Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

Tilahun Ali; Mekonnen Sisay; Mandaras Tariku; Abraham Nigussie Mekuria; Assefa Desalew

doi:10.1371/journal.pone.0257129

. 2021 Sep 10;16(9):e0257129. doi: 10.1371/journal.pone.0257129

Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

Tilahun Ali ^1,^*, Mekonnen Sisay ², Mandaras Tariku ¹, Abraham Nigussie Mekuria ², Assefa Desalew ³

Editor: Xenia Gonda⁴

PMCID: PMC8432767 PMID: 34506552

Abstract

Background

Antipsychotic agents are the basis for the pharmacological management of acute and chronic schizophrenia, bipolar disorders, mood disorders with psychotic feature, and other psychotic disorders. Antipsychotic medication use is frequently associated with unfavorable adverse effects such as extrapyramidal side effects (EPSEs). Hence, this systematic review and meta-analysis was aimed to determine the magnitude of antipsychotic-induced EPSEs.

Method

A literature search was conducted using legitimate databases, indexing services, and directories including PubMed/MEDLINE (Ovid^®), EMBASE (Ovid^®), google scholar and WorldCat to retrieve studies. Following screening and eligibility, the relevant data were extracted from the included studies using an Excel sheet and exported to STATA 15.0 software for analyses. The Random effects pooling model was used to analyze outcome measures at a 95% confidence interval. Besides, publication bias analysis was conducted. The protocol has been registered on PROSPERO with ID: CRD42020175168.

Result

In total, 15 original articles were included for the systematic review and meta-analysis. The pooled prevalence of antipsychotic-induced EPSEs among patient taking antipsychotic medications was 37% (95% CI: 18–55%, before sensitivity) and 31% (95% CI: 19–44%, after sensitivity). The prevalence of antipsychotic-induced parkinsonism, akathisia, and tardive dyskinesia was 20% (95% CI: 11–28%), 11% (95% CI: 6–17%), and 7% (95% CI: 4–9%), respectively. To confirm a small-study effect, Egger’s regression test accompanied by funnel plot asymmetry demonstrated that there was a sort of publication bias in studies reporting akathisia and tardive dyskinesia.

Conclusion

The prevalence of antipsychotic-induced EPSEs was considerably high. One in five and more than one in ten patients experienced parkinsonism and akathisia, respectively. Appropriate prevention and early management of these effects can enhance the net benefits of antipsychotics.

Introduction

Antipsychotic agents are the foundation of the pharmacological management of acute and chronic schizophrenia, bipolar mood disorders, and other psychotic disorders [1]. They are classified as first-generation antipsychotics (FGAs), also called conventional (typical) agents and second-generation antipsychotics (SGAs) which also termed as atypical agents [2]. Like other medications, antipsychotic medications have both beneficial and harmful effects at the optimum dose used for the treatment purpose [3]. One of the major side effects of antipsychotics is extrapyramidal side effects (EPSEs), as they can cause distress and worsening psychopathological states [4, 5]. EPSEs also called drug-induced movement disorders include a wide variety of movement disorders and can be classified into acute and tardive symptoms, such as parkinsonism, dystonia, tardive dyskinesia (TD), and akathisia. These are a major class of neurologic adverse effects associated with antipsychotic medications with the typical agents taking the overwhelming majority [6, 7]. This side effects can stigmatize and cause patients’ subjective distress, both of which are disincentives to continue to take medication. Moreover, they can confound the clinical assessment of negative symptoms of schizophrenia [8] and may lead to misdiagnosis and false conclusion that an increase in dose of antipsychotic medication is required, further exacerbating the problem.

An acute syndrome occur within days or weeks after starting an antipsychotic, or after increasing the dose and the tardive syndrome might be developed after months or years of antipsychotic treatment [9]. TD has been proposed to be caused by a relative cholinergic deficiency secondary to super-sensitivity of dopamine receptors in the striatum (caudate-putamen complex). Broadly, proposed mechanisms underlying these adverse events include decreased dopamine concentrations in the striatal area and dopamine hypersensitivity for drug-induced parkinsonism and TD, respectively [10, 11]. Pharmacologic treatment approaches for drug-induced parkinsonism have commonly included centrally acting anticholinergic agents such as benztropine; however, anticholinergic medications can make TD worse. Hence, switching the antipsychotic medication to those with lower propensity for parkinsonian and TD symptoms is worth mentioning [11].

Research-based evidence reported that the prevalence of antipsychotic-induced movement disorders among patients on long-term treatment with FGAs was around to be 50 to 75% [12]. SGAs such as quetiapine, olanzapine, and risperidone, have a lower liability for developing EPSEs compared with FGAs but there is some evidence of a lower risk of TD. This is because SGAs have looser interaction (lower affinity) with Dopamine (D2) receptor in the striatum [12]. Nevertheless, even with these newer agents, movement disorders are seen in a significant proportion of patients [13]. A meta-analysis of twelve trials, conducted in 2008, revealed that the annualized TD incidence was 3.9% for SGAs and 5.5% for FGAs. This data supports the relatively lower TD risk of SGAs. However, this study considered only one of the EPSEs (i.e. TD) and included clinical trials [14]. The safety of antipsychotic drugs in natural settings has been ignored. Another peer-reviewed medical literature showed that akathisia was reported to occur in 25.9% of patients [15]. A study conducted with patient medical charts at a medical center in southern Taiwan showed that, of the 123 included subjects, 35 (28.5%) were found to have at least one episode of the tardive syndrome. The prevalence of subtypes of the tardive syndrome was 21.1%, 12.5%, 2.4% and 2.4% for tardive dystonia, tardive tremor, TD and tardive akathisia, respectively [16]. Generally, the use of atypical antipsychotics may have reduced EPSEs but findings are inconsistent and drug-specific as well as available evidence are quite disagreeing each other especially for TD and akathisia [17]. Besides, SGAs differ in many properties including safety, efficacy, cost and other pharmacological profiles. Hence it is too early to conclude about their EPSE profiles [18]. Meta-analysis of studies at natural treatment settings is also worth considering to explore the magnitude of the problem in real settings.

Hence, the main aim of this study is to provide conclusive and comprehensive evidence on the prevalence of antipsychotic medication-induced EPSEs and to formulate recommendations for policymakers, programmers, researchers, and clinical practice.

Methods

Study protocol and registration

The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guideline was used for screening and eligibility evaluation of retrieved studies for systematic review and meta-analysis [19]. This systematic review and meta-analysis was conducted in accordance with the PRISMA Protocol [20]. In addition, the entire content of this systematic review and meta-analysis has been well reported in page by page in the completed PRISMA checklist (S1 Table). The study protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with a unique ID: CRD42020175168 and available online at: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42020175168&ID=CRD42020175168.

Data sources and search strategy

An electronic search was performed on legitimate databases and search engines including PubMed/ MEDLINE (Ovid), and EMBASE (Ovid), PsycInfo with predefined keywords, indexing and Medical Subject Headings (MeSH) terms until March 31^st, 2020. The keywords and MeSH terms used for searching were “antipsychotic agents”, “neuroleptic”, “major tranquilizers”, antipsychotic*, “extrapyramidal side effects”, “extrapyramidal symptoms”, EPS “movement disorders” [MeSH], EPSE, “motor disorders” [MeSH]. Searching on Google Scholar and WorldCat was also undertaken to identify other relevant works published in journals not indexed in legitimate databases and indexing interfaces, and to retrieve unpublished works (grey literature) including thesis/dissertations, institutional repositories, and organizational manuals, among others. Boolean operators (AND, OR) and truncation were used when appropriate to fine-tune the search and increase the chance of addressing relevant findings. Additionally, we back-traced the reference lists of retrieved articles to identify further relevant studies.

Inclusion and exclusion criteria

During the screening and eligibility processes, there were predefined inclusion and exclusion criteria. Observational studies (cross-sectional or cohort) addressing antipsychotic-induced EPSEs in natural settings were included. Restrictions were applied on the year of publication (i.e., 2000 and onwards) and the language of publication (articles written in English) for the sake of considering methodological updates, time sensitivity and consistency of studies. During the screening process of titles and abstracts, unrelated (off-target) articles, review papers, editorials, commentaries, opinions, qualitative studies, case reports and case series were excluded. Studies addressing drug induced-EPSEs in animal model (preclinical) as well as experimental (interventional) studies were also excluded during the selection process. We also excluded studies with incomplete information and those with mixed or non-specific outcome measures during the eligibility evaluation. At this stage, studies having irretrievable full texts (after requesting full texts from the corresponding authors via email and/or Research Gate account); studies with unrelated or insufficient outcome measures and studies with missed or ambiguous outcomes of interest were excluded.

Screening and eligibility process

The retrieved citations from various databases and search engines were imported to ENDNOTE version 7.2 software (Thomson Reuters, Stamford, CT, USA) with compatible file formats. Then, all citation lists from the aforementioned data sources were combined in one folder. Duplicate records were identified, recorded, and removed with the help of ENDNOTE software followed by careful visual inspection considering distinct referencing styles of sources in which the software could not detect as duplicate. Each record was independently assessed by two authors (TA and MS) using the predefined inclusion and exclusion criteria stated above. Following the initial screening of records with their titles and abstracts, a rigorous eligibility assessment of full texts was performed. Disagreements raised among authors during screening and eligibility process were solved with discussion and consultation of the rest authors (AD and ANM).

Data extraction

Data extraction format prepared in Microsoft Excel sheet (S2 Table) was developed to extract data from each included study. The two authors (TA and MT) independently extracted data related to methodological characteristics and outcome measures including first author, publication year, study design and populations, study settings and country, overall drug regimen, sample size, type of EPSEs and/or their components.

Critical appraisal of studies (risk of bias assessment)

Following the assessment of eligible articles, two authors (TA and ANM) independently assessed the methodological validity and analysis of outcome measures using the Joanna Briggs Institute (JBI) critical appraisal checklist for observational studies, University of Adelaide, Australia [21]. This critical appraisal was conducted to assess the internal (systematic error) and external (generalizability) validity of studies and to determine the extent to which each study has addressed the possibility of bias in its design, conduct, and analysis. The assessment tool consisted of ten and eleven design-specific questions for cross-sectional and cohort studies, respectively. They are designed to address the quality of the study for which articles were given one of the following responses for each question: Yes, No, Unclear or Not applicable. The mean score of the two authors was taken for the final decision and studies with a score of ‘Yes’ greater than or equal to half of the respective number of appraisal questions were included in the study.

Outcome measurements

In this meta-analysis, the primary outcome of interest was the magnitude of antipsychotic medications-induced overall motor disorders/EPSEs and/or one of the components (i.e., parkinsonism, akathisia, and TD). Subgroup analyses were undertaken based on the geographic location and study setting.

Data processing and analysis

The extracted data were exported from Excel to STATA 15.0 software (Stata Corporation, College Station, TX, USA) for analyses of overall outcome measures, subgroups and publication bias. Considering the variation in true effect sizes across the population, the inverse variance (IV) method with random effects pooling model was applied for meta- analysis at a 95% confidence level. The heterogeneity of studies was assessed using I² statistics. The “leave-one-out” sensitivity analysis was carried out to assess outliers that likely have a substantial impact on the overall effect size and between study heterogeneity [22]. The presence of publication bias was determined by visualization of funnel plot asymmetry supplemented with Egger’s regression test [23, 24]. Statistical tests were declared significant at cutoff point of p < 0.05 (two-sided).

Results

Search findings

A total of 1933 studies were retrieved through visiting legitimate electronic databases, indexing services, search engines, and repositories. From these, 934 duplicate studies were identified and removed using ENDNOTE followed by careful visual inspection. Then, 999 records were retained for further screening of their titles and abstracts. Among which, a total of 941 records (723 studies with titles and 218 studies with abstracts) were excluded. The full texts of the remaining 58 studies were thoroughly assessed for their eligibility and 43 of which were excluded for various reasons such as studies that didn’t report the study outcome, having incomplete information, and/or those reported vague or mixed findings. Finally, 15 studies were included in the systematic review and meta-analysis (Fig 1).

Results of critical appraisal

Studies that fulfilled the inclusion criteria were subjected for further rigorous appraisal using the JBI checklist for observational studies (cross-sectional and cohort studies with 9 to 11-scaled questions, respectively). During the quality assessment, the average quality scores of individual studies ranged between 6 and 10. Finally, 15 studies were included in systematic review and meta-analysis (S3 Table).

Study characteristics

A total of 15 studies were included in this systematic review and meta-analysis. The publication years of the included studies ranged from 2000 to 2019. Regarding the geographical distribution, the review included six studies from Europe [4, 25–29], five studies from Asia [30–34], two studies from Africa [35, 36], one study from South America [37], and one study from North America [38]. Thirteen of these studies had employed cross-sectional design [4, 26, 28–31, 33–37] with two of which being a retrospective chart review [25, 32] and the remaining two studies had employed cohort design [27, 38]. The sample size of individual studies ranged from 28 [29] to 164,417 [38]. Thirteen studies were conducted in hospital settings [4, 26–31, 33–38] whereas two studies were conducted at rehabilitation centers [25, 32]. Majority of studies were conducted on adult patients with schizophrenic or schizoaffective disorders whereas the rest studies were conducted on non-specific psychotic patients, acute psychotic patients with substance use disorder, and patients with severe mental illness. Regarding the regimen, seven studies reported mixed use of both typical and atypical antipsychotics [25, 27–30, 33, 38], five studies reported independent use of either oral or depot (IM) typical antipsychotics (primarily phenothiazines and thioxanthenes) [4, 31, 32, 35, 36] and three studies included participants who took atypical agents only [26, 34, 37]. Regarding the outcome measures, twelve studies reported the overall magnitude of antipsychotic-induced EPSEs [25, 26, 28–37]. Looking at individual components of EPSEs, nine, nine and eight studies reported drug-induced parkinsonism, akathisia and TD, respectively. All included studies utilized standardized measurement scales such as Barnes Akathisia Scale [39], Modified Simpson-Angus Scale [40] or Unified Parkinson Disease Rating Scale (UPDRS) [41], and Abnormal Involuntary Movement Scale (AIMS) [42] for rating akathisia, parkinsonism, and TD, respectively (Table 1).

Table 1. Summary of studies included in the systematic review and meta-analysis.

Author, year	Country	Design	Participants	Setting	Drug and regimen	Sample size	Overall EPSEs	TD	Akathisia	Parkinsonism
Araújo A. et al., 2016 [37]	Brazil	CS	Schizophrenic patients (age:18–65 years)	Hospital	Atypical antipsychotics (Olanzapine, risperidone, ziprasidone, Clozapine)	213	81	NS	NS	NS
Dhavale H. et al., 2004 [31]	India	CS	Psychiatric patients	Hospital	Haloperidol 2-13mg/day equivalent for 02 months	71	68	NS	NS	NS
Duangrithi D.et al., 2016 [32]	Thailand	CS (R)	Acute psychotic patients with SUD	Rehabilitation center	Depot (IM) antipsychotic agents (Haloperidol or Zuclopenthixol or combination)	153	12	NS	7/153	NS
Gebhardt S.et al., 2006 [25]	Germany	CS (R)	Adolescent psychotic patients	Rehabilitation center	Atypical (81.7%) or typical (10.8%) 0r combination (7.5%) for greater than one year	93	37	5	1	2
Ghoreishizadeh M. and Deldoost F. 2008 [34]	Iran	CS	Schizophrenic and Schizoaffective patients (age: 18–60 years)	Hospital	Risperidone 2mg/day for 6 weeks	100	28		5	23
Luft B. and Berent E., 2009 [26]	UK	CS	Psychotic patients	Hospital	Long acting (depot) antipsychotics (Risperidone) inj.	43	23	10	12	13
Mentzel L., et al., 2017 [33]	Netherlands	CS	patients with severe mental illness	Hospital	Both typical and atypical (not specified)	191	35	NS	NS	NS
Moreno-Calvete MC. 2013 [29]	Spain	CS	Schizophrenic patients (> 18 years)	Hospital	Both typical and atypical (not specified) for greater than 6 months	28	6	1	2	4
Ojagbemi A.et al., 2018 [36]	South Africa & Nigeria	CS	Schizophrenic patients (> 18 years)	Hospital	Flupenthixol decanoate (< = 30 mg) for 03 months	99	34	NS	NS	NS
Taye H.et al., 2014 [35]	Ethiopia	CS	Psychotic outpatients	Hospital	Chlorpromazine (> = 400 mg/day) equivalent	377	212	45	108	175
Desai N. et al.2017 [30]	India	CS	Psychiatric patients (20–60 years)	Hospital	Monotherapy primarily atypical and the rest typical and combination therapy	706	40	4	6	36
Loughlin AM. et al., 2019 [38]	USA	Cohort study (R)	All antipsychotic users (> 18 years)	Database	Antipsychotic agents not specified	164,417	NS	1,314	NS	NS
Misdrahi D. et al., 2019 [27]	France	Cohort	Schizophrenic patients (> 16 years)	Hospital	Monotherapy primarily atypical and the rest typical and combination therapy	674	NS	56	NS	89
Modestin J. et al., 2000 [28]	Switzerland	CS	All inpatients	Hospital inpatients	Typical (63.5%) or clozapine (23%) or both (13.5%)	200	84	44	22	40
Berardi D. et al., 2000 [4]	Italy	CS	Schizophrenic patients (20–69 years)	Community mental Health OPD	Chlorpromazine (430±337 mg) equivalent	69	NS	NS	19	19

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CS, cross-sectional; CS(R), cross-sectional with retrospective approach; SUD, substance use disorder; NS, not specified; EPSEs, extrapyramidal side effects; TD, tardive dyskinesia

Meta-analysis of outcome measures and sensitivity analysis

For estimating the overall magnitude of antipsychotic-induced EPSEs, 12 studies reporting the outcome measures were included for meta-analysis. Based on this, the pooled estimate was found to be 37% (95% CI: 18–55%). Following the ‘leave-one-out’ sensitivity analysis, the pooled EPSE estimate was considerably reduced to 31% (95% CI: 19–44%) with little change (1.00%) in the degree of heterogeneity (Fig 2A and 2B).

Subgroup analysis

Analysis stratified based on settings indicated that those patients treated at the hospital showed higher pooled antipsychotic-induced EPSEs, 33% (95% CI: 17–49%) than those treated at rehabilitation center, 13% (95% CI: 9.0–17%). Besides, subgroup analysis based on continent indicated that patients from Africa showed relatively higher drug-induced EPSEs, 51% (47–56%) whereas the prevalence was by far lower from Asia, 13% (95% CI: 4.0–21%) (Fig 3A and 3B).

Meta-analysis of EPSE components

Nine studies reported antipsychotic-induced parkinsonian symptoms. The pooled estimate of these studies was found to be 20% (95% CI: 11–28%) (Fig 4). Likewise, nine studies either alone or with other EPSE components reported the prevalence of antipsychotic-induced akathisia. Based on this, the meta-analysis of these studies showed the pooled estimate of akathisia was11% (95% CI: 6.0–17%) (Fig 5). What is more, eight studies reported tardive dyskinesia as one of the EPSEs associated with antipsychotic medications. In this regard, the pooled prevalence of tardive dyskinesia was about 7% (95% CI: 4–9%) (Fig 6).

Publication bias

To confirm a small-study effect, Egger’s regression test accompanied with funnel plot asymmetry demonstrated that there was a sort of publication bias in studies reporting akathisia (Egger’s Q = 6.43, P = 0.019) and tardive dyskinesia (Egger’s Q = 3.88, P = 0.021) (Fig 7A–7D).

Discussion

This systematic review and meta-analysis determined the pooled proportion of antipsychotic medications-induced EPSEs among patients in natural treatment settings. The pooled prevalence of antipsychotic-induced EPSEs among patient taking these medications was 37% and 31% in before and after sensitivity analysis, respectively. The pooled prevalence of antipsychotic-induced parkinsonism, akathisia, and TD were 20%, 11%, and 7%, respectively.

Anti-psychotic medications have proven efficacy in the treatment of schizophrenia and other major psychiatric conditions. Although the clear mechanism of action remains elusive and gradually evolving, most antipsychotics have shared their action on dopaminergic and serotoninergic neurotransmission. The effectiveness of antipsychotic medications depends on the activity and the specific location of these neuronal receptors. The potency of conventional (typical) antipsychotic drugs correlates closely with their affinity for the dopamine 2 (D2) receptor, blocking the effect of endogenous dopamine in different dopaminergic pathways [43]. Dopaminergic neurons have four major pathways in the CNS: mesolimbic (from the ventral tegmental area (mid-brain) to limbic system), mesocortical (mid-brain to the prefrontal cortex), nigrostriatal (substantia nigra to striatum), and tuberoinfundibular pathways (hypothalamus to anterior pituitary) [44]. Antipsychotic medication, particularly the conventional antipsychotics have higher affinity for binding with dopamine receptors in all pathways. Blockade of dopamine receptors at mesolimbic and mesocortical pathways are responsible for the treatments of positive symptoms (hallucination, delusion, disorganized speech) and worsening of negative symptoms (avolution, alogia, anhedonia), respectively [45]. However, within the basal ganglia, the blockade of dopamine receptors at the striatum (caudate-putamen complex) (a receptor for dopaminergic neuron projecting from substantia nigra pars compacta (SNpc) to striatum) is primarily responsible for antipsychotic-induced EPSEs [46, 47]. This area is predominately involved in the coordination of voluntary movements and fine-tunes motor coordination between the thalamus and cortex. Hence, blockade of primarily D2 receptors (tonic inhibitor by nature) at striatum results in excitation of thalamocortical axis and brain stem motor nuclei.

Previous studies have revealed that the prevalence, incidence, and course of EPSEs associated with antipsychotic medications are varying, due to variability in the criteria to define and identify EPSEs among clinicians [48]. This finding was slightly higher compared to a population-based study conducted in Italy that estimated the prevalence of all common categories of movement disorders was 28% [49]. This might be due to the previous study was a single population-based study.

The finding from this study on TD is consistent with a systematic review which revealed the pooled prevalence of TD was 9.4% among patients taking antipsychotics medications [14]. The pooled estimate on akathisia was found lower as compared with a reviewed medical literature which stated that 25.9% of patients had developed akathisia [15]. The difference could be due to the type of mediations taken, meaning that the previous review included those patients taking all psychotropic medication, but this finding was restricted to those who took antipsychotic medications. The previous reviews also could not quantitatively analyze (meta-analyze) studies in natural treatment settings to generate evidence-based pooled estimate.

This study revealed that the pooled prevalence of TD was found to be 7% which is higher than a previously conducted TD-specific systematic review of 1-year studies on SGAs estimated that the weighted mean annual incidence risk of TD associated with these antipsychotics was 2.1% [50]. Such a difference might be ascribed to atypical antipsychotic drugs that may induce less dopamine hypersensitivity in the caudate-putamen complex. The prevalence of antipsychotic-induced parkinsonism is consistent with a previous literature review that summarized drug-induced parkinsonism and TD range from approximately 20 to 35% among antipsychotic users [11]. The previous study was a narrative review of antipsychotic-induced movement disorders with special focus on drug-induced parkinsonism and TD. Our study provided a pooled estimate of these movement disorders from systematically reviewed articles. Generally, to reconcile the paradox of tardive and parkinsonian symptoms, considering newer treatment options with lower neurological side effects is a game changer. Antipsychotic-induced TD is difficult to treat, frequently irreversible and with low tendency of remission. Drugs that target vesicular monoamine transporter -2 (VMAT 2) inhibitors have been found effective in the management of TD without worsening other EPSEs [51].

Strength and limitations of the study

Strength

The previous studies considered only one of the EPSEs (i.e. TD, akathisia) and/or included mere clinical trials. The rest studies were narrative reviews that summarized various studies dealing about akathisia. However, such studies were not systematically selected. In this regard, the safety of antipsychotic drugs in natural settings would have been addressed. Meta-analysis of studies at natural treatment settings is also worth considering to explore the magnitude of the problem in real settings. What is more, the previous reviews also could not quantitatively analyze (meta-analyze) studies in natural treatment settings to generate evidence-based pooled estimate. This study primarily focuses on observational studies (neither preclinical nor interventional) as the experimental nature of trials in ideal settings may confound the pooled estimates of observational studies. Apart from this, most of the measurement scales for motor disorders came into clinical practice in late 1980s and mid1990s. Advances in pharmaceutical formulations in the area of antipsychotics should also be considered.

Limitation

We have initially considered subgroup analysis on both demographic and clinical factors. Nevertheless, the high heterogeneity of diagnosis (Schizophrenic, acute psychotic, SMI, psychotic with SUD, etc.…) and medication use (typical, atypical and mixed use) limited us from doing further meta-analysis. Instead, we have vividly included the age of the patients and drug regimen issues in the summary of studies. In the future, focused and drug-specific meta-analyses and scoping reviews as well as studies that address diverse methodological approaches should be considered for comparison.

Conclusion

The prevalence of antipsychotic-induced EPSEs was considerably high. In this meta-analysis, the drug-induced parkinsonism was the most prevalent EPSE followed by akathisia. Besides, one in thirteen patients experienced TD which is a difficult to treat EPSE requiring special emphasis by clinicians. Treatment should consider the paradox of tardive and parkinsonian symptoms to the minimum. Appropriate prevention and early management of these side effects can enhance the net benefits of antipsychotic therapy. Designing EPSE treatment guideline, choosing those antipsychotics which had minimal side effects and psycho-education is worth considering.

Supporting information

S1 Table. Completed PRISMA checklist.

The checklist highlights the important components addressed while conducting systematic review and meta-analysis from observational studies.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S2 Table. Data abstraction format with crude data.

The table presented the ways of data collection (study characteristics and outcome measures) in Microsoft excel format.

(XLSX)

Click here for additional data file.^{(18KB, xlsx)}

S3 Table. Critical appraisal scores of included studies.

The table shows the risk of bias assessments of studies with regard to design, conduct and analysis.

(DOCX)

Click here for additional data file.^{(189.6KB, docx)}

Acknowledgments

We would like to address our deepest gratitude to the authors of the included studies for this systematic review and meta-analysis. Also, our deepest heartfelt goes to the staff of Haramaya University, College of Health and Medical Sciences who gave us technical support.

Abbreviations

EPSEs: Extrapyramidal side effects
JBI: Joanna Briggs Institute
PICOS: Participant, Interventions/Exposure/, Comparison, Outcome, and Study setting
SSA: Sub Saharan Africa

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0257129.r001

Decision Letter 0

Ahmed Negida

7 Dec 2020

PONE-D-20-32247

Antipsychotic Induced Extrapyramidal Side Effects : A systematic review and Meta-analysis

PLOS ONE

Dear Dr. Ali,

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: No

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**********

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Reviewer #1: The authors present a systematic review and meta-analysis of antipsychotic-induced EPS. A few points to consider:

-The fourth paragraph (or second from end of section) of the introduction h isn't as informative compared to the large, meta-analyses in the preceding sentence because it is hard to tell why you are reporting these specific sentences.

-The rationale isn't entirely clear for the need for this meta-analysis when you cite large systematic reviews and patient studies on EPS. Consider being more clear for the need of your systematic review and meta-analysis

Methods

-are RCTs not an option for this type of analysis? Can you clarify your inclusion criteria in this regard?

-Why the restriction to the year 2000 and forward,

-so are you only including studies that had a primary outcome of EPS?

-I think it is rare to see quality cutoffs for inclusion into a meta-analysis. Can you cite where this methodology has been validated? Why would it be even useful to search the grey literature when it would likely fall below the cutoff with a lack of information?

-Did you consider sub-analyses by medication type? Diagnosis? Age?

-a table of characteristics of your final included studies is necessary.

-why 11 studies in the main meta-analysis when 15 included? More clarity needed.

-where are the I2 heterogeneity statistics throughout the results?

-more consideration and detail is needed regarding the included study antipsychotic type given their importance as detailed in the introduction.

Reviewer #2: Comments:

Title

1. Does the title give clear idea about the article? Yes

Abstract

2. Does the abstract concisely describe the content and scope of the project and identifies the project’s objective, its methodology and its findings, conclusions, or intended results? No

Under background, add something about mood disorder with psychotic. Because they also take antipsychotic medicine.

Under conclusion, you tried to conclude as appropriate prevention of EPSE is important. How you could come across with this recommendation?

Introduction

3. Does the introduction give clear idea about the article? YES

Please clarify the statement “They are classified as first generation or conventional (typical) antipsychotics (FGA) and second generation (atypical) antipsychotics (SGA)”

Use similar word for antipsychotic/s through the document. Also for EPS/EPSE. Use similar word and abbreviation. Sometimes you say EPS, and sometimes EPSE/s

What do you mean EPSs? The end of paragraph of introduction

What do you say by side effects which appear when anticholinergic medicine removed from the patient?

Methodology

4. Did methodology part is clear? No

Well, if specified who (author/s) were extracted data.

What do you say about data quality assessment?

Which model did you use to determine pooled prevalence?

Is all original paper report standard error? If no, what is your action? If yes, please specify.

What is about independent factors?

Results

5. Are results clear and appropriate with title? Yes

6. Revise the references as per the journal guideline

7. Generally, the paper is interesting. The most problems were found around methodology part. It needs major revision.

8. The paper needs an English language copy editing from the beginning to the end. Please focus on it.

Reviewer #3: I greatly appreciate the reviewing process and would like to propose designing a further review on the antipsychotic-induced dystonia and the relative contribution of each antipsychotic to the side effect specified in addition to the dose-related side effect threshold.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: MM

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PLoS One. 2021 Sep 10;16(9):e0257129. doi: 10.1371/journal.pone.0257129.r002

Author response to Decision Letter 0

22 Jan 2021

Response to Academic Editor and reviewers

Dear,

We would like to thank for your constructive comments to improve the manuscript titled “Antipsychotic Induced Extrapyramidal Side Effects: A systematic review and Meta-analysis” (ID: PONE-D-20-32247). Hereunder are our reaction to the academic editor and reviewers’ comments.

Comments and questions Authors response

Academic Editor

Please include the following items when submitting your revised manuscript:

� A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled ‘Response to Reviewers’.

� A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled ‘Revised Manuscript with Track Changes’.

� An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled ‘Manuscript’.

Please ensure that your manuscript meets PLOS ONE’s style requirements, including those for file naming.

During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works:

Please include a separate caption for each figure in your manuscript.

Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

� An author response letter addressing comments forwarded from the academic editor and reviewer(s); revised manuscript with track changes that highlights changes made to the original version; and a clean version of the revised manuscript are separately presented as per the request.

� We prepared the revised manuscript as per the PLOS ONE’s formatting guidelines

� Textual overlap observed between the current manuscript and previously published works has been resolved with rephrasing such statements.

� A caption/titles for figures have been included in the manuscript as per the PLOS ONE requirement

� Captions for the supporting information files have also been included at the end of the manuscript (after the reference with specified labeling)

� Overall, the comments and suggestions provided by the academic editor is accepted and corrected accordingly.

� We also incorporated nine relevant citation in the background, method and discussion sections to maintain the scientific integrity. Kindly check the track changed manuscript, please.

� We have also undergone careful language (mainly punctuation, syntax and normalization issues) and technical editions throughout the manuscript to make it clearer and easier to comprehend

� We have strictly followed PLOS ONE formatting guidelines including

o Correcting all figures using PACE (e.g. tif compatible format) with better resolution

o Rearranging the position of tables next to the paragraphs that they are first cited

o Formatting the title page, heading and subheadings of main text as per the guideline

Reviewer 1

The authors present a systematic review and meta-analysis of antipsychotic-induced EPS. A few points to consider:

1. The fourth paragraph (or second from end of section) of the introduction isn't as informative compared to the large, meta-analyses in the preceding sentence because it is hard to tell why you are reporting these specific sentences.

2. The rationale isn't entirely clear for the need for this meta-analysis when you cite large systematic reviews and patient studies on EPS. Consider being more clear for the need of your systematic review and meta-analysis

Dear,

� The points raised in the introduction part of the manuscript is revised deeply.

� The previous study considered only one of the EPSEs (i.e. TD) and included clinical trials only.

� The safety of antipsychotic drugs in natural settings has been ignored. Meta-analysis of studies at natural treatment settings is also worth considering to explore the magnitude of the problem in real settings.

� The other study was a narrative review that summarized various studies dealing about akathisia. However, such studies were not systematically selected.

� The previous reviews also could not quantitatively analyze (meta-analyze) studies in natural treatment settings to generate evidence-based pooled estimate.

� We have explicitly presented the rationale of this research in the background section in more elaborated manner.

Methods

3. are RCTs not an option for this type of analysis? Can you clarify your inclusion criteria in this regard?

� Before 2010, meta-analysis of clinical trials revolving around the components of EPSEs (TD and akathisia) were conducted. Since then, no comprehensive EPSE based studies was conducted.

� This study primarily focuses on observational studies (neither preclinical nor interventional). The experimental nature of trials in ideal settings may confound the pooled estimates of observational studies.

� In this revised manuscript, we have tried to present quite elaborated rationale, inclusion criteria and discussion for what we conducted this meta-analysis.

4. Why the restriction to the year 2000 and forward, Dear reviewer,

� We have considered methodological updates, time sensitivity and consistency of the research contents

� For instance, most of the measurement scales including Akathisia Rating Scale, Unified Parkinson Disease Rating Scale, Abnormal Involuntary Movement Scale (for TD) came in clinical practice in late 1980s and mid1990s.

� In the preliminary screening process, majority of studies about this research topic were conducted in the last 20 years (21st century).

� Advances in pharmaceutical formulations in the area of antipsychotics should also be considered

� In our case, we finally included 60% studies from 2010-2019 and 40% from 2000-2009 after PRISMA flow chart and quality assessments.

5. so are you only including studies that had a primary outcome of EPS?

-I think it is rare to see quality cutoffs for inclusion into a meta-analysis. Dear,

� As clearly explained in the methodology section, original studies addressing the magnitude of EPSE and/or one of its components (e.g., TD, DIP and/or akathisia) were included in the study once they passed the quality assessment.

� It doesn’t mean that having any of the EPS component give rise the entire EPS since one patient may experience one or all of the symptoms at a time

� The authors extracted the data meticulously with several check points

6. Can you cite where this methodology has been validated? Why would it be even useful to search the grey literature when it would likely fall below the cutoff with a lack of information? Dear,

Regarding the methodological validity, a plethora of information and published articles utilizing related methodology of systematic review and meta-analysis can be accessed from reputable journals and publishers worldwide.

Besides, to keep the scientific integrity of this systematic review and meta-analysis, we applied the following tools and protocols which are duly cited in the method section.

� This method (protocol) has been registered on PROSPERO, University of York with ID: CRD42020175168 and available online at:

� https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID= CRD42020175168&ID= CRD42020175168.

� PRISMA flow diagram

� PRISMA checklist

� Joanna Briggs institute, University of Adelaide, Australia, risk of bias (quality) assessment tools

� Publication bias assessment tools (e.g Begg’s and Mazumder)

� In systematic review and meta-analysis, searching for grey literature (unpublished thesis/dissertation, online repositories and related documents) to address relevant data for the research question IS MANDATORY. If we had considered only published articles or articles in legitimate database only, serious publication bias (funnel plot asymmetry) would have occurred for all tests. JBI and Cochrane recommend searching grey literature to minimize the publication bias.

� Studies should be excluded from analysis by their quality and relevance not by their publication status.

� Any study that did not address the primary outcome of interest (EPSE and/or its components) could not be eligible for further process.

7. Did you consider sub-analyses by medication type? Diagnosis? Age? Dear,

� We have initially considered subgroup analysis on both demographic and clinical factors. Nevertheless, the high heterogeneity of diagnosis (Schizophrenic, acute psychotic, SMI, psychotic with SUD, etc…) and medication use (typical, atypical and mixed use) hindered us from doing meta-analysis. Instead, we have included the age of the patients and drug regimen issues in the table 1 describing the study characteristics

� Fortunately, all the patients included in the study are adults and adolescents and no clear cut-off point to run subgroup analysis.

8. a table of characteristics of your final included studies is necessary.

Dear,

� We have included Table 1 in the manuscript next to the paragraph that narrate what the characteristics of the studies are all about.

� We have also amended the study characteristics section in much more elaborated way.

9. why 11 studies in the main meta-analysis when 15 included? More clarity needed. Dear reviewer,

� As we put the inclusion and exclusion criteria, original studies that address the overall EPSE only and/or one of its components are eligible for systematic review. Nevertheless, only studies with homogenous outcome measures should be retained for further quantitative synthesis (meta-analysis) accordingly.

� In this regard, few studies did not address the entire EPSE rather focused on specific symptoms such as TD or DIP.

� In line with, the authors have clarified and made critical revision on the write up and outcome measures of included studies.

10. where are the I2 heterogeneity statistics throughout the results? � The measure of heterogeneity (I2 statistics) is available in all forest plots (Figure 2 to Figure 6). We tend to focus on major finding in this study rather than narrating everything on the figures and table.

11. more consideration and detail is needed regarding the included study antipsychotic type given their importance as detailed in the introduction. Dear,

Please check the revised manuscript in this regard.

We have undergone an extensive edition throughout the document with much emphasis to introduction and result sections. In line with this, we included a column describing the type of antipsychotic medications taken and respective regimens in the table describing study characteristics.

Reviewer 2

Title

1. Does the title give clear idea about the article? Yes Thank you for your constructive comments

Abstract

2. Does the abstract concisely describe the content and scope of the project and identifies the project’s objective, its methodology and its findings, conclusions, or intended results? No

Under background, add something about mood disorder with psychotic. Because they also take antipsychotic medicine.

Under conclusion, you tried to conclude as appropriate prevention of EPSE is important. How you could come across with this recommendation? Dear reviewer,

Under the background section of abstract, mood disorder with psychotic feature was also included. Clinically heterogenous group of patients (with schizophrenic, schizoaffective, acute psychotic with substance use disorders, bipolar disorders, those with severe mental illnesses e.tc) were considered as far as they took antipsychotic medication. The objective of this study is to estimate antipsychotic-induced EPSEs regardless of neuropsychopathological features.

We have tried to rephrase the conclusion and limitation sections of the manuscript as well.

Please clarify the statement “They are classified as first generation or conventional (typical) antipsychotics (FGA) and second generation (atypical) antipsychotics (SGA)” We have amended it along with other introduction sections

Introduction

3. Does the introduction give clear idea about the article? YES

Use similar word for antipsychotic/s through the document. Also for EPS/EPSE. Use similar word and abbreviation. Sometimes you say EPS, and sometimes EPSE/s

What do you mean EPSs? The end of paragraph of introduction

What do you say by side effects which appear when anticholinergic medicine removed from the patient? Dear,

� As per your request, we have used abbreviations consistently throughout the document. We preferred to use EPSE to EPS

� For terms which were repeated for at least three times, the full term with abbreviation in the parenthesis was used at the first appearance and the abbreviation only thereafter.

� Kindly check the amendments (track-changes) made on the introduction section to clarify the rationale of this study. We have included the role of anticholinergics on the antipsychotic drug therapy.

Methodology

4. Did methodology part is clear? No

Well, if specified who (author/s) were extracted data.

What do you say about data quality assessment?

Which model did you use to determine pooled prevalence?

Is all original paper report standard error? If no, what is your action? If yes, please specify.

What is about independent factors?

Dear reviewer,

We have made extensive revision on the methodology as well.

� We included the initials of authors who were involved in data source searching, study selection process, data extraction and risk of bias (quality) assessments.

� Considering the high heterogeneity of study (primarily variation in study characteristics) triggered us to utilize random effects pooling model with inverse variance method. This is clearly specified in the data synthesis and analysis

� In practical sense, standard error is not mandatory to estimate the pooled outcome measures of this data type. Sample size and event rate are the two key variables to be used. However, to determine publication bias, meta-bias, meta regression etc, event rate and standard error of event rate are two important data sets. To do so, STATA can automatically generate the SE (seES) during computation or else we can covert it to standard error manually if confidence interval is given (in the absence of sample size).

o (UCI-LCI)/(2*invnormal)(0.975))

� The secondary outcome measures (related to independent factors) were not considered in this study due to inconsistency of findings of included studies. It is illogical to meta-analyze several explanatory variables when the method of analysis of individual studies is diverse.

Results

5. Are results clear and appropriate with title? Yes

6. Revise the references as per the journal guideline

7. Generally, the paper is interesting. The most problems were found around methodology part. It needs major revision.

8. The paper needs an English language copy editing from the beginning to the end. Please focus on it. Dear,

The references are revised as per the journal guideline

Generally, questions, comments and suggestions that were focusing in the methodology part are addressed accordingly. We have also undergone serious language editing (syntax, normalization, logical follow, cohenrence and consistency) over the last one month as well.

Reviewer 3

We will try to design a further review focusing on the antipsychotic-induced dystonia and the relative contribution of each antipsychotic agents to the side effect specified to generate evidence-based medicine in the area of antipsychotic therapy.

Regards,

Authors

Attachment

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PLoS One. doi: 10.1371/journal.pone.0257129.r003

Decision Letter 1

Ahmed Negida

30 Apr 2021

PONE-D-20-32247R1

Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

PLOS ONE

Dear Dr. Ali,

Please submit your revised manuscript by Jun 14 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have done a good job revising their manuscripts and improving the clarity of methods and results. I have no further comments

Reviewer #2: Comments

1. In the previous evaluations or comments the author(s) reacts for raised comments superficially. Or the author(s) was (were) not answer for reviewers’ comments. For example, EPSEs which is under introduction page 3 paragraph 1 line 5, and EPS which is on the same page last paragraph line 3 were not similar. Well if the author(s) incorporate deeply for the raised questions.

2. Under results (search findings), the end line of first paragraph page 7, you were exclude 43 papers because various reason. Could explain these various reasons?

3. The publication years of the included studies ranged from 2000 to 2019. I think it is too old the papers you were used from 2000.

4. Papers included in the study form both America and Africa is too few. This implies that as not enough studies were conducted with same title. Could you explain?

5. Title of the table needs modification. Table 1 page 9

6. An article you were used in the raw 10 column 2 is not clear. Which said South Africa and Nigeria

7. Please modify the strength and limitation of the study separately. It is not clear as it is.

Reviewer #3: Thank you for this informative review and would like you to consider the future focused review as mentioned before.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: MM

PLoS One. 2021 Sep 10;16(9):e0257129. doi: 10.1371/journal.pone.0257129.r004

Author response to Decision Letter 1

2 Jun 2021

All the comments and questions are incorporate in the revised manuscript

Attachment

Submitted filename: Response to reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0257129.r005

Decision Letter 2

Xenia Gonda

25 Aug 2021

Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

PONE-D-20-32247R2

Dear Dr. Ali,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Xenia Gonda

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have made revisions according to the comments from the previous round of review. I believe these revisions have made the manuscript more clear and answered the issues that were raised

Reviewer #3: I appreciate the manuscript and encourage the authors to extend the study as previously recommended in a further review.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: Yes: MM

PLoS One. doi: 10.1371/journal.pone.0257129.r006

Acceptance letter

Xenia Gonda

1 Sep 2021

PONE-D-20-32247R2

Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

Dear Dr. Ali:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Xenia Gonda

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Completed PRISMA checklist.

The checklist highlights the important components addressed while conducting systematic review and meta-analysis from observational studies.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S2 Table. Data abstraction format with crude data.

The table presented the ways of data collection (study characteristics and outcome measures) in Microsoft excel format.

(XLSX)

Click here for additional data file.^{(18KB, xlsx)}

S3 Table. Critical appraisal scores of included studies.

The table shows the risk of bias assessments of studies with regard to design, conduct and analysis.

(DOCX)

Click here for additional data file.^{(189.6KB, docx)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(39KB, docx)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(30.6KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting information files.

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PERMALINK

Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies

Tilahun Ali

Mekonnen Sisay

Mandaras Tariku

Abraham Nigussie Mekuria

Assefa Desalew

Roles

Abstract

Background

Method

Result

Conclusion

Introduction

Methods

Study protocol and registration

Data sources and search strategy

Inclusion and exclusion criteria

Screening and eligibility process

Data extraction

Critical appraisal of studies (risk of bias assessment)

Outcome measurements

Data processing and analysis

Results

Search findings

Fig 1. PRISMA flow diagram depicting the selection process of identified studies.

Results of critical appraisal

Study characteristics

Table 1. Summary of studies included in the systematic review and meta-analysis.

Meta-analysis of outcome measures and sensitivity analysis

Fig 2. Forest plot depicting the overall antipsychotic-induced EPSE (A) before and (B) after sensitivity analysis.

Subgroup analysis

Fig 3. Subgroup analysis of the overall EPSE estimate (A) Based on settings (B) Based on geographical distribution.

Meta-analysis of EPSE components

Fig 4. Forest plot depicting anti-psychotic induced parkinsonism.

Fig 5. Forest plot depicting anti-psychotic induced akathisia.

Fig 6. Forest plot depicting anti-psychotic induced tardive dyskinesia.

Publication bias

Fig 7. Funnel plot depicting publication bias (A) Overall EPSEs (B) Parkinsonism (C) Akathisia and (D) Tardive Dyskinesia.

Discussion

Strength and limitations of the study

Strength

Limitation

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Ahmed Negida

Roles

Author response to Decision Letter 0

Decision Letter 1

Ahmed Negida

Roles

Author response to Decision Letter 1

Decision Letter 2

Xenia Gonda

Roles

Acceptance letter

Xenia Gonda

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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