Selective Serotonin Reuptake Inhibitors and Adverse Effects: A Narrative Review

Round 1

Reviewer 1 Report

In this review, authors display the different SSRIs as well as the adverse events related to SSRI treatment.

Overall, the review is well written, however discussion of the results is missing. Please find below some comments for consideration.

Abstract:

• line 19: delete the reference
• line 28: words are missing after "and"

Introduction:

• please introduce here the different types of depression.
• please make sure along the paper to properly introduce and use abbreviations (e.g., SERT line 61, 205...)

Section 2

• please describe the off-label use line 72
• Line 90: please add versus wich treatment 
• In the different diseases presented from 2.1 to 2.9, SSRIs treat the depression and reduce the comorbidity associated with it. More emphasizes should be added regarding this point

Section 3

• line 210: what does that bring? It is purely descriptive and more discussion should be done

Section 4

• line 228: please provide the CYPs inhibited by SSRIs
• Please provide additional data regarding steady-state conditions reached for PK AND PD. 
• Are the PK/PD relationships known? If so, this should be added

Section 5

• Please provide incidence of these AEs when available
• For section 5.3, please provide TQT study data as well as the references.
• Line266: by how much is the risk increased?

Section 7

• line 408: as it stands this review does not discuss but only  display

References

- please pay attention here as different styles have been used, e.g., compare ref 11, 14, 20... vs ref 3, 13, 22...

Author Response

Abstract:

• line 19: delete the reference
• line 28: words are missing after "and"

Response to the author: These two points are addressed.

Introduction:

• please introduce here the different types of depression.
• please make sure along the paper to properly introduce and use abbreviations (e.g., SERT line 61, 205...)

One sentence about the different types of depression was added.  and abbreviation was defined when first mentioned around line 61.

Section 2

• please describe the off-label use line 72
• Line 90: please add versus which treatment 
• In the different diseases presented from 2.1 to 2.9, SSRIs treat the depression and reduce the comorbidity associated with it. More emphasizes should be added regarding this point

Described some of the off label uses though some are spoken about in the text that follows. 

line 90 comment: this looked at SSRIs as first line treatment of pharmacotherapy. The statement was regarding if they failed monotherapy of the SSRI and what could be done next. This was already in the text without editing.

Added some about comorbidities of depression.

Section 3

• line 210: what does that bring? It is purely descriptive and more discussion should be done

More was added about citalopram's QTc effects. The paxil section was meant to be descriptive.

Section 4

• line 228: please provide the CYPs inhibited by SSRIs
• Please provide additional data regarding steady-state conditions reached for PK AND PD. 
• Are the PK/PD relationships known? If so, this should be added

These points have been added

Section 5

• Please provide incidence of these AEs when available
• For section 5.3, please provide TQT study data as well as the references.
• Line266: by how much is the risk increased?

The QTc study data was briefly discussed when citalopram was introduced. Incidence is hard to capture in studies as they're not usually recorded with accuracy

references fixed but some are book chapters vs. journal articles so they won't have issues and volumes.

Reviewer 2 Report

TITLE:

Selective Serotonin Reuptake Inhibitors and Adverse Effects

AUTHORS:

Amber N. Edinoff ; Haseeb A. Akuly; Tony A. Hanna; Carolina O. Ochoa; Shelby J. Patti; Yahya A. Ghaffar; Alan D. Kaye; Omar Viswanath; Ivan Urits ; Andrea G. Boyer; Elyse M. Cornett; Adam M. Kaye.

SUMMARY OF THE CONTENT:

Edinof and colleagues conducted a narrative review to describe currently approved SSRIs for the treatment of depression and other indications. The authors describe, approved indications; “off-label” indications, adverse effects in children and adults.  

The authors summarize the findings from RCTs, descriptive studies and meta-analyses. At the end of the manuscript the authors focus on the suicide behavior that may appear after SSRIs treatment initiation.

OVERALL OPINION OF MANUSCRIPT:

Edinof and colleagues conducted a narrative review to examine the mechanism of actions, differences between SSRIs, PKs and PDs of SSRIs, and potential rare adverse effects of SSRIs.  This study has several strengths, including a thorough review of SSRIs characteristics. However, this study also has several important limitations that limits its contribution; these issues are described in the Specific Comments below. 

SPECIFIC CPMMENTS:

Abstract:

Please state the objective of the study at the end of the abstract, at least the primary objective. What is the knowledge gap that the authors wish to address?

Introduction:

Same as for abstract, please state the objective of the review. The authors review current and already known information about SSRIs. What does the current study add to the literature?  

Page 2, line 56: adverse effects of SSRIs need to be reviewed and monitored.

Methods:

Did the authors use a pre-specified protocol to review the literature? Which search engines were used?

Results:

How did the authors choose these adverse effects to focus on? BNased on prevalenece? Severity?

When describing the results please indicate the strengths and limitations of the mentioned studies/meta-analyses.

Risk for suicide in adolescents: one of the suggested theories is that the increase in serotonin levels in the synapse immediately after the drug initiation may give a “boost of physical energy” to the patients and that allows them to execute suicide plans, and therefore psychotherapy and monitoring in the first few weeks are crucial. Did the authors notice lower suicide attempts in RCTs or studies were monitoring and follow-up were stricter?    

Discussion:

I find the part of the covariates a bit off. The mentioned studies have other methodological issues such as selection bias, exposure misclassification, outcome misclassifications etc. that could affect the results and not just confounding, although the confounding factors mentioned by the authors are important. Maybe this paragraph should be a general paragraph about the limitations of the current studies.

Author Response

Please state the objective of the study at the end of the abstract, at least the primary objective. What is the knowledge gap that the authors wish to address?

 reply: added

Introduction:

Same as for abstract, please state the objective of the review. The authors review current and already known information about SSRIs. What does the current study add to the literature? 

Reply: added

Page 2, line 56: adverse effects of SSRIs need to be reviewed and monitored.

Reply: added "and monitored"

Methods:

Did the authors use a pre-specified protocol to review the literature? Which search engines were used?

reply: there was no pre-specified protocol

Results:

How did the authors choose these adverse effects to focus on? BNased on prevalenece? Severity?

reply: adverse effects were complied and then studies that looked at them that were clinical were included. Primary sources are the ones that were included

Round 2

Reviewer 1 Report

The comments have been appropriately addressed.