Protocol for the systematic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age

Saraswati Dhungana; Rojal Rijal; Binit Regmi; Jala Shree Bajracharya; Subriddhi Sharma; Sunil Singh; Nilam Karn; Manisha Chapagai

doi:10.1371/journal.pone.0281366

Peer Review History

Original SubmissionOctober 8, 2021
21 Nov 2022 Decision Letter - Muhammad Shahzad Aslam, Editor PONE-D-21-32408Protocol for the systemic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of agePLOS ONE Dear, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by 21 December 2022. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Reviewer #1: Yes Reviewer #2: No ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ******** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ******** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors present a protocol for a systematic review and meta-analysis of factors associated with medication non-adherence to antidepressants in individuals with depressive disorder. They propose a clear, well presented and structured protocol. The authors propose to update this research question with recent data from the literature. To do so, they will draw on previous reviews of the literature on this topic that may be worth citing in the introduction part. The authors chose to include in their review of the literature, studies including individuals with depressive disorder but also with somatic and psychiatric comorbidities. It might be interesting to justify this choice, which is not common, given that in many studies, serious somatic comorbidities such as cancer are a reason for exclusion. This inclusion criterion could be both a strength and a limitation of this future study. Finally, the authors propose to classify the factors associated with non-adherence to antidepressants into 5 categories: 1. Patient factors, 2. Community and social factors, 3. Health facility-health provider, 4. Health system, 5. Other factors. However, it might be relevant to use the quite similar categories determined by the WHO in 2003 to list these factors, which are: patient-related factors, social-economic factors, health system factors, condition-related factors and therapy-related factors. In addition, some authors in the literature are increasingly referring to intentional and unintentional adherence to classify the factors associated with non-adherence (Wroe et al., 2002; Lehane et al., 2007). Reviewer #2: Thank you for the opportunity to review the registered report protocol “Protocol for the systemic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age” Overall I believe this protocol is lacking in detail, however is otherwise sound and could be improved if the authors consider the below queries. The PROSPERO listing needs updating – says anticipated completion 01 October 2022, and hasn’t been updated since February 2022 The largest issue however is the lack of methodological detail for the meta-analysis. As it stands, in my opinion this protocol could not be reproduced based on information provided in this manuscript. Specific queries as follows: Abstract: Please provide more detail in the methods regarding meta-analytic techniques. There is currently no method proposed Consider commenting on the impact of your review in your conclusion. Why is this important? Introduction: Consider re-wording this section to be less emotive and more specific. For example, line 49 states “enormous suffering.” This term is unclear, and the paper would be improved by being more specific in your descriptions of the impact of depression in both the introduction and discussion Line 61 – remove “to name a few” Line 64 – what do you mean by updated? I don’t think you have adequately described the background literature and previous systematic reviews, so I’m struggling to see where this sits in the context of the field. A quick search online yielded the below, which could be considered Chong WW, Aslani P, Chen TF. Effectiveness of interventions to improve antidepressant medication adherence: a systematic review. International journal of clinical practice. 2011 Sep;65(9):954-75. Solmi M, Miola A, Croatto G, Pigato G, Favaro A, Fornaro M, Berk M, Smith L, Quevedo J, Maes M, Correll CU. How can we improve antidepressant adherence in the management of depression? A targeted review and 10 clinical recommendations. Brazilian Journal of Psychiatry. 2020 Jun 1;43:189-202. Ho SC, Chong HY, Chaiyakunapruk N, Tangiisuran B, Jacob SA. Clinical and economic impact of non-adherence to antidepressants in major depressive disorder: a systematic review. Journal of affective disorders. 2016 Mar 15;193:1-0. Lingam R, Scott J. Treatment non‐adherence in affective disorders. Acta Psychiatrica Scandinavica. 2002 Mar;105(3):164-72. Semahegn A, Torpey K, Manu A, Assefa N, Tesfaye G, Ankomah A. Psychotropic medication non-adherence and its associated factors among patients with major psychiatric disorders: a systematic review and meta-analysis. Systematic reviews. 2020 Dec;9(1):1-8. Line 64-65 – remove “this very important topic relating to” Line 67-69 – Why isn’t meta-analysis mentioned in your statement of aims? Materials and methods Line 83 - typo "metanalyses" please amend Line 88 – why is this restricted to July 2021? Studies are already 16 months out of date Line 133-138 – can be removed, that information was stated above Line 214-215 – the protocol should pre-dictate the analysis plan regardless of the data to remove bias in the reporting. Why is meta analysis dependent on prior review of the results? Further, what does “This will be checked upon by SS and NK” mean? More information about the meta-analysis is required. What kind of effects models will be used? How is significant and substantial heterogeneity defined? How will you estimate variance? What sub group analyses are planned (these should be pre-planned to avoid bias)? Conclusions Line 232-234 – Please be more specific in the impacts of medication adherence (i.e. remove terms like enormous suffering and add specific sequalae) and reference these statements ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0281366.r001
Revision 1
4 Dec 2022 Author Response December 4, 2022 Dear Editors and reviewers PLOS ONE We thank you for your sincere and thorough review of our systematic review protocol “Protocol for the systematic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age” manuscript number PONE-D-21-32408 and providing us the opportunity to revise it. We now better understand the critical issues with the paper after the comments made by both the reviewers. We have reviewed the protocol incorporating all the comments made by the reviewers as sincerely as possible. We have attempted to respond to each query to the best of our knowledge. We have revised our introduction, methods and conclusion section and in doing so, we have added 11 references. We now believe that the quality of the manuscript has greatly improved. Please find our point by point responses to the comments made by the reviewers as follows, where we have highlighted the comments in blue for easy readability with lines in the tracked original version where changes have been made. We have also submitted the original manuscript with track changes, revised manuscript along with the Response to the reviewers. If there are further queries and comments from you and the reviewers, we would be happy to address them. Responses to reviewers. Reviewer #1: The authors present a protocol for a systematic review and meta-analysis of factors associated with medication non-adherence to antidepressants in individuals with depressive disorder. They propose a clear, well presented and structured protocol. Authors’ response: Thank you for the positive comment. The authors propose to update this research question with recent data from the literature. To do so, they will draw on previous reviews of the literature on this topic that may be worth citing in the introduction part. Authors’ response: Thank you for pointing out this important gap in our manuscript, also raised by the second reviewer. We now have cited important articles to support our research question as follows: Lines 76-92: “Despite being a huge problem, only scant comprehensive literature is available on non- adherence to antidepressants and factors related. A review and meta-analysis on non-adherence to psychotropics concluded that patients’ attitude towards their drugs, insight level, attitude to health and stigma mainly contributed towards nonadherence. Additionally, substance use behavior, sociodemographic variables such as age, gender, education and employment, social factors such as social support and family dynamics, clinical factors such as comorbidities and polypharmacy played roles in non-adherence to psychotropics (10). We believe that nonadherence to antidepressants is also multifactorial (12) and similar factors account for it as supported by a recent systematic review by Solmi et al. (2,13). These factors have been categorized as patient- related and prescriber related (13). A review by Chong and colleagues on interventions aimed at improving adherence to antidepressants reported that multifaceted interventions involving both service user and provider with behavioral component were effective (1), which was supported by another targeted review (13). However, a meta-analysis published recently concluded that the interventions are effective only in the first six months (14).” The authors chose to include in their review of the literature, studies including individuals with depressive disorder but also with somatic and psychiatric comorbidities. It might be interesting to justify this choice, which is not common, given that in many studies, serious somatic comorbidities such as cancer are a reason for exclusion. This inclusion criterion could be both a strength and a limitation of this future study. Authors’ response: Thank you for the remark. We agree that inclusion of somatic and psychiatric comorbidities is not common in such studies. However, we feel that comorbidities are quite common in depression and by doing a thorough review of articles with comorbidities, we want to investigate the non-adherence pattern in both the groups, with and without comorbidities and if the factors affecting non- adherence are similar or different. We therefore think that this will be a strength to our study and gives direction to interventions to be tailored accordingly. Finally, the authors propose to classify the factors associated with non-adherence to antidepressants into 5 categories: 1. Patient factors, 2. Community and social factors, 3. Health facility-health provider, 4. Health system, 5. Other factors. However, it might be relevant to use the quite similar categories determined by the WHO in 2003 to list these factors, which are: patient-related factors, social-economic factors, health system factors, condition-related factors and therapy-related factors. In addition, some authors in the literature are increasingly referring to intentional and unintentional adherence to classify the factors associated with non-adherence (Wroe et al., 2002; Lehane et al., 2007). Authors’ response: Thank you for the comment. We agree that factors determined by WHO in 2003 are similar and more comprehensive compared to our categorization. We therefore plan to categorize the factors accordingly and have changed our categorization of factors to those listed by WHO as follows under section of data synthesis strategy and sub-group analysis. Lines 202-203 and 245-247 “1. patient- related factors, 2. social- economic factors, 3. health system factors, 4. condition- related factors and 5. therapy- related factors.” However, for the purpose of this manuscript, we are not considering including the classification of factors as intentional and non- intentional. However, we thank you for letting us know about this categorization in the literature. Reviewer #2: Thank you for the opportunity to review the registered report protocol “Protocol for the systemic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age” Overall I believe this protocol is lacking in detail, however is otherwise sound and could be improved if the authors consider the below queries. The PROSPERO listing needs updating – says anticipated completion 01 October 2022, and hasn’t been updated since February 2022 The largest issue however is the lack of methodological detail for the meta-analysis. As it stands, in my opinion this protocol could not be reproduced based on information provided in this manuscript. Authors’ response: Thank you for thorough scrutiny and constructive comments on our manuscript for systematic review protocol. We agree the protocol lacks detail, especially in regard to meta- analytic techniques in methodology. We, therefore, have revised our protocol providing details in the methods section for metanalytic techniques we plan to conduct. Thank you for pointing out the PROSPERO issue. We now have updated the protocol in the PROSPERO and have changed the completion date to October 2023 since we are currently in data extraction phase. Specific queries as follows: Abstract: Please provide more detail in the methods regarding meta-analytic techniques. There is currently no method proposed Consider commenting on the impact of your review in your conclusion. Why is this important? Authors’ response: Thank you for the comment. We now have provided more detail in the methods as Lines 42-44 “Finally, we will conduct meta-analysis for factors associated with non-adherence and illustrate the results with a forest plot using Stata or Revman”. We also added in lines 48-50 “The evidence generated would assist in designing interventions to address non-adherence in this group of patients leading to better productivity and quality of life.” to our conclusion as you suggested. Introduction: Consider re-wording this section to be less emotive and more specific. For example, line 49 states “enormous suffering.” This term is unclear, and the paper would be improved by being more specific in your descriptions of the impact of depression in both the introduction and discussion. Authors’ response: Thank you for this important comment. We have revised the statement and made it more specific both in introduction and discussion. In introduction, we added the following. Lines 52-58: “estimated to be one of the three leading causes, alongside HIV-AIDS and Ischemic heart disease by 2030 (1,2). It causes huge suffering in terms of economy and productivity (1,2). It is a chronic condition with high relapse and recurrent rates and increased hospitalization, leading to reduced functioning and poor quality of life and increased healthcare costs (1-4). Besides clinical and productivity issues, depression is associated with severe direct and indirect costs (1, 4-6).” Lines 69-92: “with estimates ranging between 13 – 55.7% (9) to as high as 50 to 60% (10). Non- adherence to antidepressants further exacerbates this problem, with resultant increased relapse rates, hospitalization and poor quality of life (2). Literature suggests a number of reasons for non-adherence, including adverse effects of drugs, nil or minimal response and other patient or doctor related factors (8,11). In discussion, we added the following. Lines 285-288: “The consequences are increased healthcare costs due to high rates of hospitalization and emergency visits, chronicity and residual symptoms, reduced functioning, disability and poor quality of life (2-5).” Line 61 – remove “to name a few” Authors’ response: We have removed it. Line 64 – what do you mean by updated? I don’t think you have adequately described the background literature and previous systematic reviews, so I’m struggling to see where this sits in the context of the field. A quick search online yielded the below, which could be considered. Chong WW, Aslani P, Chen TF. Effectiveness of interventions to improve antidepressant medication adherence: a systematic review. International journal of clinical practice. 2011 Sep;65(9):954-75. Solmi M, Miola A, Croatto G, Pigato G, Favaro A, Fornaro M, Berk M, Smith L, Quevedo J, Maes M, Correll CU. How can we improve antidepressant adherence in the management of depression? A targeted review and 10 clinical recommendations. Brazilian Journal of Psychiatry. 2020 Jun 1;43:189-202. Ho SC, Chong HY, Chaiyakunapruk N, Tangiisuran B, Jacob SA. Clinical and economic impact of non-adherence to antidepressants in major depressive disorder: a systematic review. Journal of affective disorders. 2016 Mar 15;193:1-0. Lingam R, Scott J. Treatment non‐adherence in affective disorders. Acta Psychiatrica Scandinavica. 2002 Mar;105(3):164-72. Semahegn A, Torpey K, Manu A, Assefa N, Tesfaye G, Ankomah A. Psychotropic medication non-adherence and its associated factors among patients with major psychiatric disorders: a systematic review and meta-analysis. Systematic reviews. 2020 Dec;9(1):1-8. Authors’ response: Thank you for pointing out this discrepancy and listing out the relevant reviews. We now have included all the articles in the introduction section to give a background on the non- adherence and factors associated relevant to the topic and why this review is needed as follows. Lines 76-92: “Despite being a huge problem, only scant comprehensive literature is available on non- adherence to antidepressants and factors related. A review and meta-analysis on non-adherence to psychotropics concluded that patients’ attitude towards their drugs, insight level, attitude to health and stigma mainly contributed towards nonadherence. Additionally, substance use behavior, sociodemographic variables such as age, gender, education and employment, social factors such as social support and family dynamics, clinical factors such as comorbidities and polypharmacy played roles in non-adherence to psychotropics (10). We believe that nonadherence to antidepressants is also multifactorial (12) and similar factors account for it as supported by a recent systematic review by Solmi et al. (2,13). These factors have been categorized as patient- related and prescriber related (13). A review by Chong and colleagues on interventions aimed at improving adherence to antidepressants reported that multifaceted interventions involving both service user and provider with behavioral component were effective (1), which was supported by another targeted review (13). However, a meta-analysis published recently concluded that the interventions are effective only in the first six months (14).” Lines 95-97: “the only comprehensive literature on factors related to nonadherence to antidepressants in depressive disorders in form of review was published in 2015 (12) and has not been updated to this date.” Line 64-65 – remove “this very important topic relating to” Authors’ response: We removed this. Line 67-69 – Why isn’t meta-analysis mentioned in your statement of aims? Authors’ response: We revised our aims. Thank you for the comment. Materials and methods Line 83 - typo "metanalyses" please amend Authors’ response: We revised it. Line 88 – why is this restricted to July 2021? Studies are already 16 months out of date Authors’ response: Initially we planned to complete the study by October 2022, and this was submitted quite some time back, hence the discrepancy in the date. Now, we plan to include articles till October 2022, which we also revised in our manuscript protocol and complete the study by October 2023. We also changed the expected date of completion in the PROSPERO list registered. Line 133-138 – can be removed, that information was stated above Authors’ response: We removed line 133-138. Line 214-215 – the protocol should pre-dictate the analysis plan regardless of the data to remove bias in the reporting. Why is meta-analysis dependent on prior review of the results? Further, what does “This will be checked upon by SS and NK” mean? More information about the meta-analysis is required. What kind of effects models will be used? How is significant and substantial heterogeneity defined? How will you estimate variance? What sub group analyses are planned (these should be pre-planned to avoid bias)? Authors’ response: Thank you very much for pointing out this flaw in our protocol. We agree the analysis plan should be well explained in the protocol prior to starting the study to minimize bias in reporting. We now have explained what we intend to do in our meta- analysis. Initially, we thought that review should be completed before planning to de meta- analysis and based on what our findings look like, we will plan to use meta- analytic techniques as appropriate. “This will be checked upon by SS and NK”. By this statement, we meant that after our findings of systematic review, the findings will be independently checked upon by two authors, namely SS and NK to examine if the findings justify the use of meta-analytic techniques. However, now that we agree that these techniques require prior writing, we removed this statement. We have provided details regarding meta-analytic techniques we intend to use in this review as follows. Lines 252-267: “Our main outcome of interest is nonadherence to antidepressants. Non-adherence to antidepressants has the potential to be labelled as dichotomous as subjective responses (Yes/ No), or continuous (in terms of scores in use of scales). For studies with dichotomous outcomes, we plan to report odd ratios or risk ratios, while for those with continuous outcomes, such as mean scores on adherence, we will report means for individual studies first, followed by reporting a combined effect estimate. If we find sufficient studies allowing meta-analysis, we will illustrate with a forest plot to provide an overall summary of effect estimates using odd ratios and mean / standardized mean differences with confidence intervals for individual studies and overall. We assume that the studies included will be heterogenous, therefore, we plan to apply random effect model. We will measure the extent of heterogeneity across the studies included using I2 (Inconsistency index) (24). I2 50%-90% will be considered to have substantial heterogeneity while 75% to 100% will be considered to have considerable heterogeneity. Variance within studies will be estimated by inverse variance weighting using residual maximum likelihood (REML) technique (25).” Lines 274-279: “We consider doing analysis of subgroups if there are good number of studies to allow subgroup analysis for example, if adequate number of studies are available in terms of specific antidepressants used to see which group of antidepressants are associated with more nonadherence to antidepressants. We also plan to do subgroup analysis based on age groups like 18 to 45, 45 to 60 and 60 and above if this is applicable.” Conclusions Line 232-234 – Please be more specific in the impacts of medication adherence (i.e. remove terms like enormous suffering and add specific sequalae) and reference these statements. Authors’ response: Thank you again for the comment. We have revised the conclusions in more specific terms as follows and referenced them. Lines 285-288 “The consequences are increased healthcare costs due to high rates of hospitalization and emergency visits, chronicity and residual symptoms, reduced functioning, disability and poor quality of life (2-5).” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0281366.r002
17 Jan 2023 Decision Letter - Muhammad Shahzad Aslam, Editor PONE-D-21-32408R1Protocol for the systemic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of agePLOS ONE Dear Dr. Dhungana, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Mar 03 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ******** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ******** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: Thank you for addressing the comments and suggestions provided by the reviewers. The responses are comprehensive and adequately address the reviewer recommendations. I have some further very minor suggestions (line numbers refer to the tracked version of the manuscript) Abstract Line 43-44: please consider removing “and illustrate the results with a forest plot using Stata or Revman” as I do not think it’s necessary in the abstract. For your consideration Methods Line 255: Will you be using odds or risk ratios? It doesn’t matter which, but I feel that it should be decided a priori to avoid any potential bias in the analysis Line 260: Will you be using mean differences or standardized mean differences? Again at your preference (but I would think standardized more appropriate) but should be decided a priori ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0281366.r003
Revision 2
18 Jan 2023 Author Response 18 January 2023 Response to reviewer Reviewer #2: Thank you for addressing the comments and suggestions provided by the reviewers. The responses are comprehensive and adequately address the reviewer recommendations. I have some further very minor suggestions (line numbers refer to the tracked version of the manuscript) Abstract Line 43-44: please consider removing “and illustrate the results with a forest plot using Stata or Revman” as I do not think it’s necessary in the abstract. For your consideration Authors’ response: Thank you for the comment. We agree with it and have removed “and illustrate the results with a forest plot using Stata or Revman” from the abstract section in lines 43-44 in tracked version. Line 255: Will you be using odds or risk ratios? It doesn’t matter which, but I feel that it should be decided a priori to avoid any potential bias in the analysis Line 260: Will you be using mean differences or standardized mean differences? Again at your preference (but I would think standardized more appropriate) but should be decided a priori. Authors’ response: Thank you for this important observation. We agree it should be decided a priori to avoid potential bias in the analysis. We therefore have decided to use odd ratios and standardized mean differences for our statistical analysis purpose. Accordingly, we removed risk ratios and mean differences in lines 254 and 259 respectively in the new tracked version. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0281366.r004
23 Jan 2023 Decision Letter - Muhammad Shahzad Aslam, Editor Protocol for the systemic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age PONE-D-21-32408R2 Dear, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ******** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ******** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: Thank you for your careful revisions of this manuscript. I have no further recommendations, however there is two small typos which should be addressed prior to publication Line 254 and 258 (tracked document): Both refer to "odd ratios" - this should be amended to "odds" ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0281366.r005
Formally Accepted
26 Jan 2023 Acceptance Letter - Muhammad Shahzad Aslam, Editor PONE-D-21-32408R2 Protocol for the systematic review and meta-analysis of factors associated with non-adherence to antidepressants in depressive disorders in those more than 18 years of age Dear Dr. Dhungana: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Muhammad Shahzad Aslam Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281366.r006

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