sound: enjoyed reading it! I have only some minor comments aimed to improve the high quality of the paper and these are outlined below:

1) The introduction should be expanded in several parts in order to provide a more in-depth scientific background to the aims and scopes of the network systematic review and meta-analysis. Moreover, it should be emphasized that antidepressants are relatively safe also on the probability to induce suicide ideation in some cases of wrong diagnosis or selected individuals with appropriate reference (see doi: 10.3389/fpsyt.2019.00294).

2) A table with predisposing condition for TdP would be useful to the reader, with recommendations on what to do to prevent. As well, as the Authors correctly wrote that physicians cautiously use and closely monitor the side effects of TCA, a brief note on what to do to monitor ADRs of TCA would be useful too.

3) A brief mention on lethality due to TCA/SSRIs and other antidepressants regarding cardiac adverse event in the case of acute intentional o non-intentional poisoning would add some more relevant informations. 

Author Response

Reviewer 1

Due to scattered data related to ventricular arrhythmias and sudden cardiac death from antidepressants, in the present paper the Authors performed a network systematic review and meta-analysis to evaluate and analyze the overall likelihood of such risks collectively. The researchers demonstrated that the use of antidepressants in patients with mental disorders was not associated with VA/SCD. TCA has the lowest risk, followed by SNRI and SSRI in comparison with a placebo. They performed a sensitivity analysis as well as meta-regression, and the result was consistent with those before doing sensitivity anal-ysis and meta-regression. The similar outcomes confirmed the low likelihood of VA/SCD from antidepressant use, especially TCA.

Overall, I found the present network systematic review and meta-analysis concise, straightforward, timely, well conducted, very interesting and scientifically sound: enjoyed reading it! I have only some minor comments aimed to improve the high quality of the paper and these are outlined below:

Responses:

We thank you for reviewing our manuscript and for your critical evaluation. We greatly appreciate reviewer’s recommendation. Given non-benign side effects from antidepressants, especially onto cardiovascular system, our team has decided to comprehensively gather relevant data to provide more understanding in the pharmacopathogenic effects in these commonly used drugs. We are delighted that this article, from the reviewer’s perspective, grant meaningful messages to whomever are interested in this topic.

1) The introduction should be expanded in several parts in order to provide a more in-depth scientific background to the aims and scopes of the network systematic review and meta-analysis. Moreover, it should be emphasized that antidepressants are relatively safe also on the probability to induce suicide ideation in some cases of wrong diagnosis or selected individuals with appropriate reference (see doi: 10.3389/fpsyt.2019.00294).

Responses:

Appreciate reviewer’s recommendation. We have comprehensively revised our introduction to provide more further details, essentially the importance of nonbenign natures of antidepressants, some background of mood disorder and the rationale of using network meta-analysis as a main method to appraise and narrate the key contents.

2) A table with predisposing condition for TdP would be useful to the reader, with recommendations on what to do to prevent. As well, as the Authors correctly wrote that physicians cautiously use and closely monitor the side effects of TCA, a brief note on what to do to monitor ADRs of TCA would be useful too.

Responses:

Appreciate reviewer’s recommendation. To address the first suggestion, we have created a table 2 which demonstrates examples of predisposing conditions for TdP and their general countermeasures. For the second suggestion, we have added a short statement explaining what to do to monitor TCA adverse drug reaction as followed “  First, physicians cautiously use and closely monitor the side effects of TCA, by routine vital sign checks, weight monitoring and serial ECG.” In a red highlight.

3) A brief mention on lethality due to TCA/SSRIs and other antidepressants regarding cardiac adverse event in the case of acute intentional o non-intentional poisoning would add some more relevant information.

Responses:

Appreciate reviewer’s recommendation. We have briefly mentioned both incidence and lethality of antidepressants based on reference number 8 (McKenzie, M.S.; McFarland, B.H. Trends in antidepressant overdoses. Pharmacoepidemiology and drug safety 2007, 16, 513-523, doi:10.1002/pds.1355)

Again, we thank you for reviewing our manuscript and for your critical evaluation.

Author Response File: Author Response.pdf

Reviewer 2 Report

1. I am not sure if the abstract allows to use abbreviations. The readers may not understand what TCA, SSRI and SNRI are. 

2. In section 2.2, please give the reference of the Cochrane Collaboration’s tool.

3. To justify why using a random-effects model rather than a fixed-effect model, the authors just mentioned "Given the possibility of be-tween-study variance". It is not clear, can the authors give more details for this reason?

4. In Figure 2, the network's edge thickness is not clear. Can the authors just show the numbers on the edges?

5. Figure 3 is weird, as the distance between 0.02 and 1 is much longer than between 1 and 2. 

6. The introduction is too short to caputre the background of the study. I would suggest the authors to include some more literature (PubMed ID: 26621261, 27777418, 29160301, 32066657, 33128939, etc.) to amplify it. 

Author Response

Reviewer 2

1. I am not sure if the abstract allows to use abbreviations. The readers may not understand what TCA, SSRI and SNRI are.

Responses:

We thank you for reviewing our manuscript and for your critical evaluation. We greatly appreciate reviewer’s recommendation. Appreciate reviewer’s recommendation. We have added full definitions of TCA , SSRI and SNRI as red highlighted.

2. In section 2.2, please give the reference of the Cochrane Collaboration’s tool.

Responses:

Appreciate reviewer’s recommendation. We have added on the reference 10 for Cochrane Collaboration’s tool “Higgins, J.P.; Altman, D.G.; Gotzsche, P.C.; Juni, P.; Moher, D.; Oxman, A.D.; Savovic, J.; Schulz, K.F.; Weeks, L.; Sterne, J.A., et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.) 2011, 343, d5928, doi:10.1136/bmj.d5928.”

3. To justify why using a random-effects model rather than a fixed-effect model, the authors just mentioned "Given the possibility of be-tween-study variance". It is not clear, can the authors give more details for this reason?

Responses:

Appreciate reviewer’s recommendation. For better clarification, we have revised the quote “given the possibility of between-study variance” to “According to heterogeneous natures of included studies, for example different methods, inclusion criteria etc.” as red highlighted in the revised manuscript

4. In Figure 2, the network's edge thickness is not clear. Can the authors just show the numbers on the edges?

Responses:

Appreciate reviewer’s recommendation. We already placed the revised image with additional information according to reviewer’s suggestion.

5. Figure 3 is weird, as the distance between 0.02 and 1 is much longer than between 1 and 2.

Responses:

Appreciate authors’ recommendations. We created a new figure 3 to be more symmetry on an x axis for better understanding the 95% CI range.

6. The introduction is too short to capture the background of the study. I would suggest the authors to include some more literature (PubMed ID: 26621261, 27777418, 29160301, 32066657, 33128939, etc.) to amplify it.

Responses:

Appreciate reviewer’s recommendation. We have comprehensively revised our introduction to provide more further details; we agree with these suggested references, and we essentially used the recommended articles to cite and help narrate complexity of mood disorder pathophysiology. These are now listed in our updated reference list.

Again, we thank you for reviewing our manuscript and for your critical evaluation.

Author Response File: Author Response.pdf

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.