Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review

Colm O'Riain; Sean Crowley; Siofra McDonagh; Nuala Murray; Alkhalaf Sukainah; Gerard Clarke; Ali S Khasan; Karen O'Connor

doi:10.12688/hrbopenres.13887.2

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Study Protocol

Revised

Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review

[version 2; peer review: 3 approved with reservations]

Colm O'Riain¹, Sean Crowley², Siofra McDonagh³, [...] Nuala Murray², Alkhalaf Sukainah⁴, Gerard Clarke^2,5, Ali S Khasan⁴, Karen O'Connor^2,6

Colm O'Riain¹, Sean Crowley², [...] Siofra McDonagh³, Nuala Murray², Alkhalaf Sukainah⁴, Gerard Clarke^2,5, Ali S Khasan⁴, Karen O'Connor^2,6

PUBLISHED 23 Jan 2025

Author details Author details

¹ Department of Psychiatry, Cork North Lee Mental Health Services, Cork, County Cork, Ireland
² Department of Psychiatry and Neurobehavioural science, University College Cork, Cork, County Cork, Ireland
³ Department of Psychiatry, School of Medicine, The University of Dublin Trinity College, Dublin, Leinster, Ireland
⁴ School of Public Health, University College Cork, Cork, County Cork, Ireland
⁵ APC Microbiome Ireland, University College Cork, Cork, County Cork, Ireland
⁶ RISE Early Intervention in Psychosis Service, South Lee Mental Health Services, Cork, Ireland

Colm O'Riain
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Sean Crowley
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Siofra McDonagh
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Nuala Murray
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology

Alkhalaf Sukainah
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Resources, Software

Gerard Clarke
Roles: Conceptualization, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Ali S Khasan
Roles: Conceptualization, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Karen O'Connor
Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Psychotic disorders are mental illnesses whose treatment often includes antipsychotic medication, a treatment option associated with metabolic side effects including weight gain. However, the influence of sex on antipsychotic-associated weight gain remains inadequately explored. We aim to synthesise the evidence on the sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment.

Methods

We will include cohort, cross-sectional, and case-control studies, randomized, and non-randomized controlled trials, which examine the association between a treated psychotic disorder and weight gain in male and female patients. PubMed, EMBASE, and PsycINFO databases will be systematically searched in accordance with a detailed search strategy. Other inclusion criteria are; only articles which mention gender or sex in the title or abstract, only data from original studies, studies where diagnosis of a psychotic disorder must be made by a medical practitioner using diagnostic guidelines, studies published in English only, and only peer-reviewed literature. Two review authors will independently review the titles and abstracts of all studies and perform data extraction and quality assessment using standardized tools. We will perform meta-analyses to estimate the overall pooled associations using the generic inverse variance method. We will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Ethics and Dissemination

This systematic review and meta-analysis, relying solely on already published data, does not necessitate ethics approval. The results will be shared at scientific gatherings and disseminated via publication in a peer-reviewed journal.

Registration

CRD42023495785

Keywords

Sex, gender, schizophrenia, treatment, tolerability, weight gain, metabolic disorder

Corresponding authors: Colm O'Riain, Sean Crowley

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2025 O'Riain C et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: O'Riain C, Crowley S, McDonagh S et al. Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review [version 2; peer review: 3 approved with reservations]. HRB Open Res 2025, 7:37 (https://doi.org/10.12688/hrbopenres.13887.2) First published: 21 Jun 2024, 7:37 (https://doi.org/10.12688/hrbopenres.13887.1) Latest published: 23 Jan 2025, 7:37 (https://doi.org/10.12688/hrbopenres.13887.2)

Revised Amendments from Version 1

In this new version of our article, we have made a number of small changes. These were mainly in response to constructive suggestions from peer review of our first version. We added additional commentary to address the possibility of meta-analysis and our expectations in finding a large degree of heterogeneity in how data is presented. While we are aiming to conduct meta-analysis wherever possible, we expect Synthesis without Meta-Analysis (SWiM) will be required to include many relevant papers which do not present their data in a way that is appropriate for meta-analysis. Given the helpful comment regarding women undergoing many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, and the recommendation of potentially including a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women, we have incorporated this a secondary outcome in our study. Also in response to peer review highlighting drug-specific meta-analysis only being a secondary outcome and its importance relevance in clinical practice, we have revised its importance in our study and moved it into the category of a primary outcome in our revised manuscript.

See the authors' detailed response to the review by Bodyl Brand

Introduction

Psychosis is a condition that affects the way the brain processes information. Psychosis is associated with an array of mental health conditions including schizophrenia, bipolar disorder, delusional disorder and severe depression. Schizophrenia is an enduring mental illness that affects up to 1% of the global population¹. It has been estimated that in 2016, it affected over 20.9 million people, and contributed 13.4 million years lived with disability (YLD) to the burden of disease globally, equivalent to 1.7% of total YLDs globally². Since the 1950’s antipsychotic medication has been the mainstay of treatment for schizophrenia and other psychotic disorders³. In their recent large network analysis, Huhn et al. compared the efficacy and tolerability of 32 oral antipsychotic drugs for multi-episode schizophrenia⁴. This study found that all antipsychotics evaluated affected overall symptoms⁴. Differences in efficacy were gradual, while the experience of side effect profile and tolerability were more marked between different antipsychotics⁴. The authors suggested the need for a greater focus on tolerability and patient preferences when selecting antipsychotic medication⁴. Other reviews, such as Stahl et al.’s, suggest that when choosing antipsychotic special consideration must be given to the adverse effects, and these can often be the deciding factor in a patient's medication compliance⁵.

Weight gain is a common side effect of many antipsychotic medications, and can lead to clinical obesity, increased cardiovascular morbidity and mortality, reduced quality of life, and poor medication compliance⁶. Olanzapine and clozapine are regarded as having the highest risk of weight gain, followed by risperidone, paliperidone, and quetiapine with moderate risk, and aripiprazole and ziprasidone are commonly regarded as having the lowest risk⁷.

Waite et al.’s qualitative study on the psychological journey of weight gain in psychosis highlights the impact of sudden antipsychotic-associated weight gain on both physical and mental well-being⁸. The study notes that patients often feel that their sudden weight gain is overshadowed by psychotic symptoms, so there is a shock realization of weight gained after symptomatic recovery. This is often characterized by a loss of self-confidence, agency, and hope⁸. Other qualitative studies have found that women find this weight gain particularly distressing when compared to men, and suggest a need for gender-specific interventions⁹. Seeman’s review substantiated this finding that some antipsychotic medication side effects, particularly weight gain, are more worrisome for women¹⁰. This review suggested that there are theoretical reasons why antipsychotic medication doses for women should be lower than guidelines recommend for men, particularly regarding clozapine and olanzapine¹⁰.

Brand et al., in their recent review, summarized the significant pharmacodynamic and pharmacokinetic differences which affect women on antipsychotics¹¹. It notes that women reach higher dopamine receptor occupancy at similar serum levels, as compared with men, since oestrogens increase dopamine sensitivity¹¹. Furthermore, it states that current treatment guidelines are based on studies predominantly conducted in men, and thus women are likely to be overmedicated¹¹. The review specifically raises the concern that women are at an increased risk of weight gain and metabolic symptoms due to this, leading to calls for female-specific antipsychotic prescribing guidelines¹¹.

Kroeze et al., in their paper, look at other receptors such as Histamine H1 and serotonin 5-HT2C and their role in antipsychotic weight gain. A major finding in their paper is that there is a large correlation between H1-Histamine receptor affinity and short-term weight gain, and that antipsychotic drugs with high H1-histamine receptor affinities are associated with significant weight gain¹²

While there have been several narrative reviews comparing the efficacy and tolerability of antipsychotics between men and women, to date there has been no systematic review comparing antipsychotic-related weight gain between men and women with psychotic disorders. Given that this symptom has been highlighted as distressing, as well as key to a person’s ongoing medication compliance and physical health, we believe that it warrants a systematic review. The antipsychotics included in this review are based on the guidelines in the Maudsley Prescribing Guidelines 14^th Edition¹³.

Aim

This systematic review and meta-analysis will aim to synthesize the available evidence, to evaluate how sex affects antipsychotic-related weight gain in patients being treated for psychotic disorders. It will focus on weight gain due to seventeen antipsychotics: haloperidol, olanzapine, quetiapine, risperidone, paliperidone, aripiprazole, clozapine, amisulpride, brexpiprazole, cariprazine, ziprasidone, lurasidone, asenapine, iloperidone, blonanserin, lumateperone, pimavanserin.

Objectives

Primary

Using available evidence, to evaluate whether patient’s sex affects antipsychotic-related weight gain for patients being treated for psychotic disorders. Where possible we will conduct meta-analysis.

If available evidence allows, to evaluate how sex affects antipsychotic-related weight gain in patients being treated for psychotic disorders, with each of 17 antipsychotic medications: a) haloperidol b) olanzapine, c) quetiapine, d) risperidone, e) paliperidone, f) aripiprazole, g) clozapine, and h) amisulpride i) brexpiprazole, j) cariprazine, k) ziprasidone, l) lurasidone, m) asenapine, n) iloperidone, o) blonanserin, p) lumateperone, and q) pimavanserin.

Secondary

If there is sufficient data, we will perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women.

Review question

Does sex affect antipsychotic-associated weight gain in patients being treated for psychotic disorders?

Methods

This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines. It will include randomized and non-randomized control trials, retrospective and prospective cohort studies, cross-sectional studies, and case-control studies. Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. The systematic review will be based on the following PICO criteria when selecting eligible studies:

Population: Male and female patients who are receiving antipsychotic medication.

Intervention: There is no intervention.

Comparison: The exposure is male or female. If male is chosen as the exposure, then female is the comparison, and if female is the exposure, then male is the comparison.

Outcomes: Antipsychotic-associated weight gain

Criteria for considering studies for the review

Inclusion criteria

➣ We will include cohort, cross-sectional, and case-control studies, randomized, and non-randomized controlled trials that noted sex differences in antipsychotic-associated weight gain of patients with psychotic disorders.
➣ Only articles which mention gender or sex in the title or abstract will be included in the review.
➣ Data must be from an original study.
➣ Diagnosis of a psychotic disorder must be made by a medical practitioner, using ICD or DSM guidelines. We expect that some of the large studies would identify cases based on one of the listed diagnostic guidelines or prescribed treatment.
➣ We will include studies published in English only, including all years from the inception of the electronic databases until Oct 2023. This would include studies not in English, but that do have English abstracts, which we would then translate if the abstract suggests it would be an eligible study.
➣ Peer-reviewed literature only will be included.

Exclusion criteria

➣ Review articles, case reports, case series, letters, commentaries, notes, editorials, grey literature and conference abstracts, and dissertations will be excluded. However, the references of previous review articles on related topics will be screened for relevant papers. We expect there will be sufficient amounts of peer-reviewed data to address our research question.
➣ Studies which did not specifically evaluate differences in antipsychotic associated weight gain due to sex, i.e. where gender or sex differences were not mentioned in the title, abstract, was not a primary outcome, or was not reported in the results.
➣ Studies focusing on transgender or intergender populations. There are patients with psychotic disorders who identify as trans, or intergender. Barr et al.’s recent review reminds us that there are indeed higher rates of psychotic disorders in these populations compared to cisgender populations and that psychotic disorders are understudied in these groups¹⁴. However, due to the limited literature on this topic and its complexity, this population falls outside the scope of this review¹⁵.
➣ Studies including patients without psychotic disorders, or where psychosis was self-reported.
➣ Studies that are not published in English.
➣ Animal studies.

Search strategy for identifying relevant studies

Bibliographic database searches

Two of reviewers (SC, or SMcD) will search the following electronic databases: PubMed, EMBASE, and PsycINFO. A detailed search strategy has been compiled and these terms will be searched according to the principles of Boolean Logic (AND, OR, NOT) and using Medical Subject Headings (MeSH). For example, (“Psychosis” OR “Schizophrenia” OR “Schizophrenia spectrum disorder”) AND (“weight gain”) AND (“Antipsychotics”). The full search strategy is outlined in Appendix 1. Searches of the electronic databases will be supplemented by hand-searching the reference lists of included studies for further potentially eligible studies. While review articles will not be included, the references of review articles on related topics will be screened for eligibility for inclusion. All papers yielded from the search will be managed together in the Mendeley reference manager to avoid duplication.

Selection of studies for inclusion in the review

Two review authors (of CO’R, SC, SMcD, or NM) will independently review the titles and abstracts of the studies. Full texts will be obtained where necessary to screen for eligibility in the systematic review and meta-analysis following the pre-defined inclusion/exclusion criteria. Where consensus on eligibility cannot be achieved, a fifth review author (KO’C) will be involved in the discussion.

Where a study is eligible for inclusion in the systematic review but does not provide adequate data to include in a meta-analysis, we will contact the corresponding authors in an attempt to obtain raw data where appropriate. If we do not get a response, we will try to contact the primary corresponding author again, or the senior author. If raw data cannot be obtained, the findings will be included individually in a separate table.

Data extraction and management

Using a standardized data collection form, two reviewers (of CO’R, SC, SMcD, or NM) will independently extract data from the eligible studies including the author and year of publication, country of origin, study design, the definition of exposure (antipsychotic used, dose) and outcome used (weight gain), the methods by which these outcomes were measured (change in weight in Kilograms, change in Body mass index, categorically coded clinically significant weight gain), length of follow-up, sample size, confounders if any, and crude and adjusted estimates for the same. Discrepancies will be discussed between the two reviewers involved, to attempt to reach a consensus. If consensus cannot be reached, there will be recourse to an additional reviewer (KO’C) as necessary.

Appraisal of the quality of included studies

Quality assessment of the included studies will be conducted by two reviewers (of CO’R, SC, SMcD, or NM) independently and agreed upon subsequently using an appropriate quality assessment tool depending on the study design. Discrepancies will be resolved by an additional reviewer (KO’C) if necessary. The Newcastle-Ottowa Scale (NOS) will be used for the quality assessment of observational studies¹⁶. In this scale there are 8 items within 3 domains and the total maximum score is 9. A study with score from 7–9 has high quality, 4–6 has high risk of bias, and 0–3 has very high risk of bias. The Cochrane risk of Bias tool will be used to quantify and classify bias in RCTs¹⁷. This scale assesses bias as a judgment (high, low, or unclear) for individual elements across five domains; selection, performance, attrition, reporting, and other. Assessment of quality of included studies will be included in results table.

Data synthesis including assessment of heterogeneity

Where the data allows, random effects meta-analyses will be performed to calculate overall pooled estimates. Data which is presented in categorical variables in the original studies, we will analyse using relative risk estimates. Studies with continuous data will be analysed using standardised weight gain mean difference. Both crude and adjusted results will be displayed using the generic inverse variance method. We will consider the estimate to be adjusted if the estimate is reported as adjusted regardless of the number of potential confounders adjusted for. Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses.

We will also perform the following subgroup/sensitivity analyses where the data allow, using RevMan 5.4:

1) According to study design (cohort vs case-control vs RCT).
2) According to the study quality (minimal/low versus moderate/high).
3) According to the length of follow-up. Short follow-up would be considered up to 12 weeks and long term follow-up would be considered longer than this.

Publication bias will be assessed using a funnel plot when we have at least 10 studies in the meta-analysis. Where any other subgroup/sensitivity analyses are identified in the process of the meta-analysis, such as analyses to explore potential high heterogeneity, these will be clearly labelled as post-hoc analyses. In terms of our secondary outcomes, where possible a meta-analysis will be conducted for each of the drugs being evaluated. If possible, a network analysis may also be carried out.

Presenting and reporting the results

A flow diagram will be included to outline the step-by-step study selection process, and a rationale provided for excluded studies. The characteristics and quality assessment of the included studies will be presented in tables. Funnel plots will be used to assess publication bias; these may be included in the paper or appendices. Pooled estimates will be presented using forest plots.

Strengths and limitations of this study

The proposed systematic review and meta-analysis included at least two reviewers in each stage which will minimize the likelihood of reviewer-based bias in the systematic review. It is anticipated that publication bias may be a limitation in this review. Studies that show an effect have an increased likelihood of being published, as well as being published in English. Due to limited resources, the systematic review search will be confined to studies published in the English language only, potentially resulting in bias as well as relevant indexed studies being overlooked. Furthermore, as discussed above in inclusion criteria, only studies which mention gender or sex in the title or abstract will be included in the review. A hand search of references of other systematic reviews in the field will be conducted to minimise this risk.

A funnel plot will be used to assess the presence of publication bias. Furthermore, the presence of confounding is a major concern in observational studies. Potential confounders may include socio-economic status, employment, age, co-morbid mental and physical health diagnoses, use of drugs or alcohol, and the differences in service provision between regions and countries. The quality of how included studies manage these confounding factors will be considered in quality assessment and data extraction. As mentioned above, our meta-analyses will display both crude and adjusted results where possible using the generic inverse variance method, basing adjustment on the definition outlined in each identified study.

Ethics and dissemination

Given that this is a protocol for a systematic review, based on published data, and will not include any human or animal participants, there is no requirement for ethics approval. It is anticipated that findings will be disseminated through publication in a peer-reviewed journal.

Discussion

Weight gain is a long established common side-effect experienced by many individuals who are being treated with antipsychotic medication^6,7,18. It can result in both physical health and mental health comorbidity^8,19. This systematic review aims to address the gap in understanding about the sex-specific impact of antipsychotic-related weight gain in patients with psychotic disorders. Several different theories, including differences in pharmacodynamics and pharmacokinetics between males and females, and the impact of different neurotransmitter pathways such as histaminergic, serotonergic, and dopaminergic signalling have also been explored^11,12,20.

By synthesizing available evidence, this review will aim to provide insights into the relationship between sex and weight gain associated with different antipsychotic medications. The findings will be a resource for clinical decision-making and contribute to the development of sex-specific prescribing guidelines for antipsychotics.

Dissemination of results is planned through publication in peer-reviewed journals. This systematic review protocol offers a structured approach to comprehensively investigate a clinically relevant aspect of antipsychotic treatment, thereby enhancing our understanding of sex-specific considerations in managing psychotic disorders.

Study status

Preliminary searches and piloting of the study selection process have been commenced and formal screening of search results against eligibility criteria will be commenced shortly.

Ethics and consent

Data availability

Underlying data

No data are associated with this article.

Extended data

Figshare: Prisma-P Checklist for "Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic disorders; A Protocol for a Systematic Review", https://www.doi.org/10.6084/m9.figshare.25308721²¹.

Figshare: Search Strategy for "Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic disorders; A Protocol for a Systematic Review", https://www.doi.org/10.6084/m9.figshare.25970134²².

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Faculty Opinions recommended

References

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2. Charlson FJ, Ferrari AJ, Santomauro DF, et al.: Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull. 2018; 44(6): 1195–203. PubMed Abstract | Publisher Full Text | Free Full Text
3. Shen WW: A history of antipsychotic drug development. Compr Psychiatry. 1999; 40(6): 407–14. PubMed Abstract | Publisher Full Text
4. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al.: Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019; 394(10202): 939–51. PubMed Abstract | Publisher Full Text | Free Full Text
5. Stahl SM, Sy S, Maguire GA: How and when to treat the most common adverse effects of antipsychotics: expert review from research to clinical practice. Acta Psychiatr Scand. 2021; 143(2): 172–80. PubMed Abstract | Publisher Full Text
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7. Musil R, Obermeier M, Russ P, et al.: Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf. 2015; 14(1): 73–96. PubMed Abstract | Publisher Full Text
8. Waite F, Langman A, Mulhall S, et al.: The psychological journey of weight gain in psychosis. Psychol Psychother. 2022; 95(2): 525–40. PubMed Abstract | Publisher Full Text | Free Full Text
9. Kreyenbuhl J, Lucksted A, Despeaux K, et al.: Understanding women veterans’ experiences with and management of weight gain from medications for serious mental illness: a qualitative study. Psychiatr Rehabil J. 2019; 42(3): 238–245. PubMed Abstract | Publisher Full Text
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12. Kroeze WK, Hufeisen SJ, Popadak BA, et al.: H1-Histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacol. 2003; 28(3): 519–526. PubMed Abstract | Publisher Full Text
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15. Barr SM, Roberts D, Thakkar KN: Psychosis in transgender and gender non-conforming individuals: a review of the literature and a call for more research. Psychiatry Res. 2021; 306: 114272. PubMed Abstract | Publisher Full Text
16. Wells GA, Shea B, O’Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
17. Higgins JPT, Savović J, Page MJ, et al.: Assessing risk of bias in a randomized trial. Cochrane Handbook for Systematic Reviews of Interventions. 2019; 205–28. Publisher Full Text
18. Hakami AY, Felemban R, Ahmad RG, et al.: The association between antipsychotics and weight gain and the potential role of Metformin concomitant use: a retrospective cohort study. Front Psychiatry. 2022; 13: 914165. PubMed Abstract | Publisher Full Text | Free Full Text
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22. https://figshare.com/articles/dataset/Search_Strategy_for_Does_Sex_affect_Antipsychotic_Associated_Weight_Gain_in_Patients_Being_Treated_for_Psychotic_disorders_A_Protocol_for_a_Systematic_Review_/25970134.

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 21 Jun 2024

Author details Author details

Nuala Murray
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology

Alkhalaf Sukainah
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Resources, Software

Gerard Clarke
Roles: Conceptualization, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Ali S Khasan
Roles: Conceptualization, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Karen O'Connor
Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 23 Jan 2025, 7:37

https://doi.org/10.12688/hrbopenres.13887.2

version 1

Published: 21 Jun 2024, 7:37

https://doi.org/10.12688/hrbopenres.13887.1

© 2025 O'Riain C et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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O'Riain C, Crowley S, McDonagh S et al. Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review [version 2; peer review: 3 approved with reservations]. HRB Open Res 2025, 7:37 (https://doi.org/10.12688/hrbopenres.13887.2)

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Open Peer Review

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Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

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Version 2

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PUBLISHED 23 Jan 2025

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Reviewer Report 10 Mar 2025

Dongyu Kang, Hartford Hospital, Hartford, USA

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15453.r45736

The authors reported a protocol for a systematic review, which aimed to investigate gender-specific differences in antipsychotic-induced weight gain among individuals with psychotic disorders.
The research objective is clinically important and under debate. The methods are well-designed and clearly described. However, there are several issues that need to be addressed.

Major issue:

1. In the introduction, the authors briefly mentioned the role of H1 and 5-HT2c receptors in AIWG. It would be more helpful for potential readers to know the background of potential mechanisms of AIWG in general before it turns to the more specific topic of gender difference. If word limits permit, I would recommend the authors to expand the paragraph 'Kroeze et al., in their paper...' and put it after, or merge into, the paragraph 'Weight gain is a common side effect...'. It would also be optimal if the authors could briefly touch on the potential gender difference regarding the mechanisms of AIWG.

2. It's confusing why the authors decided to include only the studies that mentioned 'gender' in the title or abstract. It would limit the studies included and lead to publication bias. Theoretically, any related studies that reported gender distribution and specific body weight would fit the topic.

3. Though body weight is the most straightforward measure, other measures, especially BMI, are also widely used. Especially when the topic is gender-related, BMI, as a height-adjusted measure, may be less biased.

4. The data analysis plan in the methods section is ambiguous. For example, what's considered 'weight gain' in the data pooled? Would it require the body weight before and after antipsychotic treatment? For the cross-section studies involved, how would you compare the weight gain difference between genders? Will it be a different analysis than the cohort studies?

5. Also in the methods section, it's not uncommon that individuals with psychotic disorders receive multiple antipsychotics sequentially or jointly. How would the authors address this issue during data analysis?

6. The dose of antipsychotics is extracted. However, there's no description of how it will be used in data analysis, considering that the AIWG is reported to be dose-dependent.

Minor recommends:

1. Please consider addressing the population using 'individuals with psychotic disorder' instead of 'patients with psychotic disorder' for person-first language.
2. The keywords include specifically 'schizophrenia'. However, this protocol contains multiple diagnoses but is not limited to schizophrenia.
3. Also, the 'treatment' as a keyword may confuse readers if this protocol includes interventions other than antipsychotics.
4. The keyword 'tolerability' is currently not the focus of this protocol. It could be confusing.
5. The term 'antipsychotic-induced weight gain' (AIWG) is more concise, accurate, and widely accepted if it's the authors' focus.
6. In the first paragraph of the introduction, 'Psychosis is a condition...', there are more up-to-date researches that could be cited instead. Also, in the first sentence, I would be careful about the difference between 'psychosis' and 'psychotic disorders'.
7. I would encourage the authors to revise the language for publication standards. For example, there's a grammar issue with the sentence 'Since the 1950's antipsychotic..' in the introduction.
8. In the methods section, the definition of population was different than how it was described in the inclusion criteria.
9. In the exclusion criteria, the last two seem redundant. It's already mentioned in the inclusion criteria that only English-language publications are allowed, and the research should include individuals with psychotic disorders.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: antipsychotic-induced weight gain, schizophrenia, addiction, TMS, EEG

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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PUBLISHED 21 Jun 2024

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Reviewer Report 02 Jan 2025

Clemente Garcia-Rizo Garcia-Rizo, Institut d'Investigacions Biomèdiques, August Pi I Sunyer (IDIBAPS), Barcelona, Spain

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15228.r43532

The authors propose an innovative approach in the evaluation of antipsychotic-induced weight gain (AIWG) as a classic secondary side effect mostly with second-generation antipsychotics.
The innovation comes from the latest interest in all areas of research about the different profiles of side effects according to biological sex (and not gender, as for many years most of all, authors combined both terms while currently, sex refers to biological sex and gender to the perceived/identified sex which has many implications in the daily use, but more important in psychotic disorders taken into consideration the estrogen hypothesis leading to the female peak after menopause.
This issue is of crucial importance as authors shall highlight this historical difference (gender/sex) to avoid misunderstandings. Another important concern that I understand comes from the need to avoid the huge amount of articles to review is the fact that many negative results in terms of sex differences are not going to reflect sex/gender either in the title or abstract so that authors will end with a bias towards significant differences, and although I’m not sure it can be controlled at least shall be warned.
As the estrogen hypothesis highlights, the performance of antipsychotics and their side effects vary after/before menopause, I would like to have some feedback if the authors are gonna perform a secondary analysis towards this end.
Another recent finding in naïve psychosis by Pillinger et al (10.1017/S0033291721005213), is the fact that naïve females display a worse metabolic profile at onset, so with a higher risk of developing more adverse metabolic conditions. On the same line, other authors highlight the importance of the perinatal environment (10.1016/j.pnpbp.2020.109910) as another risk factor for differential female AIWG (10.1016/j.jpsychires.2019.05.004), as intrauterine environment differs the growing of the fetus depending on sex.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Psychoneuroendocrinology, first episode psychosis, metabolism

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Reviewer Report 13 Jul 2024

Bodyl Brand, Psychiatry, University of Oxford Department of Psychiatry (Ringgold ID: 105611), Oxford, England, UK

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15228.r40916

This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.

The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:

Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?

As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women.

The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men.

The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed.

The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section.

Please add more information on in which case network meta-analyses will be performed.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Psychosis, sex differences, meta-analysis

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Author Response 23 Jan 2025

Colm O'Riain, Psychiatry, Cork North Lee Mental Health Services, Cork, Ireland

23 Jan 2025

Author Response

Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to ... Continue reading Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.
The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:
Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?"

We expect to find a great degree of heterogeneity in how the data is presented. We expect that synthesis without meta-analysis will required to include many relevant papers which do not present their data appropriately for inclusion in the meta-analysis. We have added an additional comment on this:
“Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses”.
Studies will only be included in the meta-analysis if it is possible to do so. We will need to see what are the most common ways that data is presented in the papers we find. The goal would be to compare weight gain in females versus weight gain in males, using either raw change in weight (kgs) or BMI. We expect either mean difference to be the most useful method of comparison for either BMI or raw change in weight (kgs).

Regarding: "As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women".

This is a very much appreciated comment. We have added this as a secondary outcome. We will be recording the average ages of participants both male and female in studies included in the systematic review. Perhaps that data will yield some insights. If there is enough data to perform a sensitivity analysis based on female participants age or menopausal status we will.
However, from our reading of papers evaluating antipsychotic associated weight gain, most of them do not present their data by sex, let alone female participants’ menopausal status. Age is usually given as an average for the entire study, or at best an average for females versus males. We will be aware of this comment while evaluating the data, and try to comment on it. However, we expect that there will be insufficient data about the spread of female participants ages or menopausal status to make a sensitivity analysis meaningful.

Regarding: "The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men".

Thank you for the comment. I wholeheartedly agree drug-specific meta-analyses would be very clinically useful, as you have explained above. I have moved it to being one of our primary outcomes.
However, from preliminary searches of the data, we expect that there simply will not be enough data presented appropriately for us to conduct a meta-analysis on many, if any, specific drugs.
We had this as a secondary outcome, simply because we do not believe it will be possible to carry out for many drugs, with olanzapine and clozapine being possible exceptions.
This actually highlights a point that we hope this systematic review will also highlight, namely that there is insufficient evidence comparing antipsychotic associated weight gain between men and women. There are hundreds of thousands, if not millions of papers surrounding antipsychotic associated weight gain, but only a tiny percentage of them present their data on females and males separately. This is why drug-specific meta-analyses are not an additional primary outcome, simply because we expect that there is insufficient existing literature to carry them out. If there is sufficient data, we will of course carry them out.

Regarding: "The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed".

I agree. We had considered this, but when we carried out preliminary searches without specifying “AND (“sex” or “gender” or “men” or “women” or “male” or “female”)” we simply could not get to a manageable number of papers to screen. Without this being specified, there would be hundreds of thousands of search results across each database we were evaluating, and our research team simply does not have the resources to screen that many articles. The above search specification had to be included to make the project feasible.
We will conduct a funnel plot analysis to look for selection bias.

Regarding: "The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section".

This has been amended.
We also noticed that web of science was included as one of the databased we would be searching in the abstract but not in the methods section. This has been removed. We will be searching three databases: EMBASE, PsychINFO and Pubmed.
Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.
The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:
Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?"

We expect to find a great degree of heterogeneity in how the data is presented. We expect that synthesis without meta-analysis will required to include many relevant papers which do not present their data appropriately for inclusion in the meta-analysis. We have added an additional comment on this:
“Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses”.
Studies will only be included in the meta-analysis if it is possible to do so. We will need to see what are the most common ways that data is presented in the papers we find. The goal would be to compare weight gain in females versus weight gain in males, using either raw change in weight (kgs) or BMI. We expect either mean difference to be the most useful method of comparison for either BMI or raw change in weight (kgs).

Regarding: "As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women".

This is a very much appreciated comment. We have added this as a secondary outcome. We will be recording the average ages of participants both male and female in studies included in the systematic review. Perhaps that data will yield some insights. If there is enough data to perform a sensitivity analysis based on female participants age or menopausal status we will.
However, from our reading of papers evaluating antipsychotic associated weight gain, most of them do not present their data by sex, let alone female participants’ menopausal status. Age is usually given as an average for the entire study, or at best an average for females versus males. We will be aware of this comment while evaluating the data, and try to comment on it. However, we expect that there will be insufficient data about the spread of female participants ages or menopausal status to make a sensitivity analysis meaningful.

Regarding: "The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men".

Thank you for the comment. I wholeheartedly agree drug-specific meta-analyses would be very clinically useful, as you have explained above. I have moved it to being one of our primary outcomes.
However, from preliminary searches of the data, we expect that there simply will not be enough data presented appropriately for us to conduct a meta-analysis on many, if any, specific drugs.
We had this as a secondary outcome, simply because we do not believe it will be possible to carry out for many drugs, with olanzapine and clozapine being possible exceptions.
This actually highlights a point that we hope this systematic review will also highlight, namely that there is insufficient evidence comparing antipsychotic associated weight gain between men and women. There are hundreds of thousands, if not millions of papers surrounding antipsychotic associated weight gain, but only a tiny percentage of them present their data on females and males separately. This is why drug-specific meta-analyses are not an additional primary outcome, simply because we expect that there is insufficient existing literature to carry them out. If there is sufficient data, we will of course carry them out.

Regarding: "The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed".

I agree. We had considered this, but when we carried out preliminary searches without specifying “AND (“sex” or “gender” or “men” or “women” or “male” or “female”)” we simply could not get to a manageable number of papers to screen. Without this being specified, there would be hundreds of thousands of search results across each database we were evaluating, and our research team simply does not have the resources to screen that many articles. The above search specification had to be included to make the project feasible.
We will conduct a funnel plot analysis to look for selection bias.

Regarding: "The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section".

This has been amended.
We also noticed that web of science was included as one of the databased we would be searching in the abstract but not in the methods section. This has been removed. We will be searching three databases: EMBASE, PsychINFO and Pubmed.
Competing Interests: No Competing Interests Close
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COMMENTS ON THIS REPORT

Author Response 23 Jan 2025

Colm O'Riain, Psychiatry, Cork North Lee Mental Health Services, Cork, Ireland

23 Jan 2025

Author Response

Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to ... Continue reading Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.
The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:
Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?"

We expect to find a great degree of heterogeneity in how the data is presented. We expect that synthesis without meta-analysis will required to include many relevant papers which do not present their data appropriately for inclusion in the meta-analysis. We have added an additional comment on this:
“Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses”.
Studies will only be included in the meta-analysis if it is possible to do so. We will need to see what are the most common ways that data is presented in the papers we find. The goal would be to compare weight gain in females versus weight gain in males, using either raw change in weight (kgs) or BMI. We expect either mean difference to be the most useful method of comparison for either BMI or raw change in weight (kgs).

Regarding: "As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women".

This is a very much appreciated comment. We have added this as a secondary outcome. We will be recording the average ages of participants both male and female in studies included in the systematic review. Perhaps that data will yield some insights. If there is enough data to perform a sensitivity analysis based on female participants age or menopausal status we will.
However, from our reading of papers evaluating antipsychotic associated weight gain, most of them do not present their data by sex, let alone female participants’ menopausal status. Age is usually given as an average for the entire study, or at best an average for females versus males. We will be aware of this comment while evaluating the data, and try to comment on it. However, we expect that there will be insufficient data about the spread of female participants ages or menopausal status to make a sensitivity analysis meaningful.

Regarding: "The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men".

Thank you for the comment. I wholeheartedly agree drug-specific meta-analyses would be very clinically useful, as you have explained above. I have moved it to being one of our primary outcomes.
However, from preliminary searches of the data, we expect that there simply will not be enough data presented appropriately for us to conduct a meta-analysis on many, if any, specific drugs.
We had this as a secondary outcome, simply because we do not believe it will be possible to carry out for many drugs, with olanzapine and clozapine being possible exceptions.
This actually highlights a point that we hope this systematic review will also highlight, namely that there is insufficient evidence comparing antipsychotic associated weight gain between men and women. There are hundreds of thousands, if not millions of papers surrounding antipsychotic associated weight gain, but only a tiny percentage of them present their data on females and males separately. This is why drug-specific meta-analyses are not an additional primary outcome, simply because we expect that there is insufficient existing literature to carry them out. If there is sufficient data, we will of course carry them out.

Regarding: "The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed".

I agree. We had considered this, but when we carried out preliminary searches without specifying “AND (“sex” or “gender” or “men” or “women” or “male” or “female”)” we simply could not get to a manageable number of papers to screen. Without this being specified, there would be hundreds of thousands of search results across each database we were evaluating, and our research team simply does not have the resources to screen that many articles. The above search specification had to be included to make the project feasible.
We will conduct a funnel plot analysis to look for selection bias.

Regarding: "The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section".

This has been amended.
We also noticed that web of science was included as one of the databased we would be searching in the abstract but not in the methods section. This has been removed. We will be searching three databases: EMBASE, PsychINFO and Pubmed.
Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.
The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:
Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?"

We expect to find a great degree of heterogeneity in how the data is presented. We expect that synthesis without meta-analysis will required to include many relevant papers which do not present their data appropriately for inclusion in the meta-analysis. We have added an additional comment on this:
“Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses”.
Studies will only be included in the meta-analysis if it is possible to do so. We will need to see what are the most common ways that data is presented in the papers we find. The goal would be to compare weight gain in females versus weight gain in males, using either raw change in weight (kgs) or BMI. We expect either mean difference to be the most useful method of comparison for either BMI or raw change in weight (kgs).

Regarding: "As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women".

This is a very much appreciated comment. We have added this as a secondary outcome. We will be recording the average ages of participants both male and female in studies included in the systematic review. Perhaps that data will yield some insights. If there is enough data to perform a sensitivity analysis based on female participants age or menopausal status we will.
However, from our reading of papers evaluating antipsychotic associated weight gain, most of them do not present their data by sex, let alone female participants’ menopausal status. Age is usually given as an average for the entire study, or at best an average for females versus males. We will be aware of this comment while evaluating the data, and try to comment on it. However, we expect that there will be insufficient data about the spread of female participants ages or menopausal status to make a sensitivity analysis meaningful.

Regarding: "The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men".

Thank you for the comment. I wholeheartedly agree drug-specific meta-analyses would be very clinically useful, as you have explained above. I have moved it to being one of our primary outcomes.
However, from preliminary searches of the data, we expect that there simply will not be enough data presented appropriately for us to conduct a meta-analysis on many, if any, specific drugs.
We had this as a secondary outcome, simply because we do not believe it will be possible to carry out for many drugs, with olanzapine and clozapine being possible exceptions.
This actually highlights a point that we hope this systematic review will also highlight, namely that there is insufficient evidence comparing antipsychotic associated weight gain between men and women. There are hundreds of thousands, if not millions of papers surrounding antipsychotic associated weight gain, but only a tiny percentage of them present their data on females and males separately. This is why drug-specific meta-analyses are not an additional primary outcome, simply because we expect that there is insufficient existing literature to carry them out. If there is sufficient data, we will of course carry them out.

Regarding: "The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed".

I agree. We had considered this, but when we carried out preliminary searches without specifying “AND (“sex” or “gender” or “men” or “women” or “male” or “female”)” we simply could not get to a manageable number of papers to screen. Without this being specified, there would be hundreds of thousands of search results across each database we were evaluating, and our research team simply does not have the resources to screen that many articles. The above search specification had to be included to make the project feasible.
We will conduct a funnel plot analysis to look for selection bias.

Regarding: "The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section".

This has been amended.
We also noticed that web of science was included as one of the databased we would be searching in the abstract but not in the methods section. This has been removed. We will be searching three databases: EMBASE, PsychINFO and Pubmed.
Competing Interests: No Competing Interests Close
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Bodyl Brand, University of Oxford Department of Psychiatry (Ringgold ID: 105611), Oxford, UK
Clemente Garcia-Rizo Garcia-Rizo, Institut d'Investigacions Biomèdiques, August Pi I Sunyer (IDIBAPS), Barcelona, Spain
Dongyu Kang, Hartford Hospital, Hartford, USA

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10 Mar 2025 | for Version 2

Dongyu Kang, Hartford Hospital, Hartford, USA

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Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

antipsychotic-induced weight gain, schizophrenia, addiction, TMS, EEG

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7 Views

02 Jan 2025 | for Version 1

Clemente Garcia-Rizo Garcia-Rizo, Institut d'Investigacions Biomèdiques, August Pi I Sunyer (IDIBAPS), Barcelona, Spain

7 Views Cite this report Responses(0)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Psychoneuroendocrinology, first episode psychosis, metabolism

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14 Views

13 Jul 2024 | for Version 1

Bodyl Brand, Psychiatry, University of Oxford Department of Psychiatry (Ringgold ID: 105611), Oxford, England, UK

14 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Psychosis, sex differences, meta-analysis

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Responses (1)

Author Response

23 Jan 2025

Colm O'Riain, Psychiatry, Cork North Lee Mental Health Services, Cork, Ireland

Thanks very much for your constructive review. We will be posting an updated version of our article today. (please find author responses in bold)

Regarding: "This study aims to investigate sex-specific differences in weight gain among patients with psychotic disorders receiving antipsychotic treatment, synthesizing evidence from various study types.
The research objective is important and relevant, and the design seems thorough. However, I do have some questions concerning the study design:
Based on the methods, it seems that all studies will be combined into one big meta-analysis. I believe this is not possible, could the authors please clarify this?"

We expect to find a great degree of heterogeneity in how the data is presented. We expect that synthesis without meta-analysis will required to include many relevant papers which do not present their data appropriately for inclusion in the meta-analysis. We have added an additional comment on this:
“Where meta-analysis is not possible for all data, Synthesis Without Met-Analysis (SWiM) will be used¹⁴. Given the heterogeneity of how data is presented we expect that meta-analysis may not be appropriate alone, and expect significant SWiM will be required, with or without meta-analyses”.
Studies will only be included in the meta-analysis if it is possible to do so. We will need to see what are the most common ways that data is presented in the papers we find. The goal would be to compare weight gain in females versus weight gain in males, using either raw change in weight (kgs) or BMI. We expect either mean difference to be the most useful method of comparison for either BMI or raw change in weight (kgs).

Regarding: "As women undergo many changes in terms of psychotic vulnerability as well as metabolic functioning when they reach menopause, it might be interesting to perform a sensitivity analysis on the effect of age, or the effect of reaching menopausal age in women".

This is a very much appreciated comment. We have added this as a secondary outcome. We will be recording the average ages of participants both male and female in studies included in the systematic review. Perhaps that data will yield some insights. If there is enough data to perform a sensitivity analysis based on female participants age or menopausal status we will.
However, from our reading of papers evaluating antipsychotic associated weight gain, most of them do not present their data by sex, let alone female participants’ menopausal status. Age is usually given as an average for the entire study, or at best an average for females versus males. We will be aware of this comment while evaluating the data, and try to comment on it. However, we expect that there will be insufficient data about the spread of female participants ages or menopausal status to make a sensitivity analysis meaningful.

Regarding: "The authors mention that drug-specific meta-analysis will be a secondary outcome. The authors may want to reconsider this, given the relevance for clinical practice to know these drug-specific results. For example, due to drug-dependent metabolic differences, one drug may cause more weight gain in women, another may not, which could inform clinicians to prefer one drug for women, but another one for men".

Thank you for the comment. I wholeheartedly agree drug-specific meta-analyses would be very clinically useful, as you have explained above. I have moved it to being one of our primary outcomes.
However, from preliminary searches of the data, we expect that there simply will not be enough data presented appropriately for us to conduct a meta-analysis on many, if any, specific drugs.
We had this as a secondary outcome, simply because we do not believe it will be possible to carry out for many drugs, with olanzapine and clozapine being possible exceptions.
This actually highlights a point that we hope this systematic review will also highlight, namely that there is insufficient evidence comparing antipsychotic associated weight gain between men and women. There are hundreds of thousands, if not millions of papers surrounding antipsychotic associated weight gain, but only a tiny percentage of them present their data on females and males separately. This is why drug-specific meta-analyses are not an additional primary outcome, simply because we expect that there is insufficient existing literature to carry them out. If there is sufficient data, we will of course carry them out.

Regarding: "The fact that only studies including sex or gender in the abstract or title are included may lead to selection bias, as it is likely that articles investigating sex differences but finding no effects may not mention this in the title or abstract. It may be appropriate to further elaborate on whether this consideration has been taken into account and how it is being addressed".

I agree. We had considered this, but when we carried out preliminary searches without specifying “AND (“sex” or “gender” or “men” or “women” or “male” or “female”)” we simply could not get to a manageable number of papers to screen. Without this being specified, there would be hundreds of thousands of search results across each database we were evaluating, and our research team simply does not have the resources to screen that many articles. The above search specification had to be included to make the project feasible.
We will conduct a funnel plot analysis to look for selection bias.

Regarding: "The inclusion criteria for clinical trials listed in the abstract does not seem to match those listed in het method section".

This has been amended.
We also noticed that web of science was included as one of the databased we would be searching in the abstract but not in the methods section. This has been removed. We will be searching three databases: EMBASE, PsychINFO and Pubmed.

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Competing Interests

No Competing Interests

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review

Abstract

Background

Methods

Ethics and Dissemination

Registration

Keywords

Revised Amendments from Version 1

Introduction

Aim

Objectives

Primary

Secondary

Review question

Methods

Criteria for considering studies for the review

Search strategy for identifying relevant studies

Presenting and reporting the results

Strengths and limitations of this study

Ethics and dissemination

Discussion

Study status

Ethics and consent

Data availability

Underlying data

Extended data

References

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Does Sex affect Antipsychotic Associated Weight Gain in Patients Being Treated for Psychotic Disorders: A Protocol for a Systematic Review

Abstract

Background

Methods

Ethics and Dissemination

Registration

Keywords

Revised Amendments from Version 1

Introduction

Aim

Objectives

Primary

Secondary

Review question

Methods

Criteria for considering studies for the review

Search strategy for identifying relevant studies

Presenting and reporting the results

Strengths and limitations of this study

Ethics and dissemination

Discussion

Study status

Ethics and consent

Data availability

Underlying data

Extended data

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Competing Interests Policy

Stay Updated

Are you a HRB-funded researcher?

Thank you!