Comparative Efficacy and Side-Effect Profile of Ketamine And

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PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Comparative efficacy and side effect profile of ketamine and esketamine in the treatment of unipolar and bipolar depression: protocol for a systematic review and network meta-analysis AUTHORS Zhan, Zhiqing; Wang, Xichao; Chen, Qing; Xiao, Zhidai; Zhang, Bin

VERSION 1 – REVIEW

REVIEWER Kenji Hashimoto Chiba University Center for Forensic Mental Health, Japan But I am an inventor of patent of the use of arketamine in the treatment of depression. REVIEW RETURNED 26-Sep-2020

GENERAL COMMENTS I have some minor comments. Abstract: Introduction: The sentence "Ketamine and esketamine are enantiomers" is wrong. I suggests that "Esketamine is (S)- enantiomer of ketamine" is better. Introduction: There is one article reporting head-to-head study of intravenous esketamine and intravenous ketamine in patients http://bmjopen.bmj.com/ (Correia-Melo et al, J Affect Disord 2020).

Introduction There is a pilot report showing antidepressant actions of arketamine in treatment-resistant patients with MDD (Leal et al, Eur Arch Psychiatry Clin Neurosci 2020). Please cite this paper in the introduction.

on September 24, 2021 by guest. Protected copyright. REVIEWER Jennifer Phillips University of Ottawa Institute of Mental Health Research, Canada REVIEW RETURNED 20-Nov-2020

GENERAL COMMENTS This systematic review will compare intravenous ketamine to intranasal esketamine in terms of therapeutic efficacy and side effects for the treatment of depression in patients with major depressive disorder and bipolar disorder. The study protocol is clear, well written and methodologically sound. However, I question the rationale for its publication when according to the authors stated timeline, the study has likely already occurred and the results may soon be ready for publication (within the paper, the authors state that they expect to submit the manuscript reporting their results before December 20, 2020).

General comments

BMJ Open: first published as 10.1136/bmjopen-2020-043457 on 12 February 2021. Downloaded from

The registration information should be updated as it appears the systematic review has been registered on PROSPERO (CRD42020201559).

For data collection/extraction, it is not clear how the authors plan to deal with concomitant medications. There appears to be no mention of distinguishing between ketamine/esketamine as monotherapy versus adjunctive therapy.

It is unclear what the authors mean by placebo? Will RCTs only be included if they used a true placebo as a comparator (ex. saline)? What about RCTs that compare ketamine to an active control (such as midazolam)?

I commend the authors for including examination of potential sex differences for these treatments.

Specific suggested revisions follow.

Introduction -Page 5, Line 5. Unusual to highlight cognitive deficit over all other aspects of depression and its elevated burden to the individual and society at large- recommend revising opening sentence to better define depression. -Page 5, Line 11. Please change “full dose and long-term treatment” to “adequate dose and sufficient duration”. Also, the reference for this sentence is incorrect; I assume the sentence references the STAR-D trial? Please revise. -Page 5, Line 15. For more clarity when first introducing ketamine please specify that you are referring to the racemic mixture or ketamine hydrochloride, a mixture of the R and S enantiomers. -Page 5, Line 21. Revise language, treatment with ketamine does not necessarily “require intravenous administration”. It is most

commonly administered intravenously to treat depression but other http://bmjopen.bmj.com/ routes of administration exist including oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous. -Page 5, Line 36. While true that no RCTs comparing intranasal esketamine and intravenous ketamine have been published to date, several such studies are currently ongoing- that can be mentioned here. -Page 5, Line 38. Problem with tense, this sentence refers to having conducted the systematic review already. Protocol paper should use future tense throughout. on September 24, 2021 by guest. Protected copyright.

Methods and Analysis -Page 6, Line 9. Inclusion criteria B please clarify intravenous ketamine -Page 6, Line 40-45. Inconsistent spelling of crossover (sometimes two words, sometimes hyphenated), please correct “precross- overphase”. -Page 6, Line 45. Please specify how you will deal with papers that fail to report pre-crossover phase data? Will you contact study authors directly to obtain this data? -Page 7, Table 1, Section 1.2 CNKI searing strategy. Unable to review (language).

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VERSION 1 – AUTHOR RESPONSE

Reviewing: 1

Comments to the Author: I have some minor comments. #1

Abstract: Introduction: The sentence "Ketamine and esketamine are enantiomers" is wrong. I suggests that "Esketamine is (S)- enantiomer of ketamine" is better.

Response: Thank you for this comment. As you advised, we have changed the sentence "Ketamine and esketamine are enantiomers" to "Esketamine is (S)- enantiomer of ketamine".

Revision:

Abstract: Esketamine is (S)- enantiomer of ketamine. (Page 2, Line 5)

Abstract:

Introduction: There is one article reporting head-to-head study of intravenous esketamine and intravenous ketamine in patients (Correia-Melo et al, J Affect Disord 2020).

Response: Thank you for this comment. As you advised, we have revised this sentence and cited the article (Correia-Melo et al, J Affect Disord 2020). http://bmjopen.bmj.com/ Revision:

Abstract: However, there is limited evidence comparing esketamine and ketamine in treating unipolar and bipolar depression have been published so far. (Page 2, Line 7-9)

Introduction: However, only one head- to-head study assessed the efficacy and safety of ketamine compared to esketamine. (Page 3, Line 28-30) on September 24, 2021 by guest. Protected copyright.

Introduction： There is a pilot report showing antidepressant actions of arketamine in treatment-resistant patients with MDD (Leal et al, Eur Arch Psychiatry Clin Neurosci 2020). Please cite this paper in the introduction.

Response: Thank you for this comment. As you advised, we have cited this paper in the introduction.

Revision:

Introduction: To date, there are several studies16-22 evaluating the efficacy and side effect profile of the enantiomers of ketamine, including esketamine16-21, the S (-)-enantiomer of ketamine, and arketamine22, the R (-)-enantiomer of ketamine. (Page 3, Line 26-28)

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Reference

16.Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry 2018; 75(2):139-148

17.Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry 2019; 176(6):428-438

18.Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry 2018; 175(7):620-630

19.Kryst J, Kawalec P, Pilc A. Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder. Expert Opin Pharmacother 2020; 21(1):9-20.

20.Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol 2019;22(10):616-630.

21.Fu DJ, Ionescu DF, Li X, et al. Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I). J Clin Psychiatry 2020 81(3):19m13191.

22.Leal GC, Bandeira ID, Correia-Melo FS, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci 2020. doi: 10.1007/s00406-020- 01110-5.

http://bmjopen.bmj.com/

Reviewer: 2 Comments to the Author:

This systematic review will compare intravenous ketamine to intranasal esketamine in terms of on September 24, 2021 by guest. Protected copyright. therapeutic efficacy and side effects for the treatment of depression in patients with major depressive disorder and bipolar disorder. The study protocol is clear, well written and methodologically sound. However, I question the rationale for its publication when according to the authors stated timeline, the study has likely already occurred and the results may soon be ready for publication (within the paper, the authors state that they expect to submit the manuscript reporting their results before December 20, 2020).

Response: Thank you for this comment. We apologize for the delay in carrying out this study. This study has not yet been carried out for the following reasons: As your comments, within the paper, we stated that we expect to submit the manuscript before December 20, 2020. However, as clinician, we have the responsibilities and obligations to fight against COVID-19. Thus, before the disease at steady state in China, we did not have sufficient time to carry out this study. In addition, we submitted a registration on PROSPERO in August. However, PROSPERO is currently prioritising submissions related to COVID-19. Although we had got a registration number, this registration record was

BMJ Open: first published as 10.1136/bmjopen-2020-043457 on 12 February 2021. Downloaded from automatically published exactly as submitted and the PROSPERO team has not yet checked our eligibility. Thus, we did not carry out this study.

Revision:

Date of this study: Our study has not been conducted. We plan to start study selection on 30th January 2021 and complete on 25th February 2021. Completion time of data extraction will be tentatively fixed by 30th March 2021. Data synthesis and analysis will be completed by 30th April 2021.The results of this study is expected to submit to peer-reviewed journal before 31th July 2021. (Page 1, Line 26-30)

Selection process: This process will be completed by 25th February 2021. (Page 6, Line 1)

#2 General comments The registration information should be updated as it appears the systematic review has been registered on PROSPERO (CRD42020201559).

Response: Thank you for this comment. We would update the according information on PROSPERO.

Response: Thank you for this comment. We considered studies examining any ketamine or http://bmjopen.bmj.com/ esketamine as a standalone treatment or in combination with psychotropic medications or psychotherapies. For data collection/extraction, we plan to extract the details of both standalone treatment and concomitant medications. For methods and analysis, we plan to perform network meta- analyses (NMAs) to estimate the relative effects and ranking of all available single drugs and combinations. And we will exclude combinations of drugs from the network meta-regression because we cannot be sure whether some combinations can affect the dose effects.

Revision: on September 24, 2021 by guest. Protected copyright.

Eligibility criteria: Interventions: We considered studies examining any ketamine or esketamine as a standalone treatment or in combination with psychotropic medications or psychotherapies. Any route of administration is acceptable. Comparators: Placebo including inactive control (e.g. saline) and active control (e.g. other antidepressants or anxiolytics). (Page 4, Line 12-16)

Data collection: details of interventions (e.g. ketamine or esketamine dose and route of administration, concomitant medications dose and route of administration), details of comparator (e.g. names of control measures, dose and route of administration) (Page 6, Line 6-9)

Network meta-analyses (NMA): we will calculate the ranking probabilities for all treatments (including all available single drugs and combinations) (Page 7, Line 28-29)

Sensitivity analyses and subgroup analyses: (5) dosing schedule. We excluded combinations of drugs from the network meta-regression because we cannot be sure whether some combinations can affect the dose effects. (Page 8, Line 25-27)

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I commend the authors for including examination of potential sex differences for these treatments.

Response:

Thank you for this comment. We have clarified the comparator as placebo including inactive control (e.g. saline) and active control (e.g. other antidepressants or anxiolytics). RCTs that compare ketamine to an active control (such as midazolam) will be included in our study.

In subgroup analyses, we already included sex ratio in network meta-regression.

Revision: Eligibility criteria: Comparators: Placebo including inactive control (e.g. saline) and active control (e.g. other antidepressants or anxiolytics). (Page 4, Line 15-16)

Specific suggested revisions follow. Introduction:

-Page 5, Line 5. Unusual to highlight cognitive deficit over all other aspects of depression and its elevated burden to the individual and society at large- recommend revising opening sentence to better define depression.

Response: Thank you for this comment. We have revised opening sentence to better define http://bmjopen.bmj.com/ depression.

Revision:

Introduction: Depression is a mood disorder which is characterized by feeling of sadness, helplessness and worthlessness, as well as psychological symptoms including lack of energy, sleep cycle disturbance and appetite changes. It is the leading cause of disability in the world, affecting nearly 300 million individuals globally. (Page 3, Line 4-7) on September 24, 2021 by guest. Protected copyright.

Reference:

1.Valentine, Barbara, Roberts, et al. American Psychological Association. College & Research Libraries News 2001; 62(2):215-215

2.Charlson F, Ommeren M van, Flaxman A, et al. New WHO prevalence estimates of mental disorders in conflict settings: a systematic review and meta-analysis. Lancet 2019; 394;240–248

3. Herrman H, Kieling C, McGorry P, et al. Reducing the global burden of depression: a Lancet–World Psychiatric Association Commission. Lancet 2019; 393:e42–e43

(Page 9, Line 31-35)

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-Page 5, Line 11. Please change “full dose and long-term treatment” to “adequate dose and sufficient duration”. Also, the reference for this sentence is incorrect; I assume the sentence references the STAR-D trial? Please revise.

Response: Thank you for this comment. We have revised this sentence.

Revision: Introduction: Although depressive symptoms may be reduced within several weeks following the initiation of conventional antidepressants, approximately one-third of patients fail to achieve meaningful recovery. (Page 3, Line 7-10)

Reference:

4. Corriger A, Pickering G. Ketamine and depression: a narrative review. Drug Des Devel Ther 2019; 13: 3051–3067 (Page 9, Line 36-37)

-Page 5, Line 15. For more clarity when first introducing ketamine please specify that you are referring to the racemic mixture or ketamine hydrochloride, a mixture of the R and S enantiomers.

Response: Thank you for this comment. We have specified that ketamine in our study referred to racemic mixture.

Revision: Introduction: Ketamine is a racemic mixture comprised of two enantiomers (R)-ketamine and (S)-ketamine and acts as an NMDA receptor antagonist (Page 3, Line 12-13).

Reference：

6.Jelen LA, Young AH, Stone JM. Ketamine: A tale of two enantiomers. J Psychopharmacol 2020; http://bmjopen.bmj.com/ 6:269881120959644 (Page 10, Line 1-2)

-Page 5, Line 21. Revise language, treatment with ketamine does not necessarily “require intravenous administration”. It is most commonly administered intravenously to treat depression but other routes of on September 24, 2021 by guest. Protected copyright. administration exist including oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous.

Response: Thank you for this comment. We have revised our language.

Revision: Introduction: However, the applicability of ketamine is limited in outpatient settings, for it may requires intravenous administration in the treatment of depression. (Page 3, Line 15-17)

-Page 5, Line 36. While true that no RCTs comparing intranasal esketamine and intravenous ketamine have been published to date, several such studies are currently ongoing- that can be mentioned here.

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Response: Thank you for this comment. We found that there is one article reporting head-to-head study of intravenous esketamine and intravenous ketamine in patients (Correia-Melo et al, J Affect Disord 2020), and we have cited this article in our revised manuscripts.

Revision: Introduction: However, only one head- to-head study assessed the efficacy and safety of ketamine compared to esketamine, the S (-)-enantiomer of ketamine. (Page 3, Line 28-30)

Reference:

23.Correia Melo FS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J Affect Disord.2020;264:527-534

#10

-Page 5, Line 38. Problem with tense, this sentence refers to having conducted the systematic review already. Protocol paper should use future tense throughout.

Response: Thank you for this comment. We have revised the tense in the sentence.

Revision: Introduction: Thus, a systematic review and meta-analysis will be performed to evaluate efficacy and side effect profile of ketamine and esketamine in the treatment of unipolar and bipolar depression. (Page 3, Line 33-35)

#11

Methods and Analysis

-Page 6, Line 9. Inclusion criteria B please clarify intravenous ketamine http://bmjopen.bmj.com/

Response: Thank you for this comment. As your previous comment in # 8, it is most commonly administered intravenously to treat depression but other routes of administration exist. We will consider any route of administration and we have revised Inclusion criteria B.

Revision: Eligibility criteria B. Interventions: We considered studies examining any ketamine or esketamine as a standalone treatment or in combination with psychotropic medications or psychotherapies. Any route of administration is acceptable. (Page 4, Line 12-14) on September 24, 2021 by guest. Protected copyright.

#12

-Page 6, Line 40-45. Inconsistent spelling of crossover (sometimes two words, sometimes hyphenated), please correct “precross-overphase”.

Response: Thank you for this comment. We have revised the incorrect spelling.

Revision: Eligibility criteria E. Study design: Cross-over and cluster randomised trials will be included, while quasi-randomised trials will be excluded. For cross-over studies, to address concerns around possible ‘carry over’ effects, we will use data from the pre-crossover phase. (Page 5, Line 4-6)

#13

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-Page 6, Line 45. Please specify how you will deal with papers that fail to report pre-crossover phase data? Will you contact study authors directly to obtain this data?

Response: Thank you for this comment. For papers that fail to report pre-crossover phase data, we will contact study authors to obtain this data.

Revision: Eligibility criteria: For studies that fail to report pre-crossover phase data, we will contact study authors to obtain this data. (Page 5, Line 7-8)

#14

-Page 7, Table 1, Section 1.2 CNKI searing strategy. Unable to review (language).

Response: Thank you for this comment. “Section 1.2 CNKI searing strategy.” was the Chinese translation of “Section 1.1 PubMed searching strategy.”

Both “#9艾氯胺酮(主题词)” and “#10艾司氯胺酮(主题词)” are refer to Esketamine.

VERSION 2 – REVIEW

REVIEWER Jennifer Phillips University of Ottawa Institute of Mental Health Research, Canada REVIEW RETURNED 26-Jan-2021

GENERAL COMMENTS The authors have address my comments.