The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol

Anna Zierotin; Jennifer Murphy; Brian O'Donoghue; Karen O'Connor; Michael Norton; Mary Clarke

doi:10.12688/hrbopenres.13810.1

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Study Protocol

The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol

[version 1; peer review: 2 approved with reservations]

Anna Zierotin ¹, Jennifer Murphy², Brian O'Donoghue^1,3, Karen O'Connor^4,5, Michael Norton⁶, Mary Clarke^1,7

Anna Zierotin ¹, Jennifer Murphy², [...] Brian O'Donoghue^1,3, Karen O'Connor^4,5, Michael Norton⁶, Mary Clarke^1,7

PUBLISHED 07 Dec 2023

Author details Author details

¹ Department of Psychiatry, University College Dublin, Dublin, Leinster, Ireland
² Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland
³ St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland
⁴ RISE Early Intervention in Psychosis Service, South Lee Mental Health Service, Cork, Ireland
⁵ Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, County Cork, Ireland
⁶ Recovery and Engagement Lead, Office of Mental Health Engagement and Recovery, Health Service Executive, County Dublin, Ireland
⁷ DETECT Early Intervention for Psychosis Service, County Dublin, Ireland

Anna Zierotin
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Jennifer Murphy
Roles: Investigation, Validation

Brian O'Donoghue
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

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

Michael Norton
Roles: Conceptualization, Supervision, Writing – Review & Editing

Mary Clarke
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Individuals with first-episode psychosis (FEP) face an increased risk of physical comorbidities, notably cardiovascular diseases, metabolic disorders, respiratory disorders, and certain types of cancer. Previous reviews report pooled physical health prevalence from chronic psychosis and FEP groups. By contrast, this review will focus on antipsychotic-naïve FEP cohorts and incorporate data from observational longitudinal studies and antipsychotic intervention studies to understand the progression of physical health comorbidities from the onset to later stages of psychosis. This review aims to systematically examine the short-, medium-, and long-term period prevalence of these comorbidities in FEP and variations related to demographic factors.

Methods

A systematic review will be conducted using the PRISMA and MOOSE guidelines. Medline, Embase, PsycINFO, and CINAHL+, as well as Clinical Trials gov.uk, OpenGrey, WHO International Clinical Trials Registry Platform, Current Controlled Trials, United States National Institute of Health Trials Registry, and the Irish Health Repository, will be searched from inception. Longitudinal studies exploring physical health outcomes in FEP cohorts and antipsychotic intervention studies monitoring health outcomes in antipsychotic naïve FEP individuals will be eligible for inclusion. Two reviewers will independently screen titles, abstracts, and full-text articles. Bias in individual studies will be assessed using the JBI Critical Appraisal Checklist. A meta-analysis of the short-, medium-, and long-term prevalence of cardiovascular, metabolic, cancer, and respiratory outcomes and a narrative synthesis will be conducted. If possible, a meta-regression on the impact of demographic variables will be conducted.

Conclusions

This systematic review will clarify the progression of physical health comorbidities in FEP, informing early intervention strategies and policies for this population. Subsequent findings will be submitted to a leading journal, supplemented by a recovery education module for patient groups and a lay summary for wider dissemination.

Registration

The study was registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42023431072; 17/06/2023).

Keywords

First-episode Psychosis, Physical Health Comorbidities, Metabolic Health, Cardiovascular Health, Respiratory Health, Cancer

Corresponding author: Anna Zierotin

Competing interests: No competing interests were disclosed.

Grant information: Health Research Board [CDA 2021-005, Psychosis Ireland Structured Training Program].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Zierotin A 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: Zierotin A, Murphy J, O'Donoghue B et al. The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol [version 1; peer review: 2 approved with reservations]. HRB Open Res 2023, 6:75 (https://doi.org/10.12688/hrbopenres.13810.1) First published: 07 Dec 2023, 6:75 (https://doi.org/10.12688/hrbopenres.13810.1) Latest published: 08 Jan 2025, 6:75 (https://doi.org/10.12688/hrbopenres.13810.2)

Introduction

Individuals with psychosis face an increased risk of various physical health conditions, including cardiovascular diseases, respiratory disorders, metabolic disorders, and cancer (De Hert et al., 2011; Leucht et al., 2007). The increased incidence of physical comorbidities, especially cardiovascular diseases, contributes to a significant burden of physical illness and premature mortality, with individuals with psychosis experiencing a reduced life expectancy of approximately 10–20 years compared to the general population (Firth et al., 2019). A higher prevalence of lifestyle risk factors such as smoking, poor nutrition, and disrupted sleep patterns in people with psychosis contribute to these health risks (Firth et al., 2019). Additionally, shared risk factors, including non-white ethnicity and social deprivation, contribute to distinct multimorbidity patterns in psychosis (Lawrence & Kisely, 2010; Rodrigues et al., 2021). Recent research has also reported the genetic risk for schizophrenia to be associated with cardiac structural changes that can worsen cardiac outcomes (Pillinger et al., 2023). This connection further emphasises the complex interplay between genetic and lifestyle factors in shaping the health outcomes of those with psychosis.

Metabolic syndrome, encompassing dyslipidaemia, hypertension, impaired glucose regulation, and central obesity, is prevalent in up to 69% of those with chronic schizophrenia (Vancampfort et al., 2015). Although antipsychotic use may contribute to these metabolic changes, altered glucose homeostasis is already observed in antipsychotic-naïve individuals with first-episode psychosis (FEP), suggesting that metabolic disturbances emerge from the onset of psychosis (Pillinger et al., 2017a; Pillinger et al., 2017b).

Research has indicated that two-thirds of individuals with FEP will experience metabolic changes, such as impaired glucose and lipid metabolism, as well as weight gain exceeding 7% during the initial 12 months of treatment (Alvarez-Jiménez et al., 2008; Coentre et al., 2022). These metabolic changes lead to a greater risk of cardiovascular disease, stroke, and type 2 diabetes later in life, which underlines the importance of early intervention and the need for attention to physical health changes from the initial diagnosis of psychosis. Moreover, individuals with schizophrenia face a higher risk of respiratory conditions such as chronic obstructive pulmonary disease (COPD) and pneumonia (Suetani et al., 2021), which might be linked to increased active and passive smoke exposure (Hunter et al., 2020; Lally et al., 2019), childhood exposure to air pollution (Antonsen et al., 2020; Schraufnagel et al., 2019) and socioeconomic factors (Rocha et al., 2020; Sariaslan et al., 2016).

Research on the incidence of cancer in people with psychosis has been mixed, with earlier studies concluding a generally lower cancer incidence in this population (Ananth & Burnstein, 1977) and more recent reviews finding an increased risk of certain cancer types but a decrease for others (Wootten et al., 2022; Xu et al., 2017; Zhuo & Triplett, 2018). The inconsistencies between earlier and more recent studies may partially reflect the evolving practices in diagnosing and reporting cancer among those with psychosis, emphasising the importance of updating previous findings with more contemporary health data.

Despite several systematic reviews establishing the increased prevalence of physical health disorders in individuals with psychosis (Leucht et al., 2007; Oud & Meyboom-de Jong, 2009; Suetani et al., 2021; Vancampfort et al., 2013), these reviews often report pooled prevalence data from individuals with chronic psychosis and FEP, or only report FEP baseline outcomes, limiting our understanding of the evolution of physical health outcomes in FEP. Therefore, by focusing specifically on FEP cohorts, this review aims to understand the progression of physical health comorbidities from the onset to the later stages of psychosis.

Given the limited number of longitudinal FEP cohort studies reporting physical health outcomes (Suetani et al., 2021; Vancampfort et al., 2013; Wootten et al., 2022), this review will also synthesise evidence from antipsychotic intervention studies. Antipsychotic intervention studies often conduct baseline and follow-up physical health monitoring, providing data on health outcomes, particularly metabolic health. Given that antipsychotic medication commonly constitutes first-line treatment in FEP, including these studies will allow us to capture more data about the development of physical health outcomes. While we acknowledge that clinical trials may not generalise to the broader FEP population due to specific inclusion and exclusion criteria, we aim to analyse outcomes separately and then provide a comprehensive pooled analysis.

Review questions

The primary objective of this review is to systematically examine the existing evidence relating to the short-, medium- and long-term period prevalence of cardiovascular, metabolic, cancer and respiratory comorbidities in individuals with first-episode psychosis.

1. What is the short-, medium- and long-term period prevalence of cardiovascular, metabolic, cancer and respiratory comorbidities in individuals with first-episode psychosis?

2. Does the prevalence of cardiovascular, metabolic, cancer and respiratory comorbidities vary with certain demographic factors such as age, sex, or ethnicity among individuals with first-episode psychosis?

Methods

Study registration

The study was registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42023431072; 17/06/2023). This protocol follows the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols; Moher et al., 2015; Zierotin et al., 2023) guidelines. The review will be conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 statement (Page et al., 2021) and the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines (Stroup et al., 2000).

Eligibility criteria

This review will include research reporting on the relationship between FEP and cardiovascular, metabolic, cancer and respiratory health outcomes. This will include two study types: 1) observational longitudinal studies investigating physical health outcomes in a FEP cohort and 2) antipsychotic intervention studies reporting the incidence of physical health outcomes in antipsychotic-naïve individuals with FEP. We will exclude single case studies and case series. We will also exclude studies that did not measure physical health outcomes or only measured physical health at baseline. There will be no restrictions regarding language or publication period. Studies will be selected for inclusion in the systematic review according to the following population and outcome criteria.

Population

The population includes individuals with a first-episode diagnosis of psychosis, either clinician-diagnosed, confirmed through medical records, or enrolled in a clinical program dedicated to psychosis (for example, Early Intervention in Psychosis). First-episode psychosis is defined as first treatment contact (inpatient or outpatient) regardless of the duration of untreated illness. There are no restrictions regarding the age of participants. For studies to be eligible for inclusion, individuals with FEP should have no more than 28 days of antipsychotic drug exposure at the minimal effective dose, as recommended by the Maudsley clinical guidelines (Owen et al., 2014). However, if a study’s cohort contains less than 5% of individuals with antipsychotic drug exposure longer than 28 days, it will still be considered for inclusion. Studies solely investigating organic psychotic disorders or personality disorders such as schizoid or schizotypal personality disorder will be excluded. Moreover, research focusing on individuals with psychosis with comorbid neurodivergence or neurodevelopmental disorders will also be excluded. However, if a study’s cohort contains less than 20% of individuals with the conditions above, it will still be considered for inclusion. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis. If data extraction is not possible, we will contact the authors twice within a one-month period to request the data for individuals with psychosis. If multiple reports of the same study are identified, the most complete report will be included.

Outcomes

The primary outcome is the prevalence or incidence of metabolic, cardiovascular, cancer or respiratory outcomes in individuals with FEP. Physical health outcomes must be confirmed by a clinician, enrolment in a clinical program dedicated to the physical illness, medical records, or primarily according to ICD-10 criteria. However, for interpretation consistency and considering recent updates, any ambiguities in outcomes will be assessed against the ICD-11 criteria. Eligible studies must report the prevalence/incidence of these health outcomes at a specified follow-up time point post the initial psychosis diagnosis, meaning the studies should specify the duration from the first diagnosis of psychosis to the time when these physical health outcomes were reported. There are no restrictions regarding the study time frame. In the context of this review, the terms “short-”, “medium-” and “long-term prevalence” refer to the occurrence of cardiovascular, metabolic, cancer, and respiratory comorbidities in individuals diagnosed with first-episode psychosis (FEP) over specific time intervals post-diagnosis. Specifically, “short-term prevalence” assesses these comorbidities from >0–12 months following an FEP diagnosis, “medium-term prevalence” spans from 13–36 months post-diagnosis, and “long-term prevalence” encompasses both 37–60 months post-diagnosis and periods exceeding 5 years. The secondary outcome of interest concerns the impact of demographic and study variables, such as age, sex, ethnicity and study year, on the prevalence of cardiovascular, metabolic, cancer and respiratory comorbidities.

Information sources

The following databases will be searched from inception for publications: Medline, Embase, PsycInfo, and CINAHL+. Grey literature, including ClinicalTrials gov.uk, OpenGrey, WHO International Clinical Trials Registry Platform, Current Controlled Trials, United States National Institute of Health Trials Registry, and the Irish Health Repository, will be searched. The searches will be re-run prior to the final analysis.

Search strategy

The literature search strategy will use Medical Subject Headings (MeSH) and text words related to first-episode psychosis, metabolic, cardiovascular, cancer and respiratory outcomes. The search terms for the physical disorders are adapted from previous publications on similar topics (Leucht et al., 2007; Onyeka et al., 2019). The search strategy was produced with the help of a librarian and follows the below structure:

First-episode psychosis terms AND metabolic outcomes OR cardiovascular outcomes OR cancer terms OR respiratory outcomes

The full search strategy can be found in Table 1.

Table 1. This table lists the search terms, and Boolean operators used to identify studies on psychotic disorders and their associations with cardiovascular, metabolic, respiratory and cancer outcomes.

The keywords are grouped by database (Medline, PsycINFO, EMBASE, CINAHL+) to illustrate the tailored search strategies used for each database.

Concept	Database				Keywords
Concept	Medline (via Ovid)	PsycNFO (via Ovid	EMBASE (Via Ovid)	CINAHL+ (via Ebesco)	Keywords
Psychotic disorders AND	((first episode* or first-episode* or first* or recent or early* or new* or initial* or "newly admitted") adj2 (psychos?s or psychotic or schizo* or delusion* or paranoi*))	((first episode* or first-episode* or first* or recent or early* or new* or initial* or "newly admitted") adj2 (psychos?s or psychotic or schizo* or delusion* or paranoi*))	((first episode* or first-episode* or first* or recent or early* or new* or initial* or "newly admitted") adj2 (psychos?s or psychotic or schizo* or delusion* or paranoi*))	((“first episode” or “first-episode” or first* or recent or early* or new* or initial* or “newly admitted”) N2 (psychos?s or psychotic or schizo* or delusion* or paranoi*))	First-episode psychosis or first-episode schizophrenia/delusional disorder/paranoid disorder
Cancer OR	(Cancer* or neoplasm* or carcinoma* or carcinogen* or (malignan* adj (tumo?r* or lesion)) or metastas* or melanoma? or sarcoma? or Mesothel?oma or polycyth?emia vera or Myelodysplastic or leukemia or leucaemia or myelofibrosis or cyst? or neurofibroma? or glioma? or lymphoma?) or exp neoplasms/	(Cancer* or neoplasm* or carcinoma* or carcinogen* or (malignan* adj (tumo?r* or lesion)) or metastas* or melanoma? or sarcoma? or Mesothel?oma or polycyth?emia vera or Myelodysplastic or leukemia or leucaemia or myelofibrosis or cyst? or neurofibroma? or glioma? or lymphoma?) or exp neoplasms/	(Cancer* or neoplasm* or carcinoma* or carcinogen* or (malignan* adj (tumo?r* or lesion)) or metastas* or melanoma? or sarcoma? or Mesothel?oma or polycyth?emia vera or Myelodysplastic or leukemia or leucaemia or myelofibrosis or cyst? or neurofibroma? or glioma? or lymphoma?) or exp neoplasm/	Cancer* or neoplasm* or carcinoma* or carcinogen* or (malignan* W1 (tumo#r* or lesion)) or metastas* or melanoma# or sarcoma# or Mesothel#oma or polycyth#emia vera or Myelodysplastic or leukemia or leucaemia or myelofibrosis or cyst# or neurofibroma# or glioma# or lymphoma# or (MH "Neoplasms+")	Cancer or neoplasms or malignant tumour or malignant lesion or carcinoma or melanoma or metastasis or sarcoma or mesothelioma or polycythemia vera or leukaemia or myelodysplastic syndromes or myelofibrosis or neurofibroma or glioma or lymphoma or cyst
Metabolic outcomes	(Diabet* or T2DM or mellitus or glucose or hyperglycaemia or insulin or prediabet* or cholesterol or triglycerides or "blood pressure" or metabolic or hypertensi* or hyperlipid* or hyperlipo* or lipoprotein* or MetS or HbA1c or cardiometabolic or "waist circumference" or "body mass index" or BMI or hypercholesterol* or hypertriglycerid* or "high density lipoprotein" or "low density lipoprotein") or exp diabetes mellitus/ or exp metabolic syndrome X/ or exp dyslipidemia/ or exp hypertension/ or exp cholesterol/ or exp hyperlipoproteinemia/ or exp hypertriglyceridemia/ or exp hyperlipidemia/ or exp Hypercholesterolemia/ or exp obesity/ or exp Hyperglycemia/ or exp obesity/ or exp cholesterol/ or exp insulin/	(Diabet* or T2DM or mellitus or glucose or hyperglycaemia or insulin or prediabet* or cholesterol or triglycerides or "blood pressure" or metabolic or hypertensi* or hyperlipid* or hyperlipo* or lipoprotein* or MetS or HbA1c or cardiometabolic or "waist circumference" or "body mass index" or BMI or hypercholesterol* or hypertriglycerid* or "high density lipoprotein" or "low density lipoprotein") or exp diabetes mellitus/ or exp metabolic syndrome X/ or exp hypertension/ or exp cholesterol/ or exp hyperlipoproteinemia/ or exp hypertriglyceridemia/ or exp hyperlipidemia/ or exp Hypercholesterolemia/ or exp obesity/ or exp Hyperglycemia/ or exp obesity/ or exp cholesterol/ or exp insulin/	(Diabet* or T2DM or mellitus or glucose or hyperglycaemia or insulin or prediabet* or cholesterol or triglycerides or "blood pressure" or metabolic or hypertensi* or hyperlipid* or hyperlipo* or lipoprotein* or MetS or HbA1c or cardiometabolic or "waist circumference" or "body mass index" or BMI or hypercholesterol* or hypertriglycerid* or "high density lipoprotein" or "low density lipoprotein") or exp diabetes mellitus/ OR exp metabolic syndrome X/ OR exp dyslipidemia OR exp hypertension/ OR exp cholesterol/ OR exp hyperlipoproteinemia/ OR exp hypertriglyceridemia/ OR exp hyperlipidemia OR exp Hypercholesterolemia/ OR exp obesity/ OR exp Hyperglycemia/ OR exp obesity/ OR exp cholesterol/ OR exp insulin	(Diabet* or T2DM or mellitus or glucose or hyperglycaemia or insulin or prediabet* or cholesterol or triglycerides or "blood pressure" or metabolic or hypertensi* or hyperlipid* or hyperlipo* or lipoprotein* or MetS or HbA1c or cardiometabolic or "waist circumference" or "body mass index" or BMI or hypercholesterol* or hypertriglycerid* or "high density lipoprotein" or "low density lipoprotein") or (MH "Metabolic Syndrome X+") OR (MH "Hypertension+") OR (MH "Obesity+") OR (MH "Cholesterol+") OR (MH "Hyperglycemia+") OR (MM "Diabetes Mellitus, Type 2") OR (MH "Hypercholesterolemia+") OR (MH "Hyperlipoproteinemia+") OR (MH "Insulin Resistance+")	Diabetes mellitus or glucose or insulin or hyperglycaemia or prediabetes cholesterol or triglycerides or blood pressure or metabolic syndrome or hypertension or hyperlipidaemia or lipoprotein or HbA1c or cardiometabolic or waist circumference or body mass index or BMI or hypercholesterolemia or hypertriglyceridemia or high density lipoprotein or low density lipoprotein
Respiratory outcomes OR	(((respiratory or lung) adj (disease or condition or infection* or inflammation or disorder* or aspiration or syndrome)) or asthma or bronch?t?s or emphysema or pulmon?ry or COPD or pneumon* or tuberculosis or apn?ea or apneia or airway obstruct* or chronic obstruct* or infl?enza or sinusitis or pharyngitis or tonsillitis or laryng?t?s or dyspnoea or pleuritis or pl?urisy or orthopnoea or nasal polyps or rhinitis or cough or tracheitis or empyema or bronchial or SARS or asphyx?a or D?spha?ia or tuberculosis) or Respiratory Tract Diseases/ or Bronchial Diseases/ or Asthma/ or Bronchitis/ or Laryngeal Diseases/ or Lung Diseases/ or Nasal Obstruction/ or Nasal Polyps/ or Sinusitis/ or Rhinitis/ or Pleural Diseases/ or Pleurisy/ or Tuberculosis, Pleural/ or Apnea/ or Cough/ or Dyspnea/ or Respiratory Aspiration/ or Airway Obstruction/ or Common Cold/ or Empyema, Pleural/ or Influenza, Human/ or Laryngitis/ or Pharyngitis/ or Pleurisy/ or Pneumonia/ or Rhinitis/ or Severe Acute Respiratory Syndrome/ or Sinusitis/ or Tracheitis/ or Tuberculosis/	(((respiratory or lung) adj (disease or condition or infection* or inflammation or disorder* or aspiration or syndrome)) or asthma or bronch?t?s or emphysema or pulmon?ry or COPD or pneumon* or tuberculosis or apn?ea or apneia or airway obstruct* or chronic obstruct* or infl?enza or sinusitis or pharyngitis or tonsillitis or laryng?t?s or dyspnoea or pleuritis or pl?urisy or orthopnoea or nasal polyps or rhinitis or cough or tracheitis or empyema or bronchial or SARS or asphyx?a or D?spha?ia or tuberculosis) or Respiratory Tract Diseases/ or Bronchial Diseases/ or Asthma/ or Bronchitis/ or Laryngeal Diseases/ or Lung Diseases/ or Nasal Obstruction/ or Nasal Polyps/ or Sinusitis/ or Rhinitis/ or Pleural Diseases/ or Pleurisy/ or Tuberculosis, Pleural/ or Apnea/ or Cough/ or Dyspnea/ or Respiratory Aspiration/ or Airway Obstruction/ or Common Cold/ or Empyema, Pleural/ or Influenza, Human/ or Laryngitis/ or Pharyngitis/ or Pleurisy/ or Pneumonia/ or Rhinitis/ or Severe Acute Respiratory Syndrome/ or Sinusitis/ or Tracheitis/ or Tuberculosis/	(((respiratory or lung) adj (disease or condition or infection* or inflammation or disorder* or aspiration or syndrome)) or asthma or bronch?t?s or emphysema or pulmon?ry or COPD or pneumon* or tuberculosis or apn?ea or apneia or airway obstruct* or chronic obstruct* or infl?enza or sinusitis or pharyngitis or tonsillitis or laryng?t?s or dyspnoea or pleuritis or pl?urisy or orthopnoea or nasal polyps or rhinitis or cough or tracheitis or empyema or bronchial or SARS or asphyx?a or D?spha?ia or tuberculosis) or Respiratory Tract Diseases/ or Bronchial Diseases/ or Asthma/ or Bronchitis/ or Laryngeal Diseases/ or Lung Diseases/ or Nasal Obstruction/ or Nasal Polyps/ or Sinusitis/ or Rhinitis/ or Pleural Diseases/ or Pleurisy/ or Tuberculosis, Pleural/ or Apnea/ or Cough/ or Dyspnea/ or Respiratory Aspiration/ or Airway Obstruction/ or Common Cold/ or Empyema, Pleural/ or Influenza, Human/ or Laryngitis/ or Pharyngitis/ or Pleurisy/ or Pneumonia/ or Rhinitis/ or Severe Acute Respiratory Syndrome/ or Sinusitis/ or Tracheitis/ or Tuberculosis/	(((respiratory or lung) adj (disease or condition or infection* or inflammation or disorder* or aspiration or syndrome)) or asthma or bronch#t#s or emphysema or pulmon#ry or COPD or pneumon* or tuberculosis or apn#ea or apneia or airway obstruct* or chronic obstruct* or infl#enza or sinusitis or pharyngitis or tonsillitis or laryng#t#s or dyspnoea or pleuritis or pl#urisy or orthopnoea or nasal polyps or rhinitis or cough or tracheitis or empyema or bronchial or SARS or asphyx#a or D#spha#ia or tuberculosis) or (MM "Asthma") OR (MM "Bronchitis") OR (MM "Laryngitis") OR (MM "Laryngeal Diseases") OR (MM "Lung Diseases") OR (MM "Pneumonia") OR (MM "Apnea") OR (MM "Cough") OR (MM "Aspiration") OR (MM "Dyspnea") OR (MH "Rhinitis, Allergic, Perennial") OR (MH "Rhinitis, Allergic, Seasonal") OR (MM "Common Cold") OR (MM "Empyema") OR (MM "Influenza") OR (MM "Pharyngitis") OR (MM "Pleurisy") OR (MM "Rhinitis") OR (MM "Severe Acute Respiratory Syndrome") OR (MM "Sinusitis") OR (MM "Tonsillitis") OR (MM "Tuberculosis, Pulmonary")	Respiratory disease or lung disease or asthma or bronchitis or emphysema or pulmonary disease or COPD or pneumonia or tuberculosis or apnoea or influenza or airway obstructive or sinusitis or influenza or pharyngitis or tonsillitis or laryngitis or pharyngitis or pleuritis or dyspnoea or pleuritis or orthopnoea or empyema or cough or tracheitis nasal polyp or tuberculosis or SARS or asphyxia or dysphagia or tuberculosis
Cardiovascular outcomes	(cardiovascular or Cardiovascular disease* or ((coronary or isch#emic) adj2 (disease or occlusion or stenos#s or thrombos#s)) or (myocardial adj (isch#emia or infarct)) or ((coronary or myocardial or heart or cardiac) adj2 (revasculari#ation or angioplasty or atherectomy or bypass)) or ((heart or cardiac or ventricular) adj failure) or angina or ((ventricular or systolic or diastolic) adj (dysfunction or impairment)) or (stroke or cerebrovascular accident) or ((brain or cerebral or intracranial) adj2 (infarct or thrombos?s or embolism)) or transient isc#emic attack or tachycardi* or heart attack* or (heart adj2 (attack or disease)) or left ventricular hypertrophy) or Cardiovascular Diseases/ or exp Myocardial Ischemia/ or exp Angina Pectoris/ or exp Myocardial Revascularization/ or exp Heart Failure/ or exp Ventricular Dysfunction/ or exp brain ischemia/ or exp intracranial arterial diseases/ or exp "intracranial embolism and thrombosis"/ or exp stroke/	“cardiovascular disease” OR ((coronary or isch?emic) adj2 (disease or occlusion or stenos#s or thrombos#s)) OR (myocardial adj (isch?emia or infarct)) OR ((coronary or myocardial or heart or cardiac) adj2 (revasculari?ation or angioplasty or atherectomy or bypass)) OR ((heart or cardiac or ventricular) adj failure) OR angina OR ((ventricular or systolic or diastolic) adj (dysfunction or impairment)) OR (stroke or ‘cerebrovascular accident’) OR ((brain or cerebral or intracranial) adj2 (infarct* or thrombos?s or embolism)) OR ‘transient isc?emic attack’ OR tachycardi* OR ‘heart attack*’ OR (heart adj2 (attack or disease)) OR ‘left ventricular hypertrophy’ or cardiovascular disorders/ or exp heart disorders/ or exp arteriosclerosis/ or exp ischemia/ OR cerebrovascular disorders/ OR cerebral arteriosclerosis/ OR exp cerebral ischemia/ OR cerebrovascular accidents/	“cardiovascular disease” OR ((coronary or isch?emic) adj2 (disease or occlusion or stenos#s or thrombos#s)) OR (myocardial adj (isch?emia or infarct)) OR ((coronary or myocardial or heart or cardiac) adj2 (revasculari?ation or angioplasty or atherectomy or bypass)) OR ((heart or cardiac or ventricular) adj failure) OR angina OR ((ventricular or systolic or diastolic) adj (dysfunction or impairment)) OR (stroke or ‘cerebrovascular accident’) OR ((brain or cerebral or intracranial) adj2 (infarct* or thrombos?s or embolism)) OR ‘transient isc?emic attack’ OR tachycardi* OR ‘heart attack*’ OR (heart adj2 (attack or disease)) OR ‘left ventricular hypertrophy’ or cardiovascular disease/ OR ischemic heart disease/ OR exp acute coronary syndrome/ OR exp angina pectoris/ OR coronary artery atherosclerosis/ OR coronary artery obstruction/ OR coronary artery thrombosis/ OR exp heart infarction/ OR heart muscle ischemia/ OR ischemic cardiomyopathy/ OR angina pectoris/ OR heart muscle revascularization/ OR heart failure/ OR heart ventricle function/ cerebrovascular disease/ OR exp brain infarction/ OR exp brain ischemia/ OR exp cerebrovascular accident/	"cardiovascular disease" OR ((coronary or isch#emic) N2 (disease or occlusion or stenos#s or thrombos#s)) OR (myocardial N (isch#emia or infarct)) OR ((coronary or myocardial or heart or cardiac) N2 (revasculari#ation or angioplasty or atherectomy or bypass)) OR ((heart or cardiac or ventricular) N failure) OR angina OR ((ventricular or systolic or diastolic) N (dysfunction or impairment)) OR (stroke or "cerebrovascular accident") OR ("brain" OR "cerebral" OR "intracranial") W2 ("infarct" OR "thrombos?s" OR "embolism") OR AB ("brain" OR "cerebral" OR "intracranial") W2 ("infarct" OR "thrombos?s" OR "embolism") OR Tl ("ventricular" OR "systolic" OR "diastolic") W1 ("dysfunction" OR "impairment") OR AB ("ventricular" OR "systolic" OR "diastolic") W1 ("dysfunction" OR "impairment") OR Tl ("heart" OR "cardiac" OR "ventricular") W1 "failure" OR AB ("heart" OR "cardiac" OR "ventricular") W1 "failure" OR Tl ("coronary" OR "myocardial" OR "heart" OR "cardiac") W2 ("revasculari#ation" OR "angioplasty" OR "atherectomy" OR "bypass") OR AB ("coronary" OR "myocardial" OR "heart" OR "cardiac") W2 ("revasculari#ation" OR "angioplasty" OR "atherectomy" OR "bypass") OR "angina" OR (MH "Cerebral lschemia+") OR (MH "lntracranial Arterial Diseases+") OR (MH "lntracranial Embolism and Thrombosis+") OR (MH "Stroke+") OR (MH "Ventricular Dysfunction+") OR (MH "Heart Failure+") OR (MH "Myocardial Revascularization+") OR (MH "Myocardial lschemia+") OR (MH "Cardiovascular Diseases")	Cardiovascular diseases or ischemic heart diseases or acute coronary syndrome or myocardial ischemia or myocardial infarct or cardiac failure or ventricular dysfunction or angina or coronary artery atherosclerosis or coronary artery obstruction or thrombosis or heart infarct or ischemia or cardiomyopathy or stroke or cerebrovascular disease or heart failure

Study selection

Studies will be deduplicated in Endnote and uploaded to Rayyan for screening. Two reviewers will independently undertake the screening process in two rounds: the first round will involve title and abstract screening, and the second round will focus on full-text screening. A third reviewer will resolve any discrepancies between the reviewers at each stage.

Data extraction

Two reviewers will extract data independently according to a pre-piloted Microsoft Excel form. Discrepancies will be identified and resolved through discussion (with a third reviewer where necessary). Where study data is not reported (e.g., conference abstracts), authors will be contacted up to two times within a one-month period to request relevant data.

The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information. In the case of missing data, study investigators will be contacted for unreported data or additional details. Selected articles will be stored and managed using EndNote X9 Reference Manager Library.

Risk of bias in individual studies

Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data (Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer.

Strategy of data synthesis

A narrative synthesis will be used to synthesise and summarise the findings and to explore relationships in the data. If two or more studies are available, a random-effects meta-analysis of prevalence with 95% confidence and prediction intervals will be calculated for studies investigating outcomes within the same disease category (metabolic, cardiovascular, cancer or respiratory outcomes) at >0–12 months, at 13–36 months, at 37–60 months, and after more than 5 years after a FEP diagnosis (e.g., one meta-analysis on FEP cohort studies at 13–36 month follow up reporting the prevalence of respiratory outcomes). We will also conduct meta-analyses on the prevalence of specific physical health outcomes that are reported on in two or more studies at 0–12 months, at 13–36 months, at 37–60 months, and after more than 5 years.

Heterogeneity between prevalence estimates will be assessed using the I² statistic, Tau-squared, and prediction intervals. We will also generate Forest plots for the prevalence estimates and their 95% CI of the individual studies and pooled estimates. Forest plots will be examined visually, looking for potential outliers. We will conduct sensitivity analyses based on study quality and exclude studies at high risk of bias. Publication bias will be assessed with a funnel plot and the Begg and Egger tests.

Analysis of subgroups

Sensitivity analyses will be conducted for associations supported by previous literature or convincing evidence. The following factors will be considered: study design, study year, studies that adjusted for age/sex, studies that adjusted for smoking at baseline, studies that adjusted for BMI or obesity at baseline, studies that adjusted for physical activity levels at baseline; studies that adjusted for the presence of co-occurring mental disorders at baseline; studies that adjusted for exposure to childhood maltreatment at baseline; studies that adjusted for use of psychotropic medications/substances; studies sponsored by a pharmaceutical company, and studies that adjusted for general medical burden at baseline.

A meta-regression analysis of moderators of interest will be conducted if there are more than 10 studies available on one specific illness (e.g., Metabolic syndrome) at one of the pre-specified time periods:

(a) Mean age

(b) Ethnicity

(d) % smokers

(e) % taking antipsychotic medication

(f) % alcohol or substance use disorder

(g) Study year

Public and patient involvement and dissemination plans

Public and Patient Involvement (PPI) has been actively engaged in the development of the research question and the systematic review protocol to ensure the relevance and appropriateness of this review. The completed review will be submitted to a leading journal in this field. Drawing from the insights of the review, we plan to create a recovery education module, informed by both the study findings and PPI feedback, to further support and inform patient groups. To make our findings accessible and comprehensible to a broader audience, a lay summary will be added to the review and disseminated to interested patient groups, with the continuous involvement of PPI to ensure its clarity and relevance.

Study status

The systematic review is currently at the stage of data extraction. Database searching and screening have been completed.

Discussion

Individuals with FEP experience significant health disparities, demonstrated by increased rates of premature mortality and a variety of physical comorbidities (Firth et al., 2019). This systematic review seeks to consolidate the existing knowledge on the prevalence of physical health comorbidities among this group.

An important focus of our review is the health trajectory from FEP onset to subsequent stages. Past reviews often group FEP with chronic psychosis, potentially masking the trajectory of physical health comorbidities (Leucht et al., 2007; Oud & Meyboom-de Jong, 2009). Our review dissects the prevalence of cardiovascular, metabolic, cancer, and respiratory comorbidities across varying post-diagnosis durations to provide a detailed health outlook for this cohort. A key component of our review evaluates the influence of demographic variables on prevalence rates. Understanding these demographic nuances can aid in public service planning and preparedness, ensuring communities are better equipped to address these challenges. By only including studies with antipsychotic-naïve individuals with FEP, we aim to achieve a better appreciation of the baseline physical health changes after entering mental health services.

We also anticipate certain limitations in our review. The reported prevalence rates may not accurately represent the true prevalence of specific physical health disorders among individuals with FEP. Prior research has indicated that conditions like cancer tend to be diagnosed at more advanced stages compared to the general population (Wootten et al., 2022). Additionally, diagnostic overshadowing could further lead to underreporting physical health issues (Molloy et al., 2023; Shefer et al., 2014).

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA-P checklist for ‘The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol’. https://doi.org/10.6084/m9.figshare.24162756 (Zierotin et al., 2023).

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

Faculty Opinions recommended

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Version 2

VERSION 2 PUBLISHED 07 Dec 2023

Author details Author details

Anna Zierotin
Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation

Jennifer Murphy
Roles: Investigation, Validation

Brian O'Donoghue
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

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

Michael Norton
Roles: Conceptualization, Supervision, Writing – Review & Editing

Mary Clarke
Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

Health Research Board [CDA 2021-005, Psychosis Ireland Structured Training Program].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 08 Jan 2025, 6:75

https://doi.org/10.12688/hrbopenres.13810.2

version 1

Published: 07 Dec 2023, 6:75

https://doi.org/10.12688/hrbopenres.13810.1

© 2023 Zierotin A 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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Zierotin A, Murphy J, O'Donoghue B et al. The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol [version 1; peer review: 2 approved with reservations]. HRB Open Res 2023, 6:75 (https://doi.org/10.12688/hrbopenres.13810.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 07 Dec 2023

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Reviewer Report 10 Dec 2024

Luigi Francesco Saccaro, University of Geneva, Geneva, Switzerland

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15114.r43606

GENERAL COMMENTS

This well-designed, preregistered protocol clearly outlines a systematic review and meta-analysis investigating the short-, medium-, and long-term prevalence of metabolic, cardiovascular, respiratory, and oncologic comorbidities in antipsychotic-naïve or minimally exposed individuals with FEP, aiming to understand the progression of physical health comorbidities.
Observational longitudinal studies and antipsychotic intervention studies will primarily be reviewed to estimate the prevalence of comorbidities across different time intervals and to explore demographic influences. The protocol is expected to adhere to PRISMA and MOOSE guidelines, incorporating a comprehensive search strategy across multiple databases and grey literature, dual independent screening, data extraction, and risk of bias assessment using validated tools (e.g., the JBI Critical Appraisal Checklist). The planned meta-analyses of prevalence data, along with sensitivity analyses and meta-regressions, appear methodologically sound.
Finally, the study intends to generate evidence applicable to early intervention strategies, with a focus on incorporating public and patient involvement (PPI) for dissemination and practical application.

While the clinical relevance and interest of the review are clear, several points need to be addressed, as outlined below.

TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

ABSTRACT
Please briefly mention the main expected limitations in the abstract.

INTRODUCTION
The introduction is well-written and provides appropriate context.

METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.

The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

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: Psychiatry

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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Author Response 08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

08 Jan 2025

Author Response

1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
... Continue reading 1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
Page 1
“The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review and meta-analysis protocol.”

2. ABSTRACT
Please briefly mention the main expected limitations in the abstract.

Response: We thank the Reviewer for their comment. We have added a sentence in the Abstract highlighting potential limitations, including heterogeneity across studies in diagnostic criteria and the risk of underreporting certain physical comorbidities.
Page 3
“Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.”

3. INTRODUCTION
The introduction is well-written and provides appropriate context.

4. METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

Response: We thank the Reviewer for their comment. In the revised manuscript, we now specify that studies with fewer than 10 participants will be classified as case series and excluded. This numeric cutoff (n<10) is stated to ensure clarity in our eligibility criteria.
Page 5
“We will exclude single case studies and case series, specifically defining studies with fewer than 10 participants as case series.”

5. While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

Response: We thank the Reviewer for their comment. We have updated the manuscript to clarify our approach for unresponsive authors: if authors do not reply after two contact attempts within one month, we will proceed without the missing data and consider using sensitivity analyses or excluding that study if the missing data critically affect results.
Page 15
“If authors remain unresponsive, we will either proceed with analyses excluding the missing data or, if the absence critically impairs the study’s utility, exclude that study from meta-analyses and note it in sensitivity analyses. We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

6. A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

Response: We thank the Reviewer for their comment. We have added a new supplementary Table S1 in the revised protocol, presenting our inclusion/exclusion criteria.

7. The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Response: We thank the Reviewer for their comment. After re-evaluating our approach, we have removed the strict exclusion of personality disorders from our protocol. We will instead include all studies that meet our definition of first-episode psychosis (FEP), acknowledging that a subset of participants may have co-occurring personality disorders.

8. Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

Response: We thank the Reviewer for their comment. We have included the below statement that we will examine study IDs, recruitment sites, time frames, and researcher groups to identify overlapping populations. If we identify multiple reports from the same cohort, we will include the most comprehensive dataset.
Page 15
“We will check for overlapping cohorts by examining recruitment site, time frame, and researcher groups. If multiple publications arise from the same study population, we will include the most comprehensive data set.”

9. More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.
Response: We thank the reviewer for their comment. We included more detail on the involvement of PPI in the design of the protocol.

Page 17
“One of the co-authors has lived experience of FEP and serves as an expert by experience, having actively contributed to formulating the protocol and shaping the research question. They will also be involved in interpreting the findings and co-creating dissemination materials.”

10. The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

Response: We thank the Reviewer for their comment. We have updated our data extraction plan to include collection of chlorpromazine-equivalent dosages or similar standardized measures when reported.
Page 15
“We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

11. There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Response: We thank the Reviewer for their comment. We included an explanation that all reported diagnoses will first be recorded as stated (e.g., ICD-10, ICD-11), and where necessary, we will conduct subgroup or sensitivity analyses to account for diagnostic discrepancies. We will also cross-reference ICD-11 criteria when outcomes are ambiguously classified.

12. Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

Response: We thank the Reviewer for their comment. After reconsidering the feedback, we have decided to remove the strict exclusion criteria and associated thresholds for organic psychotic disorders, personality disorders, and neurodevelopmental disorders. Instead, we will include all studies where participants meet a first-episode psychosis (FEP) definition, without imposing a predefined maximum percentage of comorbid presentations, to better capture real-world clinical populations. Regarding antipsychotic exposure, we will maintain the 28-day principle as a guideline for identifying ‘antipsychotic-naïve or minimally exposed’ cohorts, but we will not exclude studies solely if a small proportion of participants exceed this duration. Rather than enforcing a strict 5% threshold, we will record each study’s criteria for antipsychotic exposure, note the proportion of participants exceeding 28 days, and where data permit, conduct sensitivity analyses to determine whether including those with slightly extended exposure materially alters our results. This approach preserves the intent of capturing truly early-stage cohorts while recognizing practical variations in clinical settings.

Page 6
“If a study includes a subset with longer exposure, we will not automatically exclude it but will document the proportion and, if feasible, conduct sensitivity analyses to examine any impact on overall findings.”

13. DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Response: We thank the reviewer for their comment. We have revised the Discussion to more explicitly acknowledge these limitations, explaining how our strict inclusion/exclusion criteria may affect generalizability. We also emphasize possible geographical bias, noting that published studies on FEP often come from high-income nations, potentially limiting applicability to low-resource settings.
Page 17
“We acknowledge that excluding personality disorders may limit the generalizability of our findings to individuals on the broader psychosis spectrum. Additionally, diagnostic differences (e.g., ICD-10 vs. ICD-11) and variation in how outcomes are measured may introduce heterogeneity in prevalence estimates, which we aim to address via subgroup or sensitivity analyses. We also note that many included studies are likely to be conducted in high-income countries, which can reduce the representativeness of the results in low- and middle-income contexts. Despite these potential limitations, the findings of this review will provide insights that can inform clinical practice and early intervention strategies”

14. Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

Response: We thank the Reviewer for their comment. We included more details on the concrete clinical implications and future research directions in the discussion.
Page 18
“The findings can inform targeted interventions and timely management of metabolic, cardiovascular, respiratory, and oncologic risks, as well as highlight the need for embedding structured physical health assessments and integrated care strategies into early intervention services for FEP, informing. Future longitudinal research should evaluate the effectiveness of these approaches while examining genetic, lifestyle, and socioeconomic mechanisms underlying disparities in physical health outcomes.”

15. MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

Response: We thank the Reviewer for their comment. We have carefully reviewed the manuscript to ensure each abbreviation (FEP) is defined at first mention and used consistently thereafter. We have also checked the manuscript for typographical and grammatical errors.
1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
Page 1
“The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review and meta-analysis protocol.”

2. ABSTRACT
Please briefly mention the main expected limitations in the abstract.

Response: We thank the Reviewer for their comment. We have added a sentence in the Abstract highlighting potential limitations, including heterogeneity across studies in diagnostic criteria and the risk of underreporting certain physical comorbidities.
Page 3
“Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.”

3. INTRODUCTION
The introduction is well-written and provides appropriate context.

4. METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

Response: We thank the Reviewer for their comment. In the revised manuscript, we now specify that studies with fewer than 10 participants will be classified as case series and excluded. This numeric cutoff (n<10) is stated to ensure clarity in our eligibility criteria.
Page 5
“We will exclude single case studies and case series, specifically defining studies with fewer than 10 participants as case series.”

5. While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

Response: We thank the Reviewer for their comment. We have updated the manuscript to clarify our approach for unresponsive authors: if authors do not reply after two contact attempts within one month, we will proceed without the missing data and consider using sensitivity analyses or excluding that study if the missing data critically affect results.
Page 15
“If authors remain unresponsive, we will either proceed with analyses excluding the missing data or, if the absence critically impairs the study’s utility, exclude that study from meta-analyses and note it in sensitivity analyses. We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

6. A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

Response: We thank the Reviewer for their comment. We have added a new supplementary Table S1 in the revised protocol, presenting our inclusion/exclusion criteria.

7. The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Response: We thank the Reviewer for their comment. After re-evaluating our approach, we have removed the strict exclusion of personality disorders from our protocol. We will instead include all studies that meet our definition of first-episode psychosis (FEP), acknowledging that a subset of participants may have co-occurring personality disorders.

8. Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

Response: We thank the Reviewer for their comment. We have included the below statement that we will examine study IDs, recruitment sites, time frames, and researcher groups to identify overlapping populations. If we identify multiple reports from the same cohort, we will include the most comprehensive dataset.
Page 15
“We will check for overlapping cohorts by examining recruitment site, time frame, and researcher groups. If multiple publications arise from the same study population, we will include the most comprehensive data set.”

9. More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.
Response: We thank the reviewer for their comment. We included more detail on the involvement of PPI in the design of the protocol.

Page 17
“One of the co-authors has lived experience of FEP and serves as an expert by experience, having actively contributed to formulating the protocol and shaping the research question. They will also be involved in interpreting the findings and co-creating dissemination materials.”

10. The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

Response: We thank the Reviewer for their comment. We have updated our data extraction plan to include collection of chlorpromazine-equivalent dosages or similar standardized measures when reported.
Page 15
“We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

11. There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Response: We thank the Reviewer for their comment. We included an explanation that all reported diagnoses will first be recorded as stated (e.g., ICD-10, ICD-11), and where necessary, we will conduct subgroup or sensitivity analyses to account for diagnostic discrepancies. We will also cross-reference ICD-11 criteria when outcomes are ambiguously classified.

12. Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

Response: We thank the Reviewer for their comment. After reconsidering the feedback, we have decided to remove the strict exclusion criteria and associated thresholds for organic psychotic disorders, personality disorders, and neurodevelopmental disorders. Instead, we will include all studies where participants meet a first-episode psychosis (FEP) definition, without imposing a predefined maximum percentage of comorbid presentations, to better capture real-world clinical populations. Regarding antipsychotic exposure, we will maintain the 28-day principle as a guideline for identifying ‘antipsychotic-naïve or minimally exposed’ cohorts, but we will not exclude studies solely if a small proportion of participants exceed this duration. Rather than enforcing a strict 5% threshold, we will record each study’s criteria for antipsychotic exposure, note the proportion of participants exceeding 28 days, and where data permit, conduct sensitivity analyses to determine whether including those with slightly extended exposure materially alters our results. This approach preserves the intent of capturing truly early-stage cohorts while recognizing practical variations in clinical settings.

Page 6
“If a study includes a subset with longer exposure, we will not automatically exclude it but will document the proportion and, if feasible, conduct sensitivity analyses to examine any impact on overall findings.”

13. DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Response: We thank the reviewer for their comment. We have revised the Discussion to more explicitly acknowledge these limitations, explaining how our strict inclusion/exclusion criteria may affect generalizability. We also emphasize possible geographical bias, noting that published studies on FEP often come from high-income nations, potentially limiting applicability to low-resource settings.
Page 17
“We acknowledge that excluding personality disorders may limit the generalizability of our findings to individuals on the broader psychosis spectrum. Additionally, diagnostic differences (e.g., ICD-10 vs. ICD-11) and variation in how outcomes are measured may introduce heterogeneity in prevalence estimates, which we aim to address via subgroup or sensitivity analyses. We also note that many included studies are likely to be conducted in high-income countries, which can reduce the representativeness of the results in low- and middle-income contexts. Despite these potential limitations, the findings of this review will provide insights that can inform clinical practice and early intervention strategies”

14. Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

Response: We thank the Reviewer for their comment. We included more details on the concrete clinical implications and future research directions in the discussion.
Page 18
“The findings can inform targeted interventions and timely management of metabolic, cardiovascular, respiratory, and oncologic risks, as well as highlight the need for embedding structured physical health assessments and integrated care strategies into early intervention services for FEP, informing. Future longitudinal research should evaluate the effectiveness of these approaches while examining genetic, lifestyle, and socioeconomic mechanisms underlying disparities in physical health outcomes.”

15. MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

Response: We thank the Reviewer for their comment. We have carefully reviewed the manuscript to ensure each abbreviation (FEP) is defined at first mention and used consistently thereafter. We have also checked the manuscript for typographical and grammatical errors.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

08 Jan 2025

Author Response

1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
... Continue reading 1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
Page 1
“The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review and meta-analysis protocol.”

2. ABSTRACT
Please briefly mention the main expected limitations in the abstract.

Response: We thank the Reviewer for their comment. We have added a sentence in the Abstract highlighting potential limitations, including heterogeneity across studies in diagnostic criteria and the risk of underreporting certain physical comorbidities.
Page 3
“Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.”

3. INTRODUCTION
The introduction is well-written and provides appropriate context.

4. METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

Response: We thank the Reviewer for their comment. In the revised manuscript, we now specify that studies with fewer than 10 participants will be classified as case series and excluded. This numeric cutoff (n<10) is stated to ensure clarity in our eligibility criteria.
Page 5
“We will exclude single case studies and case series, specifically defining studies with fewer than 10 participants as case series.”

5. While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

Response: We thank the Reviewer for their comment. We have updated the manuscript to clarify our approach for unresponsive authors: if authors do not reply after two contact attempts within one month, we will proceed without the missing data and consider using sensitivity analyses or excluding that study if the missing data critically affect results.
Page 15
“If authors remain unresponsive, we will either proceed with analyses excluding the missing data or, if the absence critically impairs the study’s utility, exclude that study from meta-analyses and note it in sensitivity analyses. We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

6. A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

Response: We thank the Reviewer for their comment. We have added a new supplementary Table S1 in the revised protocol, presenting our inclusion/exclusion criteria.

7. The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Response: We thank the Reviewer for their comment. After re-evaluating our approach, we have removed the strict exclusion of personality disorders from our protocol. We will instead include all studies that meet our definition of first-episode psychosis (FEP), acknowledging that a subset of participants may have co-occurring personality disorders.

8. Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

Response: We thank the Reviewer for their comment. We have included the below statement that we will examine study IDs, recruitment sites, time frames, and researcher groups to identify overlapping populations. If we identify multiple reports from the same cohort, we will include the most comprehensive dataset.
Page 15
“We will check for overlapping cohorts by examining recruitment site, time frame, and researcher groups. If multiple publications arise from the same study population, we will include the most comprehensive data set.”

9. More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.
Response: We thank the reviewer for their comment. We included more detail on the involvement of PPI in the design of the protocol.

Page 17
“One of the co-authors has lived experience of FEP and serves as an expert by experience, having actively contributed to formulating the protocol and shaping the research question. They will also be involved in interpreting the findings and co-creating dissemination materials.”

10. The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

Response: We thank the Reviewer for their comment. We have updated our data extraction plan to include collection of chlorpromazine-equivalent dosages or similar standardized measures when reported.
Page 15
“We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

11. There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Response: We thank the Reviewer for their comment. We included an explanation that all reported diagnoses will first be recorded as stated (e.g., ICD-10, ICD-11), and where necessary, we will conduct subgroup or sensitivity analyses to account for diagnostic discrepancies. We will also cross-reference ICD-11 criteria when outcomes are ambiguously classified.

12. Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

Response: We thank the Reviewer for their comment. After reconsidering the feedback, we have decided to remove the strict exclusion criteria and associated thresholds for organic psychotic disorders, personality disorders, and neurodevelopmental disorders. Instead, we will include all studies where participants meet a first-episode psychosis (FEP) definition, without imposing a predefined maximum percentage of comorbid presentations, to better capture real-world clinical populations. Regarding antipsychotic exposure, we will maintain the 28-day principle as a guideline for identifying ‘antipsychotic-naïve or minimally exposed’ cohorts, but we will not exclude studies solely if a small proportion of participants exceed this duration. Rather than enforcing a strict 5% threshold, we will record each study’s criteria for antipsychotic exposure, note the proportion of participants exceeding 28 days, and where data permit, conduct sensitivity analyses to determine whether including those with slightly extended exposure materially alters our results. This approach preserves the intent of capturing truly early-stage cohorts while recognizing practical variations in clinical settings.

Page 6
“If a study includes a subset with longer exposure, we will not automatically exclude it but will document the proportion and, if feasible, conduct sensitivity analyses to examine any impact on overall findings.”

13. DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Response: We thank the reviewer for their comment. We have revised the Discussion to more explicitly acknowledge these limitations, explaining how our strict inclusion/exclusion criteria may affect generalizability. We also emphasize possible geographical bias, noting that published studies on FEP often come from high-income nations, potentially limiting applicability to low-resource settings.
Page 17
“We acknowledge that excluding personality disorders may limit the generalizability of our findings to individuals on the broader psychosis spectrum. Additionally, diagnostic differences (e.g., ICD-10 vs. ICD-11) and variation in how outcomes are measured may introduce heterogeneity in prevalence estimates, which we aim to address via subgroup or sensitivity analyses. We also note that many included studies are likely to be conducted in high-income countries, which can reduce the representativeness of the results in low- and middle-income contexts. Despite these potential limitations, the findings of this review will provide insights that can inform clinical practice and early intervention strategies”

14. Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

Response: We thank the Reviewer for their comment. We included more details on the concrete clinical implications and future research directions in the discussion.
Page 18
“The findings can inform targeted interventions and timely management of metabolic, cardiovascular, respiratory, and oncologic risks, as well as highlight the need for embedding structured physical health assessments and integrated care strategies into early intervention services for FEP, informing. Future longitudinal research should evaluate the effectiveness of these approaches while examining genetic, lifestyle, and socioeconomic mechanisms underlying disparities in physical health outcomes.”

15. MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

Response: We thank the Reviewer for their comment. We have carefully reviewed the manuscript to ensure each abbreviation (FEP) is defined at first mention and used consistently thereafter. We have also checked the manuscript for typographical and grammatical errors.
1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
Page 1
“The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review and meta-analysis protocol.”

2. ABSTRACT
Please briefly mention the main expected limitations in the abstract.

Response: We thank the Reviewer for their comment. We have added a sentence in the Abstract highlighting potential limitations, including heterogeneity across studies in diagnostic criteria and the risk of underreporting certain physical comorbidities.
Page 3
“Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.”

3. INTRODUCTION
The introduction is well-written and provides appropriate context.

4. METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

Response: We thank the Reviewer for their comment. In the revised manuscript, we now specify that studies with fewer than 10 participants will be classified as case series and excluded. This numeric cutoff (n<10) is stated to ensure clarity in our eligibility criteria.
Page 5
“We will exclude single case studies and case series, specifically defining studies with fewer than 10 participants as case series.”

5. While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

Response: We thank the Reviewer for their comment. We have updated the manuscript to clarify our approach for unresponsive authors: if authors do not reply after two contact attempts within one month, we will proceed without the missing data and consider using sensitivity analyses or excluding that study if the missing data critically affect results.
Page 15
“If authors remain unresponsive, we will either proceed with analyses excluding the missing data or, if the absence critically impairs the study’s utility, exclude that study from meta-analyses and note it in sensitivity analyses. We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

6. A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

Response: We thank the Reviewer for their comment. We have added a new supplementary Table S1 in the revised protocol, presenting our inclusion/exclusion criteria.

7. The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Response: We thank the Reviewer for their comment. After re-evaluating our approach, we have removed the strict exclusion of personality disorders from our protocol. We will instead include all studies that meet our definition of first-episode psychosis (FEP), acknowledging that a subset of participants may have co-occurring personality disorders.

8. Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

Response: We thank the Reviewer for their comment. We have included the below statement that we will examine study IDs, recruitment sites, time frames, and researcher groups to identify overlapping populations. If we identify multiple reports from the same cohort, we will include the most comprehensive dataset.
Page 15
“We will check for overlapping cohorts by examining recruitment site, time frame, and researcher groups. If multiple publications arise from the same study population, we will include the most comprehensive data set.”

9. More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.
Response: We thank the reviewer for their comment. We included more detail on the involvement of PPI in the design of the protocol.

Page 17
“One of the co-authors has lived experience of FEP and serves as an expert by experience, having actively contributed to formulating the protocol and shaping the research question. They will also be involved in interpreting the findings and co-creating dissemination materials.”

10. The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

Response: We thank the Reviewer for their comment. We have updated our data extraction plan to include collection of chlorpromazine-equivalent dosages or similar standardized measures when reported.
Page 15
“We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

11. There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Response: We thank the Reviewer for their comment. We included an explanation that all reported diagnoses will first be recorded as stated (e.g., ICD-10, ICD-11), and where necessary, we will conduct subgroup or sensitivity analyses to account for diagnostic discrepancies. We will also cross-reference ICD-11 criteria when outcomes are ambiguously classified.

12. Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

Response: We thank the Reviewer for their comment. After reconsidering the feedback, we have decided to remove the strict exclusion criteria and associated thresholds for organic psychotic disorders, personality disorders, and neurodevelopmental disorders. Instead, we will include all studies where participants meet a first-episode psychosis (FEP) definition, without imposing a predefined maximum percentage of comorbid presentations, to better capture real-world clinical populations. Regarding antipsychotic exposure, we will maintain the 28-day principle as a guideline for identifying ‘antipsychotic-naïve or minimally exposed’ cohorts, but we will not exclude studies solely if a small proportion of participants exceed this duration. Rather than enforcing a strict 5% threshold, we will record each study’s criteria for antipsychotic exposure, note the proportion of participants exceeding 28 days, and where data permit, conduct sensitivity analyses to determine whether including those with slightly extended exposure materially alters our results. This approach preserves the intent of capturing truly early-stage cohorts while recognizing practical variations in clinical settings.

Page 6
“If a study includes a subset with longer exposure, we will not automatically exclude it but will document the proportion and, if feasible, conduct sensitivity analyses to examine any impact on overall findings.”

13. DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Response: We thank the reviewer for their comment. We have revised the Discussion to more explicitly acknowledge these limitations, explaining how our strict inclusion/exclusion criteria may affect generalizability. We also emphasize possible geographical bias, noting that published studies on FEP often come from high-income nations, potentially limiting applicability to low-resource settings.
Page 17
“We acknowledge that excluding personality disorders may limit the generalizability of our findings to individuals on the broader psychosis spectrum. Additionally, diagnostic differences (e.g., ICD-10 vs. ICD-11) and variation in how outcomes are measured may introduce heterogeneity in prevalence estimates, which we aim to address via subgroup or sensitivity analyses. We also note that many included studies are likely to be conducted in high-income countries, which can reduce the representativeness of the results in low- and middle-income contexts. Despite these potential limitations, the findings of this review will provide insights that can inform clinical practice and early intervention strategies”

14. Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

Response: We thank the Reviewer for their comment. We included more details on the concrete clinical implications and future research directions in the discussion.
Page 18
“The findings can inform targeted interventions and timely management of metabolic, cardiovascular, respiratory, and oncologic risks, as well as highlight the need for embedding structured physical health assessments and integrated care strategies into early intervention services for FEP, informing. Future longitudinal research should evaluate the effectiveness of these approaches while examining genetic, lifestyle, and socioeconomic mechanisms underlying disparities in physical health outcomes.”

15. MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

Response: We thank the Reviewer for their comment. We have carefully reviewed the manuscript to ensure each abbreviation (FEP) is defined at first mention and used consistently thereafter. We have also checked the manuscript for typographical and grammatical errors.
Competing Interests: No competing interests were disclosed. Close
Report a concern

Views

Reviewer Report 14 Mar 2024

A Dregan, King's College London, London, England, UK

Approved with Reservations

https://doi.org/10.21956/hrbopenres.15114.r38110

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

Partly
Is the study design appropriate for the research question?

Yes
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: Multiple long-term conditions epidemiology and patterning in people with mental health conditions.

CITE

Report a concern

Author Response 08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

08 Jan 2025

Author Response

The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. ... Continue reading The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. The questions are well detailed and clear, and the search strategy and data resources look appropriate for the purposes of the review. This Reviewer has several major questions that needs clarification.

1. Why not focusing on the bidirectional association between FEP and physical LTCs? Some young people with FEP will have pre-existing LTCs that might be negatively impacted by antipsychotic prescribing/FEP symptoms. This is particularly relevant given the focus on prevalence rather than incidence of physical LTCs.

We thank the Reviewer for their comment. In the revised protocol, we now acknowledge that some individuals may have pre-existing LTCs prior to, or at the time of, their FEP diagnosis. We have added a clarifying statement in the Introduction and Methods sections to note that while our primary focus is on the short-, medium-, and long-term prevalence of specific LTCs post-FEP diagnosis, we recognize that some comorbid conditions might precede FEP or be exacerbated by antipsychotic treatment and have added it to our data extraction.

Page 4
“ It also considers that certain comorbid conditions may have been present prior to FEP diagnosis and can be exacerbated by FEP or subsequent antipsychotic treatment.”
Page 5
“Since some participants may have pre-existing comorbidities prior to FEP, the data extraction will consider whether these conditions emerged prior to or following FEP diagnosis.”

2. Antipsychotics are not specific to FEP ( severe anxiety, mood) - would the review exclude interventions in non-FEP patients?

We thank the Reviewer for their comment. Our review aims to include only those antipsychotic intervention studies where participants are antipsychotic-naïve FEP individuals or have no more than 28 days’ antipsychotic exposure (as per Maudsley clinical guidelines). We have clarified in the Eligibility Criteria section that studies focusing on non-FEP populations (e.g., those with severe anxiety or mood disorders alone) will be excluded.

Page 5
“Studies that primarily focus on non-FEP populations, such as those with severe anxiety or mood disorders will be excluded. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis.”

3. Related to 2. - antipsychotics might moderate/mediate the association between FEP and physical LTCs - should be included as a specific aim/RQ.

We thank the Reviewer for their comment. We included the role of antipsychotic medication as a potential moderating or mediating factor between FEP and physical comorbidities as a specific research question:

Page 5
“2. To what extent do antipsychotic medications moderate or mediate the association between FEP and these physical comorbidities?”

4. Some of the details in the Population section might be best placed in the Eligibility criteria and further justified. For instance, why the need to exclude organic psychotic disorders?

We thank the Reviewer for their comment. We have removed the blanket exclusion of organic psychotic disorders from the revised protocol to ensure that our review reflects the heterogeneity of first-episode psychosis presentations.

5. How would quality of included studies be assessed?

We thank the Reviewer for their comment. We will use the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data to assess the quality of included studies:

Page 15
“Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data ( Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer. This tool will help assess study quality based on criteria such as sample representativeness, reliability of outcome measurement, and appropriateness of statistical analysis. The results of this appraisal will inform sensitivity analyses, where we may exclude high-risk studies to assess their impact on pooled estimates.”

6. Social deprivation is a major determinant of FEP and physical LTCs, as it is parental mental health history. Might be worth extending the moderators list.

We thank the Reviewer for their comment. We have now extended the Analysis of subgroups section to include social deprivation status as well as parental mental health history where reported. We note that these factors will be extracted from studies if provided, and we will conduct subgroup/meta-regression analyses on them where there are sufficient data (≥10 studies).

Page 15
“The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, social deprivation measures, parental mental health history, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information.”

Page 16
“Analysis of Subgroups
…We will also include additional variables such as social deprivation status and parental mental health history if reported.”
The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. The questions are well detailed and clear, and the search strategy and data resources look appropriate for the purposes of the review. This Reviewer has several major questions that needs clarification.

1. Why not focusing on the bidirectional association between FEP and physical LTCs? Some young people with FEP will have pre-existing LTCs that might be negatively impacted by antipsychotic prescribing/FEP symptoms. This is particularly relevant given the focus on prevalence rather than incidence of physical LTCs.

We thank the Reviewer for their comment. In the revised protocol, we now acknowledge that some individuals may have pre-existing LTCs prior to, or at the time of, their FEP diagnosis. We have added a clarifying statement in the Introduction and Methods sections to note that while our primary focus is on the short-, medium-, and long-term prevalence of specific LTCs post-FEP diagnosis, we recognize that some comorbid conditions might precede FEP or be exacerbated by antipsychotic treatment and have added it to our data extraction.

Page 4
“ It also considers that certain comorbid conditions may have been present prior to FEP diagnosis and can be exacerbated by FEP or subsequent antipsychotic treatment.”
Page 5
“Since some participants may have pre-existing comorbidities prior to FEP, the data extraction will consider whether these conditions emerged prior to or following FEP diagnosis.”

2. Antipsychotics are not specific to FEP ( severe anxiety, mood) - would the review exclude interventions in non-FEP patients?

We thank the Reviewer for their comment. Our review aims to include only those antipsychotic intervention studies where participants are antipsychotic-naïve FEP individuals or have no more than 28 days’ antipsychotic exposure (as per Maudsley clinical guidelines). We have clarified in the Eligibility Criteria section that studies focusing on non-FEP populations (e.g., those with severe anxiety or mood disorders alone) will be excluded.

Page 5
“Studies that primarily focus on non-FEP populations, such as those with severe anxiety or mood disorders will be excluded. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis.”

3. Related to 2. - antipsychotics might moderate/mediate the association between FEP and physical LTCs - should be included as a specific aim/RQ.

We thank the Reviewer for their comment. We included the role of antipsychotic medication as a potential moderating or mediating factor between FEP and physical comorbidities as a specific research question:

Page 5
“2. To what extent do antipsychotic medications moderate or mediate the association between FEP and these physical comorbidities?”

4. Some of the details in the Population section might be best placed in the Eligibility criteria and further justified. For instance, why the need to exclude organic psychotic disorders?

We thank the Reviewer for their comment. We have removed the blanket exclusion of organic psychotic disorders from the revised protocol to ensure that our review reflects the heterogeneity of first-episode psychosis presentations.

5. How would quality of included studies be assessed?

We thank the Reviewer for their comment. We will use the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data to assess the quality of included studies:

Page 15
“Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data ( Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer. This tool will help assess study quality based on criteria such as sample representativeness, reliability of outcome measurement, and appropriateness of statistical analysis. The results of this appraisal will inform sensitivity analyses, where we may exclude high-risk studies to assess their impact on pooled estimates.”

6. Social deprivation is a major determinant of FEP and physical LTCs, as it is parental mental health history. Might be worth extending the moderators list.

We thank the Reviewer for their comment. We have now extended the Analysis of subgroups section to include social deprivation status as well as parental mental health history where reported. We note that these factors will be extracted from studies if provided, and we will conduct subgroup/meta-regression analyses on them where there are sufficient data (≥10 studies).

Page 15
“The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, social deprivation measures, parental mental health history, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information.”

Page 16
“Analysis of Subgroups
…We will also include additional variables such as social deprivation status and parental mental health history if reported.”
Competing Interests: No competing interests. Close
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Author Response 08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

08 Jan 2025

Author Response

The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. ... Continue reading The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. The questions are well detailed and clear, and the search strategy and data resources look appropriate for the purposes of the review. This Reviewer has several major questions that needs clarification.

1. Why not focusing on the bidirectional association between FEP and physical LTCs? Some young people with FEP will have pre-existing LTCs that might be negatively impacted by antipsychotic prescribing/FEP symptoms. This is particularly relevant given the focus on prevalence rather than incidence of physical LTCs.

We thank the Reviewer for their comment. In the revised protocol, we now acknowledge that some individuals may have pre-existing LTCs prior to, or at the time of, their FEP diagnosis. We have added a clarifying statement in the Introduction and Methods sections to note that while our primary focus is on the short-, medium-, and long-term prevalence of specific LTCs post-FEP diagnosis, we recognize that some comorbid conditions might precede FEP or be exacerbated by antipsychotic treatment and have added it to our data extraction.

Page 4
“ It also considers that certain comorbid conditions may have been present prior to FEP diagnosis and can be exacerbated by FEP or subsequent antipsychotic treatment.”
Page 5
“Since some participants may have pre-existing comorbidities prior to FEP, the data extraction will consider whether these conditions emerged prior to or following FEP diagnosis.”

2. Antipsychotics are not specific to FEP ( severe anxiety, mood) - would the review exclude interventions in non-FEP patients?

We thank the Reviewer for their comment. Our review aims to include only those antipsychotic intervention studies where participants are antipsychotic-naïve FEP individuals or have no more than 28 days’ antipsychotic exposure (as per Maudsley clinical guidelines). We have clarified in the Eligibility Criteria section that studies focusing on non-FEP populations (e.g., those with severe anxiety or mood disorders alone) will be excluded.

Page 5
“Studies that primarily focus on non-FEP populations, such as those with severe anxiety or mood disorders will be excluded. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis.”

3. Related to 2. - antipsychotics might moderate/mediate the association between FEP and physical LTCs - should be included as a specific aim/RQ.

We thank the Reviewer for their comment. We included the role of antipsychotic medication as a potential moderating or mediating factor between FEP and physical comorbidities as a specific research question:

Page 5
“2. To what extent do antipsychotic medications moderate or mediate the association between FEP and these physical comorbidities?”

4. Some of the details in the Population section might be best placed in the Eligibility criteria and further justified. For instance, why the need to exclude organic psychotic disorders?

We thank the Reviewer for their comment. We have removed the blanket exclusion of organic psychotic disorders from the revised protocol to ensure that our review reflects the heterogeneity of first-episode psychosis presentations.

5. How would quality of included studies be assessed?

We thank the Reviewer for their comment. We will use the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data to assess the quality of included studies:

Page 15
“Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data ( Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer. This tool will help assess study quality based on criteria such as sample representativeness, reliability of outcome measurement, and appropriateness of statistical analysis. The results of this appraisal will inform sensitivity analyses, where we may exclude high-risk studies to assess their impact on pooled estimates.”

6. Social deprivation is a major determinant of FEP and physical LTCs, as it is parental mental health history. Might be worth extending the moderators list.

We thank the Reviewer for their comment. We have now extended the Analysis of subgroups section to include social deprivation status as well as parental mental health history where reported. We note that these factors will be extracted from studies if provided, and we will conduct subgroup/meta-regression analyses on them where there are sufficient data (≥10 studies).

Page 15
“The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, social deprivation measures, parental mental health history, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information.”

Page 16
“Analysis of Subgroups
…We will also include additional variables such as social deprivation status and parental mental health history if reported.”
The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. The questions are well detailed and clear, and the search strategy and data resources look appropriate for the purposes of the review. This Reviewer has several major questions that needs clarification.

1. Why not focusing on the bidirectional association between FEP and physical LTCs? Some young people with FEP will have pre-existing LTCs that might be negatively impacted by antipsychotic prescribing/FEP symptoms. This is particularly relevant given the focus on prevalence rather than incidence of physical LTCs.

We thank the Reviewer for their comment. In the revised protocol, we now acknowledge that some individuals may have pre-existing LTCs prior to, or at the time of, their FEP diagnosis. We have added a clarifying statement in the Introduction and Methods sections to note that while our primary focus is on the short-, medium-, and long-term prevalence of specific LTCs post-FEP diagnosis, we recognize that some comorbid conditions might precede FEP or be exacerbated by antipsychotic treatment and have added it to our data extraction.

Page 4
“ It also considers that certain comorbid conditions may have been present prior to FEP diagnosis and can be exacerbated by FEP or subsequent antipsychotic treatment.”
Page 5
“Since some participants may have pre-existing comorbidities prior to FEP, the data extraction will consider whether these conditions emerged prior to or following FEP diagnosis.”

2. Antipsychotics are not specific to FEP ( severe anxiety, mood) - would the review exclude interventions in non-FEP patients?

We thank the Reviewer for their comment. Our review aims to include only those antipsychotic intervention studies where participants are antipsychotic-naïve FEP individuals or have no more than 28 days’ antipsychotic exposure (as per Maudsley clinical guidelines). We have clarified in the Eligibility Criteria section that studies focusing on non-FEP populations (e.g., those with severe anxiety or mood disorders alone) will be excluded.

Page 5
“Studies that primarily focus on non-FEP populations, such as those with severe anxiety or mood disorders will be excluded. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis.”

3. Related to 2. - antipsychotics might moderate/mediate the association between FEP and physical LTCs - should be included as a specific aim/RQ.

We thank the Reviewer for their comment. We included the role of antipsychotic medication as a potential moderating or mediating factor between FEP and physical comorbidities as a specific research question:

Page 5
“2. To what extent do antipsychotic medications moderate or mediate the association between FEP and these physical comorbidities?”

4. Some of the details in the Population section might be best placed in the Eligibility criteria and further justified. For instance, why the need to exclude organic psychotic disorders?

We thank the Reviewer for their comment. We have removed the blanket exclusion of organic psychotic disorders from the revised protocol to ensure that our review reflects the heterogeneity of first-episode psychosis presentations.

5. How would quality of included studies be assessed?

We thank the Reviewer for their comment. We will use the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data to assess the quality of included studies:

Page 15
“Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data ( Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer. This tool will help assess study quality based on criteria such as sample representativeness, reliability of outcome measurement, and appropriateness of statistical analysis. The results of this appraisal will inform sensitivity analyses, where we may exclude high-risk studies to assess their impact on pooled estimates.”

6. Social deprivation is a major determinant of FEP and physical LTCs, as it is parental mental health history. Might be worth extending the moderators list.

We thank the Reviewer for their comment. We have now extended the Analysis of subgroups section to include social deprivation status as well as parental mental health history where reported. We note that these factors will be extracted from studies if provided, and we will conduct subgroup/meta-regression analyses on them where there are sufficient data (≥10 studies).

Page 15
“The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, social deprivation measures, parental mental health history, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information.”

Page 16
“Analysis of Subgroups
…We will also include additional variables such as social deprivation status and parental mental health history if reported.”
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Version 2

VERSION 2 PUBLISHED 07 Dec 2023

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Version 1 07 Dec 23	read	read

A Dregan, King's College London, London, UK
Luigi Francesco Saccaro, University of Geneva, Geneva, Switzerland
Anna Waterreus, University of Western Australia, Crawley, Australia

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23 Jan 2025 | for Version 2

A Dregan, King's College London, London, England, UK

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Approved

I am satisfied with the authors responses to my earlier concerns and I have no further comments. I recommend the article for indexing.

Competing Interests

No competing interests were disclosed.

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.

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23 Jan 2025 | for Version 2

Anna Waterreus, University of Western Australia, Crawley, Australia

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Approved

Thank you for asking me to review this revised study protocol for a systematic review and meta-analysis investigating the prevalence of physical health co-morbities over time in people in their first episode of psychosis.
This document clearly outlines the rationale and methodology for this study.

The abstract and introduction states that people are followed from FEP onset, however, the description in the eligibility criteria is more accurate in that people are being followed from first diagnosis. In some countries the period of time between onset and diagnosis may be short but in others it may not be.

In the last paragraph in Methods the sentence "There will be no restrictions regarding language or publication period." is repeated twice and needs correcting.

Data extraction
A supplementary file which includes the data extract form would enhance the study's replicability.

Data with be extracted on co-morbid substance use disorders. However, what about those people who are using illicit substances but are not diagnosed with a disorder?
Cannabis is commonly used by people with psychotic disorders and may have a positive impact on cardiometabolic risk factors in people with psychotic disorders, in particular in regard to obesity and diabetes, as shown in my 2016 paper.¹A Dutch study² of people with psychotic or mood disorders, reported that cannabis users had smaller waist circumferences and lower diastolic blood pressure than non-users, and Liemburg et al.³ documented that cannabis use was associated with lower BMI in people with psychotic disorders. Studies^4-6 in first-episode psychosis participants showed cannabis users had a better metabolic profile than non-users and that, over time, cannabis users gained significantly less weight and were less likely to experience harmful changes in other metabolic measures.
¹Waterreus A, et al. 2016 (Ref 1)
²Bruins J, et al 2016 (Ref 2)
³Liemburg EJ, et al. 2016 (Ref 3)
⁴Scheffler F, et al. 2018 (Ref 4)
⁵Vázquez-Bourgon J, et al. 2019 (Ref 5)
⁶Stiles E, et al. 2020 (Ref 6)

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?

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

Not applicable

References

1. Waterreus A, Di Prinzio P, Watts GF, Castle D, et al.: Metabolic syndrome in people with a psychotic illness: is cannabis protective?. Psychol Med. 2016; 46 (8): 1651-62 PubMed Abstract | Publisher Full Text
2. Bruins J, Pijnenborg MG, Bartels-Velthuis AA, Visser E, et al.: Cannabis use in people with severe mental illness: The association with physical and mental health--a cohort study. A Pharmacotherapy Monitoring and Outcome Survey study.J Psychopharmacol. 2016; 30 (4): 354-62 PubMed Abstract | Publisher Full Text
3. Liemburg EJ, Bruins J, van Beveren N, Islam MA, et al.: Cannabis and a lower BMI in psychosis: What is the role of AKT1?. Schizophr Res. 2016; 176 (2-3): 95-99 PubMed Abstract | Publisher Full Text
4. Scheffler F, Kilian S, Chiliza B, Asmal L, et al.: Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders.Schizophr Res. 2018; 199: 90-95 PubMed Abstract | Publisher Full Text
5. Vázquez-Bourgon J, Setién-Suero E, Pilar-Cuéllar F, Romero-Jiménez R, et al.: Effect of cannabis on weight and metabolism in first-episode non-affective psychosis: Results from a three-year longitudinal study.J Psychopharmacol. 2019; 33 (3): 284-294 PubMed Abstract | Publisher Full Text
6. Stiles E, Alcover KC, Stiles B, Oluwoye O, et al.: Cannabis use and metabolic syndrome among clients with first episode psychosis.Early Interv Psychiatry. 2021; 15 (4): 1051-1055 PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

My research focuses on people with psychotic disorders and their physical health outcomes.

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.

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10 Jan 2025 | for Version 2

Luigi Francesco Saccaro, University of Geneva, Geneva, Switzerland

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Approved

The authors have addressed all comments appropriately, and I look forward to the results of this interesting meta-analysis. Best of luck!

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Psychiatry

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.

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14 Views

10 Dec 2024 | for Version 1

Luigi Francesco Saccaro, University of Geneva, Geneva, Switzerland

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?

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

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Psychiatry

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Author Response

08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

1. TITLE
The title is appropriate, but I suggest including a reference to the potential meta-analysis.

We thank the Reviewer for their comment. We have revised the manuscript title:
Page 1
“The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review and meta-analysis protocol.”

2. ABSTRACT
Please briefly mention the main expected limitations in the abstract.

Response: We thank the Reviewer for their comment. We have added a sentence in the Abstract highlighting potential limitations, including heterogeneity across studies in diagnostic criteria and the risk of underreporting certain physical comorbidities.
Page 3
“Potential limitations include the risk of diagnostic heterogeneity across studies and possible underreporting of certain comorbidities.”

3. INTRODUCTION
The introduction is well-written and provides appropriate context.

4. METHODS

The protocol should specify the cutoff sample size to define and exclude a case series, for example, n<11, to ensure clarity in eligibility criteria.

Response: We thank the Reviewer for their comment. In the revised manuscript, we now specify that studies with fewer than 10 participants will be classified as case series and excluded. This numeric cutoff (n<10) is stated to ensure clarity in our eligibility criteria.
Page 5
“We will exclude single case studies and case series, specifically defining studies with fewer than 10 participants as case series.”

5. While the protocol mentions contacting authors twice for missing data, it does not outline fallback strategies for unresponsive authors (a common situation unfortunately…). Alternative approaches, such as imputing missing data or excluding studies, should be provided to address this limitation.

Response: We thank the Reviewer for their comment. We have updated the manuscript to clarify our approach for unresponsive authors: if authors do not reply after two contact attempts within one month, we will proceed without the missing data and consider using sensitivity analyses or excluding that study if the missing data critically affect results.
Page 15
“If authors remain unresponsive, we will either proceed with analyses excluding the missing data or, if the absence critically impairs the study’s utility, exclude that study from meta-analyses and note it in sensitivity analyses. We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

6. A supplementary table summarizing inclusion and exclusion criteria in a structured format (e.g., PICOS or CoCoPop) would enhance transparency. This table should include a detailed list of DSM-5 diagnoses under consideration. For example, it is unclear whether Type I bipolar disorder is included, and a justification for either choice is necessary.

Response: We thank the Reviewer for their comment. We have added a new supplementary Table S1 in the revised protocol, presenting our inclusion/exclusion criteria.

7. The exclusion of personality disorders should be better justified given the increasing body of literature exploring the psychosis spectrum.

Response: We thank the Reviewer for their comment. After re-evaluating our approach, we have removed the strict exclusion of personality disorders from our protocol. We will instead include all studies that meet our definition of first-episode psychosis (FEP), acknowledging that a subset of participants may have co-occurring personality disorders.

8. Additionally, the protocol should provide further details on how studies involving overlapping populations will be identified and managed to avoid duplication and ensure accurate synthesis.

Response: We thank the Reviewer for their comment. We have included the below statement that we will examine study IDs, recruitment sites, time frames, and researcher groups to identify overlapping populations. If we identify multiple reports from the same cohort, we will include the most comprehensive dataset.
Page 15
“We will check for overlapping cohorts by examining recruitment site, time frame, and researcher groups. If multiple publications arise from the same study population, we will include the most comprehensive data set.”

9. More specific details on the involvement of patients and the public (PPI) in the design of the protocol would be helpful to clarify the extent of their contributions.
Response: We thank the reviewer for their comment. We included more detail on the involvement of PPI in the design of the protocol.

Page 17
“One of the co-authors has lived experience of FEP and serves as an expert by experience, having actively contributed to formulating the protocol and shaping the research question. They will also be involved in interpreting the findings and co-creating dissemination materials.”

10. The protocol should also include plans to extract data on average chlorpromazine equivalents or another standardized measure of antipsychotic dosage as a covariate, to facilitate comparisons across studies.

Response: We thank the Reviewer for their comment. We have updated our data extraction plan to include collection of chlorpromazine-equivalent dosages or similar standardized measures when reported.
Page 15
“We will also collect data on average chlorpromazine equivalents or another standardized antipsychotic dosage measure when reported, to facilitate cross-study comparisons.”

11. There should be greater specificity regarding how inconsistencies in diagnostic criteria between studies, such as differences between ICD-10 and ICD-11, will be harmonized or accounted for in the analysis.

Response: We thank the Reviewer for their comment. We included an explanation that all reported diagnoses will first be recorded as stated (e.g., ICD-10, ICD-11), and where necessary, we will conduct subgroup or sensitivity analyses to account for diagnostic discrepancies. We will also cross-reference ICD-11 criteria when outcomes are ambiguously classified.

12. Finally, the thresholds of 5% for antipsychotic exposure and 20% for neurodivergence require justification, ideally supported by prior literature or pilot analyses, to ensure these decisions are evidence-based.

Response: We thank the Reviewer for their comment. After reconsidering the feedback, we have decided to remove the strict exclusion criteria and associated thresholds for organic psychotic disorders, personality disorders, and neurodevelopmental disorders. Instead, we will include all studies where participants meet a first-episode psychosis (FEP) definition, without imposing a predefined maximum percentage of comorbid presentations, to better capture real-world clinical populations. Regarding antipsychotic exposure, we will maintain the 28-day principle as a guideline for identifying ‘antipsychotic-naïve or minimally exposed’ cohorts, but we will not exclude studies solely if a small proportion of participants exceed this duration. Rather than enforcing a strict 5% threshold, we will record each study’s criteria for antipsychotic exposure, note the proportion of participants exceeding 28 days, and where data permit, conduct sensitivity analyses to determine whether including those with slightly extended exposure materially alters our results. This approach preserves the intent of capturing truly early-stage cohorts while recognizing practical variations in clinical settings.

Page 6
“If a study includes a subset with longer exposure, we will not automatically exclude it but will document the proportion and, if feasible, conduct sensitivity analyses to examine any impact on overall findings.”

13. DISCUSSION & CONCLUSIONS

The discussion should expand on the limitations of the study, particularly those highlighted in the methods section that could not be fully addressed. For instance, the implications of excluding personality disorders and the potential impact of diagnostic inconsistencies on the findings should be explicitly discussed.

The representativeness of the included studies is another area requiring attention. For example, studies from high-income countries may not reflect the prevalence or progression of physical health comorbidities in low- and middle-income settings. This disparity should be explicitly acknowledged, and its implications for generalizability should be considered.

Response: We thank the reviewer for their comment. We have revised the Discussion to more explicitly acknowledge these limitations, explaining how our strict inclusion/exclusion criteria may affect generalizability. We also emphasize possible geographical bias, noting that published studies on FEP often come from high-income nations, potentially limiting applicability to low-resource settings.
Page 17
“We acknowledge that excluding personality disorders may limit the generalizability of our findings to individuals on the broader psychosis spectrum. Additionally, diagnostic differences (e.g., ICD-10 vs. ICD-11) and variation in how outcomes are measured may introduce heterogeneity in prevalence estimates, which we aim to address via subgroup or sensitivity analyses. We also note that many included studies are likely to be conducted in high-income countries, which can reduce the representativeness of the results in low- and middle-income contexts. Despite these potential limitations, the findings of this review will provide insights that can inform clinical practice and early intervention strategies”

14. Further details on the concrete clinical implications of the review's findings would strengthen the discussion. For example, how might the findings inform potential interventions or changes in clinical practice? Suggesting future research directions, such as investigating the mechanisms underlying disparities in physical health outcomes or conducting longitudinal studies to evaluate intervention effectiveness, would also add value.

Response: We thank the Reviewer for their comment. We included more details on the concrete clinical implications and future research directions in the discussion.
Page 18
“The findings can inform targeted interventions and timely management of metabolic, cardiovascular, respiratory, and oncologic risks, as well as highlight the need for embedding structured physical health assessments and integrated care strategies into early intervention services for FEP, informing. Future longitudinal research should evaluate the effectiveness of these approaches while examining genetic, lifestyle, and socioeconomic mechanisms underlying disparities in physical health outcomes.”

15. MINOR COMMENTS

All abbreviations should be defined upon their first use, including those in table legends. Abbreviations should then be used consistently throughout the text. For example, “FEP” and “first-episode psychosis” are used interchangeably in the current draft, and this inconsistency should be corrected.

Additionally, typos and grammatical mistakes should be corrected to improve the overall readability of the manuscript.

Response: We thank the Reviewer for their comment. We have carefully reviewed the manuscript to ensure each abbreviation (FEP) is defined at first mention and used consistently thereafter. We have also checked the manuscript for typographical and grammatical errors.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

14 Views

14 Mar 2024 | for Version 1

A Dregan, King's College London, London, England, UK

14 Views Cite this report Responses(1)

Approved With Reservations

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

Partly
Is the study design appropriate for the research question?

Yes
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

Multiple long-term conditions epidemiology and patterning in people with mental health conditions.

Respond to this report

Responses (1)

Author Response

08 Jan 2025

Anna Zierotin, Department of Psychiatry, University College Dublin, Dublin, Ireland

The work represents the protocol of a proposed study to synthesize current evidence on the link between FEP and antipsychotic drugs with a restricted number of major physical long-term conditions. The questions are well detailed and clear, and the search strategy and data resources look appropriate for the purposes of the review. This Reviewer has several major questions that needs clarification.

1. Why not focusing on the bidirectional association between FEP and physical LTCs? Some young people with FEP will have pre-existing LTCs that might be negatively impacted by antipsychotic prescribing/FEP symptoms. This is particularly relevant given the focus on prevalence rather than incidence of physical LTCs.

We thank the Reviewer for their comment. In the revised protocol, we now acknowledge that some individuals may have pre-existing LTCs prior to, or at the time of, their FEP diagnosis. We have added a clarifying statement in the Introduction and Methods sections to note that while our primary focus is on the short-, medium-, and long-term prevalence of specific LTCs post-FEP diagnosis, we recognize that some comorbid conditions might precede FEP or be exacerbated by antipsychotic treatment and have added it to our data extraction.

Page 4
“ It also considers that certain comorbid conditions may have been present prior to FEP diagnosis and can be exacerbated by FEP or subsequent antipsychotic treatment.”
Page 5
“Since some participants may have pre-existing comorbidities prior to FEP, the data extraction will consider whether these conditions emerged prior to or following FEP diagnosis.”

2. Antipsychotics are not specific to FEP ( severe anxiety, mood) - would the review exclude interventions in non-FEP patients?

We thank the Reviewer for their comment. Our review aims to include only those antipsychotic intervention studies where participants are antipsychotic-naïve FEP individuals or have no more than 28 days’ antipsychotic exposure (as per Maudsley clinical guidelines). We have clarified in the Eligibility Criteria section that studies focusing on non-FEP populations (e.g., those with severe anxiety or mood disorders alone) will be excluded.

Page 5
“Studies that primarily focus on non-FEP populations, such as those with severe anxiety or mood disorders will be excluded. If mixed samples (for example, severe mental illness groups) are used, we will attempt to extract the data specific to people with psychosis.”

3. Related to 2. - antipsychotics might moderate/mediate the association between FEP and physical LTCs - should be included as a specific aim/RQ.

We thank the Reviewer for their comment. We included the role of antipsychotic medication as a potential moderating or mediating factor between FEP and physical comorbidities as a specific research question:

Page 5
“2. To what extent do antipsychotic medications moderate or mediate the association between FEP and these physical comorbidities?”

4. Some of the details in the Population section might be best placed in the Eligibility criteria and further justified. For instance, why the need to exclude organic psychotic disorders?

We thank the Reviewer for their comment. We have removed the blanket exclusion of organic psychotic disorders from the revised protocol to ensure that our review reflects the heterogeneity of first-episode psychosis presentations.

5. How would quality of included studies be assessed?

We thank the Reviewer for their comment. We will use the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data to assess the quality of included studies:

Page 15
“Two reviewers will independently assess the risk of bias in included studies using the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data ( Munn et al., 2015). Disagreements between reviewers will be resolved by discussion with a third reviewer. This tool will help assess study quality based on criteria such as sample representativeness, reliability of outcome measurement, and appropriateness of statistical analysis. The results of this appraisal will inform sensitivity analyses, where we may exclude high-risk studies to assess their impact on pooled estimates.”

6. Social deprivation is a major determinant of FEP and physical LTCs, as it is parental mental health history. Might be worth extending the moderators list.

We thank the Reviewer for their comment. We have now extended the Analysis of subgroups section to include social deprivation status as well as parental mental health history where reported. We note that these factors will be extracted from studies if provided, and we will conduct subgroup/meta-regression analyses on them where there are sufficient data (≥10 studies).

Page 15
“The extracted information will include authors, title, publication year, country, study design, data collection timeframe, setting, recruitment, inclusion/exclusion criteria, the number of participants, age, sex, ethnicity, psychosis diagnosis type, method of diagnosing, medication status, year of follow-up, method of diagnosing physical outcomes, prevalence/incidence estimates at baseline and at >0–12 months, or 13–36 months, or 37–60 months, or after more than 5 years after a FEP diagnosis, percentage smoking, comorbid mental disorders/substance abuse disorders, social deprivation measures, parental mental health history, covariates adjusted for, control group/comparator data, funding sources/conflicts of interest, and additional information.”

Page 16
“Analysis of Subgroups
…We will also include additional variables such as social deprivation status and parental mental health history if reported.”

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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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The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol

Abstract

Background

Methods

Conclusions

Registration

Keywords

Introduction

Review questions

Methods

Study registration

Eligibility criteria

Population

Outcomes

Information sources

Search strategy

Table 1. This table lists the search terms, and Boolean operators used to identify studies on psychotic disorders and their associations with cardiovascular, metabolic, respiratory and cancer outcomes.

Study selection

Data extraction

Risk of bias in individual studies

Strategy of data synthesis

Analysis of subgroups

Public and patient involvement and dissemination plans

Study status

Discussion

Data availability

Underlying data

Reporting guidelines

References

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The short-, medium-, and long-term prevalence of physical health comorbidities in first-episode psychosis: a systematic review protocol

Abstract

Background

Methods

Conclusions

Registration

Keywords

Introduction

Review questions

Methods

Study registration

Eligibility criteria

Population

Outcomes

Information sources

Search strategy

Table 1. This table lists the search terms, and Boolean operators used to identify studies on psychotic disorders and their associations with cardiovascular, metabolic, respiratory and cancer outcomes.

Study selection

Data extraction

Risk of bias in individual studies

Strategy of data synthesis

Analysis of subgroups

Public and patient involvement and dissemination plans

Study status

Discussion

Data availability

Underlying data

Reporting guidelines

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

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Are you a HRB-funded researcher?

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