European Journal of Clinical Pharmacology

https://doi.org/10.1007/s00228-018-2498-1

REVIEW

Efficacy and safety of aripiprazole for the treatment of schizophrenia:

an overview of systematic reviews
Esther Letícia Amorim Ribeiro 1 & Tácio de Mendonça Lima 1 & Marcio Eduardo Bergamini Vieira 2 & Sílvia Storpirtis 1 &
Patricia Melo Aguiar 1

Received: 25 March 2018 / Accepted: 31 May 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose To conduct an overview to summarize the efficacy and safety of aripiprazole for the treatment of schizophrenia.
Methods A literature search was performed in PubMed, the Cochrane Library, LILACS, and the Centre for Reviews and
Dissemination, for articles published until March 31, 2017. We included systematic reviews with meta-analyses of randomized
controlled trials assessing the efficacy, and/or the safety of aripiprazole, for patients with schizophrenia. Two authors indepen-
dently performed the study selection, data extraction, and quality assessment. The Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) approach and the Risk of Bias in Systematic Review (ROBIS) tool were used to
appraise the quality of evidence and the risk of bias in the reviews, respectively.
Results Fourteen studies fulfilled the inclusion criteria. Aripiprazole showed efficacy similar to that of both typical and atypical
antipsychotic drugs (except olanzapine and amisulpride). Aripiprazole caused significantly lower weight gain and alterations in
glucose and cholesterol levels, as compared to clozapine, risperidone, and olanzapine. In addition, aripiprazole caused signifi-
cantly fewer general extrapyramidal side effects, less use of antiparkinsonian drugs, and akathisia, compared with typical
antipsychotic drugs and risperidone. The overall quality of evidence in the reviews ranged from Bvery low^ to Bmoderate,^
principally because of the risk of bias of original trials, inconsistency, and imprecision in the outcomes. According to the ROBIS
tool, there are four reviews with Bhigh^ risk of bias and five with Bunclear^ risk of bias.
Conclusions Aripiprazole exhibited efficacy similar to that of other antipsychotic drugs and a better safety profile than that of
typical (i.e., less some extrapyramidal side effects) and atypical (i.e., less metabolic changes) antipsychotic drugs.

Keywords Mental disorder . Schizophrenia . Aripiprazole . Systematic review . Overview

Introduction mal motor behavior (including catatonia), hallucinations, and

Schizophrenia is a psychotic disorder characterized by abnor-
malities in one or more of the following five aspects: delusions,
disorganized thinking (speech), grossly disorganized or abnor-
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00228-018-2498-1) contains supplementary
material, which is available to authorized users.
* Patricia Melo Aguiar
aguiar.pm@usp.br; patyaguiar14@hotmail.com
1
Department of Pharmacy, Faculty of Pharmaceutical Sciences,
University of Sao Paulo, Av. Prof. Lineu Prestes, 580 - Conj. das
Químicas - Bloco 13 - Cidade Universitária Butantã, Sao
Paulo, Brazil
2
Psychiatry Clinic, University Hospital of University Sao Paulo, Sao
Paulo, Brazil
negative symptoms [1]. Its median estimate of lifetime preva-
lence is approximately 0.5%, worldwide [2]. The characteristic
symptoms of schizophrenia affect the quality of life of the
patients and their families. Recent estimates indicate that the
burden of the disease continues to increase and leads to impor-
tant disability in several aspects of the individual’s personal,
social, and occupational functioning [3]. The factors contribut-
ing to this disability include the high relapse rate, disease chro-
nicity, and stigma [4]. Furthermore, people with schizophrenia
have a 2.5 times higher risk for premature death, associated
with suicide or comorbid somatic conditions [5].
The treatment of schizophrenia comprises multiple efforts,
including the approach by a multidisciplinary team, and often
requires the use of antipsychotics, classified into first-
generation (typical) or second-generation (atypical) drugs.
Typical antipsychotic drugs were developed in the 1950s

and are strong dopamine D2 receptor antagonists. As a result
of their inadequate therapeutic potential and associated ad-
verse events, principally extrapyramidal side effects (EPSE),
novel antipsychotic drugs emerged in the 1980s—the second-
generation antipsychotics [6]. Although they are effective and
have a more secure profile for the treatment of movement
disorders [7], these second-generation drugs are associated
with higher risk for metabolic disturbances, i.e., weight gain
and changes in glucose and cholesterol levels [8].
Due to the debilitating nature of schizophrenia and the ad-
verse events that may occur during use of antipsychotic drugs
and further worsen the patient’s condition, a comparative anal-
ysis of the available drug therapies is necessary for the determi-
nation of the best options. The optimal method for this compar-
ison is through systematic reviews, which are considered the
gold standard of evidence in health care. This type of study
involves the application of scientific strategies, in ways that limit
bias, for the collection, critical appraisal, and assembly of all
studies addressing a specific question. It may also be accompa-
nied by meta-analysis, which uses statistical techniques to com-
bine and synthesize the data from the primary studies into a
single quantitative estimate or measure of the effect [9].
Given the great availability of published systematic re-
views with or without meta-analysis, it is a challenge for the
health professionals to keep up-to-date. Thus, a new type of
study called Boverview^ has been proposed that evaluates and
summarizes the results of the systematic reviews [10]. To our
knowledge, there is no published overview on the use of
aripiprazole in schizophrenia. In this sense, this overview
aimed to summarize the information presented in systematic
reviews with meta-analysis, in order to evaluate the efficacy
and safety of aripiprazole, compared with that of placebo or
other antipsychotics, for the treatment of schizophrenia.
Methods
The protocol of this overview was registered on the
International Prospective Register of Systematic Reviews
(PROSPERO; http://www.crd.york.ac.uk/PROSPERO/;
registration number, CRD42017068626).
Literature search
A comprehensive literature search was performed in
Medline/PubMed, LILACS, the Cochrane Library, and
the Centre for Reviews and Dissemination (CRD), for
articles published until March 31, 2017. The search strat-
egy included the use of Medical Subject Headings
(MeSH) terms or text words related to the health condi-
tion (schizophrenia), intervention (aripiprazole), and type
of study (systematic review with meta-analysis). The full
search strategy of all databases is showed in Appendix 1.
Eur J Clin Pharmacol
In addition, a search was held within the reference lists of
the appraised studies to identify any potential study that
could have been missed.
Study selection
After searching the databases, the selection process was per-
formed in three stages: (1) exclusion of repeated records, (2)
analysis of the titles and abstracts, and (3) analysis of the full-
text articles. The studies were independently selected by two
authors (E.L.A.R. and T.M.L.), with any disagreement re-
solved by a third author (P.M.A.). When the full text could
not be obtained, the corresponding authors were contacted by
e-mail and/or via ResearchGate (www.researchgate.net).
To be included in this overview, the articles had to meet the
following criteria: (1) must be a systematic review with meta-
analysis of randomized controlled trials (RCTs); (2) must be
published in English, Portuguese, or Spanish; (3) must have
evaluated the effect of aripiprazole, in comparison with place-
bo or other antipsychotic drugs; (4) must report the outcomes
of interest for efficacy and/or safety; and (5) must include
patients with schizophrenia or other types of schizophrenia-
like psychoses (e.g., schizophreniform and schizoaffective
disorders). Articles were excluded if being reviews without a
clear search strategy; systematic reviews without meta-
analysis; updated systematic reviews (only the last version
was considered); meta-analyses not from systematic reviews;
or systematic reviews with meta-analysis that included anoth-
er target population, intervention, or primary study designs.
The efficacy of the antipsychotic therapy was evaluated
according to the Positive and Negative Syndrome Scale
(PANSS), used for measuring symptom severity in pa-
tients with schizophrenia [11]. This scale involves 30
items that are commonly aggregated into three subscales
(positive, negative, and general psychopathology), each
including several specific symptoms. High scores indicate
greater disease severity. For the evaluation of safety out-
come measures, we considered EPSE (such as general
EPSE, anxiety, agitation, akathisia, dystonia, and parkin-
sonism) along with metabolic changes (such as weight
gain and changes in glucose and cholesterol levels).
These safety outcomes were selected for analysis, since
the increased occurrence of EPSE is principally related
to typical antipsychotics, and metabolic changes are asso-
ciated with atypical antipsychotics.
Data extraction
Data extraction was performed by two independent re-
searchers (E.L.A.R. and T.M.L.), and any disagreement was
resolved by a third author (P.M.A.). The following informa-
tion was collected on a spreadsheet preformatted in Microsoft
Excel®: author(s) and year of publication, literature search,
Eur J Clin Pharmacol
target population, number of RCTs and patients included in
the meta-analysis, intervention, comparators, outcome mea-
sures, effect size, heterogeneity or inconsistency, and funding
source.
Quality assessment
The quality of evidence for the outcomes of interest was evalu-
ated by the Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) approach [12]. The
quality of evidence is classified into four levels: high, moderate,
low, and very low (indicates confidence in effect estimate) and
the quality of evidence starts as high when RCTs are analyzed.
The risk of bias (i.e., methodological limitations), publication
bias, indirectness, imprecision, and inconsistency are factors
responsible for reducing the level of evidence of the outcome.
Network meta-analyses were evaluated, considering the adjust-
ments proposed by Salanti et al., 2014 [13]. The evidence pro-
file was established from an explicit judgment of each of these
factors using GRADEpro computer software (https://gradepro.
org/). Two authors (E.L.A.R. and T.M.L.) used this tool
independently, and any disagreement was resolved by a third
author (P.M.A.).
The ROBIS tool (phases 2 and 3) was used to assess the
risk of bias in systematic reviews. Specifically, it addresses the
degree to which the review methods minimized the risk of bias
in the effect estimates and conclusion of systematic reviews.
Phase 2 covers four domains through which bias may be in-
troduced into a systematic review: eligibility criteria, identifi-
cation and selection of studies, data collection and study ap-
praisal, and synthesis and findings. Phase 3 assesses the over-
all risk of bias in the interpretation of review findings. Risk of
bias in each phase is judged as Blow,^ Bhigh,^ or Bunclear^
[14]. One author (T.M.L.) conducted the evaluation of the
studies, and a second one (P.M.A.) verified this evaluation.
Data synthesis
The characteristics of systematic reviews, and the quality of
evidence and their risk of bias, were descriptively summarized
using systematically structured tables. The estimates of effect
size from meta-analyses (and their 95% confidence intervals
[95% CI]) were expressed as mean difference (MD), standard-
ized mean difference (SMD), odds ratio (OR), relative risk (RR),
or event rate (ER), depending on what the authors had reported.
Results
Search results
A total of 185 potentially relevant records were collected upon
database searching (Fig. 1). After removing duplicates and
screening titles and abstracts, 159 records were excluded. The
remaining 26 records were selected for full-text examination, of
which 14 systematic reviews with meta-analysis on aripiprazole
for the treatment of schizophrenia fully met the eligibility criteria
and were included in the overview [15–28]. The excluded stud-
ies, and the reasons for their exclusion, are detailed in Appendix
2. The dataset with the full selection process of the systematic
reviews is shown in Appendix 3. All included systematic re-
views were published in English between 2008 and 2017.
Characteristics of the included systematic reviews
Characteristics of the 14 studies included in this overview are
shown in Table 1. Most studies included patients of any age
[15, 16, 18–23, 27] and the rest included only patients above
18 years [17, 24–26, 28]. Most systematic reviews used the
Diagnostic and Statistical Manual of Mental Disorders
(Fourth Edition; DSM-IV) and the tenth revision of the
International Statistical Classification of Diseases and
Related Health Problems (ICD-10), as diagnostic criteria for
schizophrenia and other psychotic disorders (schizoaffective
disorder, schizophreniform disorder, or delusional disorder).
Direct evidence was principally used for the comparison
between aripiprazole and other interventions. However, some
studies used indirect evidence, based on the Bucher’s method
of adjusted indirect comparison [20] and Bayesian network
meta-analysis [15, 19, 23, 24]. Olanzapine [15, 18, 20, 21,
23, 25, 27, 28] and risperidone [15, 18, 21, 23, 27, 28] were
the antipsychotics compared to aripiprazole, in most cases.
Other common comparators were placebo, haloperidol,
ziprasidone, quetiapine, clozapine, and amisulpride.
Seven studies assessed efficacy outcomes, according to the
PANSS criteria [15, 18, 20–23, 26], while 12 studies assessed
safety outcomes concerning EPSE and metabolic changes.
Anxiety [16–18, 26, 27], agitation [16–18, 28], akathisia
[16–18, 25, 28], dystonia [18], parkinsonism [18], and use
of antiparkinsonian medication [16, 18, 21, 23] were reported
as EPSE. Relating to metabolic changes, weight gain [15, 16,
18, 19, 21, 23, 24, 26, 27], blood glucose [18, 27], and cho-
lesterol levels [18, 27] were reported.
Most reviews [15–19, 21–23, 27] received research
funding from governments, universities, research healthcare
centers, public health systems, or national institutes. Two stud-
ies received research funding from the industry [24, 26], two
did not report a source of support [25, 28], and one declared no
support from any organization [20].
Results on efficacy
PANSS
Aripiprazole-based therapy presented significant reduction in
total PANSS (very low quality), positive PANSS (moderate
 Eur J Clin Pharmacol

Fig. 1 Study selection flowchart Records identified through

through literature search. RCT, database searching (185):
randomized controlled trials
PUBMED (153) Additional records identified by
CDR (18) reviewing the references in the
LILACS (5) studies found
COCHRANE (9) (n = 0)

Records after duplicates

removed (n = 156) Records excluded [not a systematic
review, not evaluate patients with
schizophrenia, the intervention analyzed
Records screened on titles is not aripiprazole and an inappropriate
and abstracts (n = 156) objective]

Full-text articles assessed for Full-text articles excluded, with

eligibility (n = 26) reasons:
- Did not report the type of primary
study (n = 1)
- Did not report the type of disease
Studies included in the
evaluated (n = 1)
overview (n = 14)
- Aripiprazole data could not be
extracted (n = 1)
- Did not include only RCT (n = 2)
- Not a systematic review (n = 2)
- Systematic reviews updated (n = 2)
- Full-text article could not be obtained
(n = 3)

quality), and negative PANSS (low quality) upon direct com-
parison to placebo [26] (Table 2). In addition, mixed compari-
son showed a significant reduction in total PANSS compared to
that resulting from placebo (low quality) [23]. Regarding atyp-
ical antipsychotics, aripiprazole showed a less significant reduc-
tion in total PANSS compared to that induced by olanzapine
(moderate quality) and amisulpride (very low quality) [15, 21,
23]. However, the results from the comparison between
aripiprazole and risperidone or paliperidone were inconsistent,
since the different inclusion criteria adopted in the studies [15,
23]. In contrast, aripiprazole was significantly superior than
risperidone in reducing the negative PANSS upon short-term
use (moderate quality) [18]. Aripiprazole did not show a signif-
icant benefit over typical antipsychotic drugs [22, 23].
exception, Oya et al. [26] did not show any significant difference
by a direct comparison of intramuscular aripiprazole to placebo
(dichotomous measure). About atypical antipsychotic drugs,
aripiprazole induced weight gain to a significantly lower extent
than did clozapine, risperidone, and olanzapine (very low or
moderate quality) (dichotomous measure) [15, 18] and most
atypical antipsychotics (continuous measure) [18, 23, 27], with
the exceptions of lurasidone, ziprasidone, amilsupride, and
asenapine [23]. It is worth noting that the findings were incon-
sistent among the studies comparing aripiprazole’s and
risperidone’s effect on body weight increase, since Rummel-
Kluge et al. [27] did not present significant differences in their
results. Besides, aripiprazole did not induce significant changes
in body weight gain compared to typical antipsychotics [22, 23].

Results on adverse events Changes in glucose and cholesterol levels

Weight gain All systematic reviews on this outcome showed that

Weight gain was evaluated either as a continuous (magnitude of
the body weight increase) and/or as a dichotomous measure
(increase ≥ 7.0% of the body weight) (Table 3). All systematic
reviews on this outcome showed that aripiprazole significantly
induced weight gain (dichotomous and continuous measure),
compared with placebo (very low or low quality). As an
aripiprazole significantly reduced the increase in blood glu-
cose levels [18] or induced the increase in blood glucose to a
significantly lower extent than did risperidone, clozapine, and
olanzapine (low or moderate quality evidence) [18, 27].
Furthermore, aripiprazole induced an increase in cholesterol
levels to a significantly lower extent than did olanzapine (low
or moderate quality evidence) [18, 27] (Table 3).
Table 1 Characteristics of systematic reviews on aripiprazole use in schizophrenia
Authors, year Literature search Target population;
type of comparison
Bai et al., 2017 [15] 2005 to December 31, 2014 Chinese patients with acute
schizophrenia and PANSS
total scores ≥60 at the
baseline (any age); indirect
and mixed comparison
(bayesian network
meta-analysis)
Belgamwar et al., Until August 2008 Patients with schizophrenia,
2011 [16] schizophreniform disorder
or schizoaffective disorder
(any age); direct comparison
Bhattacharjee et al., Until November 2007 Patients with schizophrenia,
2008 [17] schizophreniform disorder
or schizoaffective disorder
(≥ 18 years); direct
comparison
Khanna et al., Until November 2012 Patients with schizophrenia,
2014 [18] schizophreniform disorder
or schizoaffective disorder
(any age); direct comparison
Klemp et al., 2011 [19] 1950 to March 2011 Patients with schizophrenia;
(any age); mixed
comparison (bayesian
network meta-analysis)
Kunitomi et al., January 1990 to June 2012 Patients with schizophrenia;
2014 [20] (any age); indirect
comparison (Bucher’s
method)
Leucht et al., 2009 [21] Until May 2007 (CSG register) Patients with schizophrenia,
and September 2007 (Medline) schizophreniform disorder,
schizoaffective disorder
or delusional disorder
(any age); direct
comparison
Leucht et al., 2009 [22] Until October 2006 (Medline) Patients with schizophrenia,
schizophreniform disorder,
schizoaffective disorder
or delusional disorder
(any age); direct comparison
Leucht et al., 2013 [23] Until September 2012 Patients with schizophrenia,
schizophreniform disorder,
schizoaffective disorder or
delusional disorder (any age);
indirect and mixed
comparison (bayesian
network meta-analysis)
Majer et al., 2015 [24] January 2002 to May 2013 Patients with schizophrenia;
(≥ 18 years); mixed
Intervention Comparator
Aripiprazole Paliperidone, risperidone,
ziprasidone, clozapine,
olanzapine, amisulpride,
or quetiapine
Aripiprazole Placebo or no treatment
Aripiprazole Haloperidol or perphenazine
Aripiprazole Clozapine, olanzapine,
quetiapine, risperidone,
ziprasidone, amisulpride,
zotepine, or sertindole
Aripiprazole Placebo
Aripiprazole Olanzapine
Aripiprazole Olanzapine or risperidone
Aripiprazole Haloperidol, perphenazine,
or placebo
Aripiprazole Clozapine, amisulpride,
olanzapine, risperidone,
paliperidone, zotepine,
haloperidol, sertindole,
ziprasidone, chlorpromazine,
asenapine, lurasidone, or
iloperidone
Aripiprazole Placebo
(intramuscular or oral)
Outcome measure
PANSS total, weight
gain, and EPSE
Akathisia, EPSE, anxiety,
agitation, use of
antiparkinson medication,
weight gain (≥ 7.0%)
EPSE, akathisia, agitation,
anxiety (short term)
PANSS total (short and medium
term), PANSS positive,
PANSS negative, EPSE,
anxiety, agitation, akathisia,
dystonia, use of antiparkinson
medication, parkinsonism,
weight gain, body weight,
cholesterol (including LDL
and HDL) levels, blood
glucose (increased and
average endpoint)
Weight gain (≥ 7.0%), EPSE
PANSS total
PANSS total, PANSS
positive, PANSS negative
PANSS total, PANSS positive,
PANSS negative, body
weight, EPSE, use of
antiparkinson medication
PANSS total, body weight, use
of antiparkinson medication
Body weight (≥ 7.0%), EPSE
Funding source
National Program on Key
Eur J Clin Pharmacol
Basic Research Project
North Staffordshire
Combined Health Care
NHS Trust
Academic Unit of Psychiatry
of University of Leeds
Psychiatrische Klinik der
München, Freistaat Bayern;
Nottingham Healthcare NHS
Trust; University of Nottingham;
Cochrane Schizophrenia Group;
Bundesministerium für Bildung
und Forschung; National Institute
of Health Research of
United Kingdon
Research Council of Norway
None
German Federal Ministry of Education
and Research, NIMH’s Advanced
Center for Intervention and
Services Research Center,
Maryland Psychiatric
Research Center
National Institute of Mental Health
German Ministry of Education
and Research
Industry
 Eur J Clin Pharmacol

General extrapyramidal side effects

Technische Universität München,

Health, Advanced Center for

German Federal Ministry of

Psychiatric Research Center

National Institute of Mental

Research Center, Maryland

Intervention and Services
Education and Research,
Regarding general EPSE, the results from the comparison of
aripiprazole to placebo were inconsistent. Direct comparisons
did not provide significant results [16, 26], while indirect com-
Funding source

None declared
parisons showed that aripiprazole significantly increased gen-

No declare
eral EPSE [19, 24]. These results presented very low or low
Industry
quality evidence. One systematic review [18] reported a sig-
nificant difference in favor of aripiprazole, compared to ris-
Body weight, cholesterol levels, peridone (moderate quality). No significant difference was
PANSS total, PANSS positive,

gain, body weight, anxiety,

Akathisia, agitation, anxiety,

PANSS negative, weight

found in the general EPSE caused by aripiprazole and other

atypical antipsychotics [15, 18]. On the other hand,
Outcome measure

aripiprazole induced general EPSE to a significantly lower

blood glucose

extent than did typical antipsychotic drugs (moderate quality

dystonia
Akathisia

evidence) [17] (Table 4).

EPSE

Akathisia and dystonia

placebo) or oral aripiprazole
once a month (considering
perphenazine, haloperidol,

olanzapine, or ziprasidone
quetiapine, or risperidone
Placebo, aripiprazole 50 mg

Two studies [16, 28] reported that aripiprazole increased the

Olanzapine or risperidone

risk of akathisia to a significantly greater extent than did pla-

Placebo, risperidone,
Placebo, olanzapine,

cebo (low quality), as can be seen in Table 4. However, Oya et

Comparator

al. [26] did not observe significant differences in the compar-

ison between intramuscular aripiprazole and placebo (very
CSG Cochrane Schizophrenia Group, EPSE extrapyramidal side effects, PANNS Positive and Negative Syndrome Scale

low quality). In addition, Khanna et al. [18] reported that

aripiprazole increased the risk of akathisia to a significantly
lower extent than did risperidone (moderate quality evidence),
(intramuscular once

but the risk was similar to that associated with other atypical
antipsychotics. Thomas et al. [28] showed that aripiprazole
Intervention

Aripiprazole

Aripiprazole

Aripiprazole

Aripiprazole
a month)

increased significantly the occurrence of akathisia, compared

with olanzapine, ziprasidone, and risperidone (moderate qual-
ity evidence). On the other hand, aripiprazole was associated
with a significantly lower risk of akathisia than were typical
schizophreniform disorder,
schizoaffective disorder or

schizoaffective disorder);

antipsychotics (low quality evidence) [17]. For dystonia,

Patients with schizophrenia,
Patients with schizophrenia

Patients with schizophrenia

Patients with schizophrenia

delusional disorder (any
age); direct comparison

or related disorder (ex.,

network meta-analysis)
comparison (bayesian

(18–65 years); direct

Khanna et al. [18] showed that aripiprazole caused this effect

(≥ 18 years); direct
type of comparison

direct comparison
Target population;

to a significantly greater extent than did risperidone (moderate

comparison

comparison

quality) and to a significantly lower extent than did clozapine

(low quality) [18]. No significant difference was reported be-
tween oral and intramuscular aripiprazole administration in
regard to the induction of akathisia and dystonia (very low
quality) [26].

Agitation and anxiety

Until June 25, 2015

Until January 2009

Literature search

Until June 2014

Belgamwar et al. [16] reported a significant difference in favor

1967 to 2010

of aripiprazole on the risk of agitation, compared to placebo

(low quality evidence). Nevertheless, three studies [17, 18, 28]
did not show significant differences upon comparison of
aripiprazole to typical and atypical antipsychotic drugs. Two
Table 1 (continued)

Thomas et al., 2015 [28]

Rummel-Kluge et al.,

systematic reviews showed no significant difference between

Oya et al., 2015 [26]

aripiprazole and placebo or typical antipsychotics, for the oc-

Moteshafi et al.,
Authors, year

2012 [25]

2010 [27]

currence of anxiety [17, 18]. About atypical antipsychotics,

Khanna et al. [18] reported that aripiprazole induced anxiety
to a significantly greater extent than did risperidone and
Table 2 PANSS results of systematic reviews on aripiprazole use in schizophrenia

Authors, year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity or Publication bias Quality of
measure patientsa model [95% CI or CrI] incosistencyc evidence
(p value)b
Eur J Clin Pharmacol

Bai et al., OLA vs. ARI PANSS total 49/5230 FE MD = − 5.57 [− 9.13; − 2.00] (p < 0.05) NA No asymmetry in Very lowd, e, f, g
2017 [15] PAL vs. ARI PANSS total 49/5230 FE MD = − 5.17 [− 7.87; − 2.49] (p < 0.05) 0.551 the funnel plot Very lowd, e, f, g
AMI vs. ARI PANSS total 49/5230 FE MD = − 5.05 [− 8.06; − 1.43] (p < 0.05) NA Very lowd, e, f, g
RIS vs. ARI PANSS total 49/5230 FE MD = − 1.71 [− 3.66; 0.23] (NS) 0.678 Very lowd, e, f, g, h
ZIP vs. ARI PANSS total 49/5230 FE MD = − 1.05 [− 3.90; 1.76] (NS) 0.621 Very lowd, e, f, g, h
CLO vs. ARI PANSS total 49/5230 FE MD = − 0.38 [− 4.56; 3.83] (NS) 0.373 Very lowd, e, f, g, h
QUE vs. ARI PANSS total 49/5230 FE MD = − 0.13 [− 3.90; 3.69] (NS) 0.570 Very lowd, e, f, g, h
Khanna et al., ARI vs. CLO PANSS total 23/1638 RE MD = − 0.10 [− 1.41; 1.22] (p = 0.88) i2 = 64.0% NR Very lowd, e, h, i
2014 [18] (short term) (p = 0.00001)
ARI vs. CLO PANSS total 3/236 RE MD = − 5.41 [− 8.42; − 2.41] i2 = 0.0% (p = 0.65) NR Lowd, b, j
(medium term) (p = 0.00041)
ARI vs. CLO PANSS positive 22/1523 RE MD = 0.27 [− 0.48; 1.02] (p = 0.48) i2 = 72.0% NR Very lowd, e, i
(p < 0.00001)
ARI vs. CLO PANSS negative 23/1640 RE MD = − 0.61 [− 1.53; 0.30] (p = 0.19) i2 = 81.0% NR Very lowd, e, h, i
(p < 0.00001)
ARI vs. CLO PANSS 19/1330 RE MD = − 0.27 [− 0.78; 0.23] (p = 0.29) i2 = 0.0% (p = 0.61) NR Lowd, e, h
psychopathological
ARI vs. QUE PANSS total 10/831 RE MD = − 0.88 [− 3.15; 1.40] (p = 0.45) i2 = 57.0% (p = 0.01) NR Very lowd, e, h, i
(short term)
ARI vs. QUE PANSS positive 8/683 RE MD = − 0.83 [− 1.99; 0.32] (p = 0.16) i2 = 68.0% (p = 0.003) NR Very lowd, e, h, i
ARI vs. QUE PANSS negative 7/543 RE MD = − 0.48 [− 1.17; 0.21] (p = 0.17) i2 = 4.0% (p = 0.40) NR Lowd, e, h
ARI vs. RIS PANSS total 78/5793 RE MD = − 0.69 [− 1.49; 0.11] (p = 0.091) i2 = 52.0% NR Very lowd, e, h, i
(short term) (p < 0.00001)
ARI vs. RIS PANSS positive 40/3205 RE MD = 0.02 [− 0.37; 0.41] (p = 0.92) i2 = 25.0% (p = 0.08) NR Lowd, e, h
2
ARI vs. RIS PANSS negative 37/2976 RE MD = − 0.64 [− 1.04; − 0.25] (p = 0.0014) i = 24.0% (p = 0.10) NR Moderated, e
ARI vs. RIS PANSS 58/4243 RE MD = − 0.25 [− 0.71; 0.20] (p = 0.28) i2 = 36.0% (p = 0.004) NR Very lowd, e, h, i
psychopathological
ARI vs. ZIP PANSS total 7 /689 RE MD = − 1.74 [− 3.68; 0.20] (p = 0.079) i2 = 0.0% (p = 0.98) NR Lowd, e, h
ARI vs. ZIP PANSS positive 2/146 RE MD = − 0.16 [− 1.36; 1.04] (p = 0.80) i2 = 0.0% (p = 0.79) NR Lowd, e, h
ARI vs. ZIP PANSS negative 4/272 RE MD = − 0.31 [− 1.23; 0.61] (p = 0.51) i2 = 0.0% (p = 0.77) NR Lowd, e, h
ARI vs. OLA PANSS total 11/1500 RE MD = 0.61 [− 0.23; 1.46] (p = 0.15) i2 = 22.0% (p = 0.23) NR Lowd, e, h
(short term)
ARI vs. OLA PANSS total 2/139 RE MD = 0.80 [− 5.26; 6.87] (p = 0.80) i2 = 0.0% (p = 0.53) NR Lowd, e, h
(medium term)
ARI vs. OLA PANSS positive 7/1043 RE MD = 0.71 [0.17; 1.26] (p = 0.011) i2 = 5.0% (p = 0.39) NR Lowd, e, h
ARI vs. OLA PANSS negative 6/967 RE MD = 0.42 [− 0.25; 1.09] (p = 0.22) i2 = 0.0% (p = 0.68) NR Lowd, e, h
Kunitomi et al., OLA vs. ARI PANSS total 11/2723 RE MD = − 6.04 [− 9.74; − 2;34] (p < 0.05) NA NR Very lowe, f, g
2014 [20] (PLB as
comparator)
OLA vs. ARI PANSS total 7/908 RE MD = − 5.90 [− 13.79; 1.99] (NS) NA NR Very lowe, f, h, g
(RIS as
comparator)
Leucht et al., ARI vs. OLA PANSS total 2/794 FE MD = 4.96 [1.85; 8.06] (p = 0.002) i2 = NR (p = 0.65) NR Moderatee
2009 [21] ARI vs. RIS PANSS total 2/372 FE MD = 1.50 [− 2.96; 5.96] (p = 0.509) i2 = NR (p = 1.00) NR Lowe, f
ARI vs. RIS PANSS positive 2/372 FE MD = 1.25 [− 0.25; 2.75] (p = 0.103) i2 = NR (p = 0.37) NR Lowe, h
ARI vs. RIS PANSS negative 2/372 FE MD = − 0.45 [− 1.78; 0.87] (p = 0.502) i2 = NR (p = 0.73) NR Lowe, h
Leucht et al., ARI vs. HAL. PANSS total 5/2049 RE SMD = − 0.05 [− 0.14; 0.05] (p = 0.326) NR No asymmetry in Very lowe, h, k
2009 [22] PER. PLB the funnel plot; p
Egger = 0.362
ARI vs. HAL. PANSS positive 4/1983 RE SMD = 0.03 [− 0.06; 0.12] (p = 0.508) NR NR Very lowe, h, k
PER. PLB
Table 2 (continued)

Authors, year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity or Publication bias Quality of
measure patientsa model [95% CI or CrI] incosistencyc evidence
(p value)b

ARI vs. HAL. PANSS negative 5/2049 RE SMD = − 0.09 [− 0.19; 0.01] (p = 0.07) NR NR Very lowe, h, k
PER. PLB
Leucht et al., CLO vs. ARI PANSS total NR/NR NR SMD = − 0.45 [− 0.62; − 0.28] (p < 0.05) NA NR Moderated, e
2013 [23] AMI vs. ARI PANSS total NR/NR NR SMD = − 0.23 [− 0.37; − 0.08] (p < 0.05) NA NR Moderated, e
OLA vs. ARI PANSS total NR/NR NR SMD = − 0.16 [− 0.25; − 0.07] (p < 0.05) NS NR Moderated, e
RIS vs. ARI PANSS total NR/NR NR SMD = − 0.13 [− 0.23–0.03] (p < 0.05) NS NR Moderated, e
PAL vs. ARI PANSS total NR/NR NR SMD = − 0.07 [− 0.20; 0.08] (NS) NA NR Lowd, e, h
ZOT vs. ARI PANSS total NR/NR NR SMD = − 0.06 [− 0.25; 0.14] (NS) NA NR Lowd, e, h
HAL vs. ARI PANSS total NR/NR NR SMD = − 0.02 [− 0.12; 0.08] (NS) NS NR Lowd, e, h
QUE vs. ARI PANSS total NR/NR NR SMD = − 0.01 [− 0.12; 0.11] (NS) NS NR Lowd, e, h
ARI vs. SER PANSS total NR/NR NR SMD = − 0.04 [− 0.19; 0.11] (NS) NA NR Lowd, e, h
ARI vs. ZIP PANSS total NR/NR NR SMD = − 0.04 [− 0.16; 0.09] (NS) NS NR Lowd, e, h
ARI vs. CPZ PANSS total NR/NR NR SMD = − 0.05 [− 0.22; 0.13] (NS) NA NR Lowd, e, h
ARI vs. ASE PANSS total NR/NR NR SMD = − 0.05 [− 0.20; 0.10] (NS) NA NR Lowd, e, h
ARI vs. LUR PANSS total NR/NR NR SMD = − 0.10 [− 0.25; 0.05] (NS) NA NR Lowd, e, h
ARI vs. ILO PANSS total NR/NR NR SMD = − 0.10 [− 0.24; 0.03] (NS) NA NR Lowd, e, h
ARI vs. PLB PANSS total NR/NR NR SMD = − 0.43 [− 0.52; − 0.34] NS NR Lowd, e, h
(p < 0.05)
Oya et al., ARI IM vs. PLB PANSS total 3/1126 RE SMD = − 0.65 [− 0.90; − 0.41] i2 = 75.0% (NR) NR Very lowe, i, l
2015 [26] (p < 0.00001)
ARI IM vs. PLB PANSS positive 2/729 RE SMD = − 0.85 [− 1.01; − 0.69] i2 = 0.0% (NR) NR Moderatee
(p < 0.00001)
ARI IM vs. PLB PANSS negative 2/729 RE SMD = − 0.44 [− 0.59; − 0.28] i2 = 0.0% (NR) NR Lowe, l
(p < 0.00001)
ARI IM vs. ARI Oral PANSS total 2/984 RE SMD = − 0.08 [− 0.31; 0.14] (p = 0.46) i2 = 69.0% (NR) NR Very lowe, h, i

P value < 0.05 is considered statistically significant

AMI amisulpride, ARI aripiprazole, ASE asenapine, CLO clozapine, CPZ chlorpromazine, EPSE extrapyramidal side effects, FE fixed effects, HAL haloperidol, ILO iloperidone, IM intramuscular, LUR lurasidone, MD
mean difference, NR no related, NS not significant, OLA olanzapine, OR odds ratio, PAL paliperidone, PANSS Positive and Negative Syndrome Scale, PER perphenazine, PLB placebo, QUE quetiapine, RE random
effects, RIS risperidone, SER sertindole, SMD standardized mean difference, ZIP ziprasidone, ZOT zotepine
a
Network meta-analyzes: all the studies that compose the network of evidence are presented
b
Bayesian network meta-analysis: the combined effect is presented with its respective credibility interval (CrI)
c
Network meta-analysis: only the consistency of closed-loop comparisons is evaluated
d
Most trials with unclear or lack of blinding of participants and personnel
e
Most trials with unclear random sequence generation and/or allocation concealment
f
The assumption of transitivity cannot be assessed
g
Impossible to assess the heterogeneity of the direct meta-analysis and/or inconsistency
h
Imprecision, 95% CI or CrI includes both benefit and harm
i
High unexplained heterogeneity
j
Imprecision, total population size < 400 patients
k
Statistical heterogeneity was not measured but there is a clear direction of effect
l
Imprecision, did not report minimal clinically important difference but overlapped the threshold for appreciable benefit (MD or SMD ± 0.5)
Eur J Clin Pharmacol
Table 3 Metabolic change results of systematic reviews on aripiprazole use in schizophrenia

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity or Publication Quality of
measure patientsa model [95.0% CI or CrI] incosistencyc bias evidence
(P value)b
Eur J Clin Pharmacol

Bai et al., ARI vs. AMI Weight gain 30/3210 FE OR = 0.24 [0.00; 2.20] (NS) NA NR Very lowd, e, f, g
2017 [15] ARI vs. ZIP Weight gain 30/3210 FE OR = 0.22 [0.00; 1.44] (NS) 0.897 Very lowd, e, f, g
ARI vs. QUE Weight gain 30/3210 FE OR = 0.34 [0.00; 24.85] (NS) 0.994 Very lowd, e, f, g
ARI vs. PAL Weight gain 30/3210 FE OR = 0.12 [0.00; 1.33] (NS) NA Very lowd, e, f, g
ARI vs. RIS Weight gain 30/3210 FE OR = 0.06 [0.00; 0.34] (p < 0.05) 0.689 Very lowd, e, g
ARI vs. CLO Weight gain 30/3210 FE OR = 0.06 [0.01; 0.41] (p < 0.05) 0.692 Very lowd, e, g
ARI vs. OLA Weight gain 30/3210 FE OR = 0.04 [0.00; 0.34] (p < 0.05) NA Very lowd, e, g
Belgamwar et al., ARI vs. PLB Weight gain 3/1035 FE RR = 2.55 [1.35; 4.82] (p = 0.0039) i2 = 13.0% (p = 0.32) NR Lowd, h
2011 [16]
Khanna et al., ARI vs. CLO Weight gain 18/1318 RE RR = 0.13 [0.08; 0.22] (p < 0.00001) i2 = 24.0% (p = 0.17) NR Moderated
2014 [18] (short term)
ARI vs. CLO Increase blood 5/410 RE RR = 0.12 [0.04; 0.37] (p = 0.00019) i2 = 0.0% (p = 0.81) NR Lowd, h
glucose (short
term)
ARI vs. CLO Final blood 2/134 RE MD = − 0.52 [− 0.83; − 0.22] i2 = 0.0% (p = 0.56) NR Lowd, i
glucose (mmol/L) (p = 0.00086)
ARI vs. QUE Weight gain 10/823 RE RR = 0.45 [0.24; 0.85] (p = 0.013) i2 = 0.0% (p = 0.47) NR Lowd, h
2
ARI vs. RIS Weight gain 58/4623 RE RR = 0.22 [0.17; 0.29] (p < 0.00001) i = 6.0% (p = 0.34) NR Moderated
(short term)
ARI vs. RIS Final body 5/465 RE MD = − 2.30 [− 4.17; − 0.44] (p = 0.015) i2 = 89.0% (p < 0.0001) NR Lowd, j
weight (kg)
ARI vs. RIS Final total 2/240 RE MD = − 0.02 [− 0.19; 0.14] (p = 0.80) i2i2 = 0.0% (p = 0.43) NR Lowd, f
cholesterol
(mmol/L)
ARI vs. RIS Final LDL 2/240 RE MD = 0.07 [− 0.11; 0.26] (p = 0.44) i2 = 14.0% (p = 0.28) NR Lowd, f
cholesterol
(mmol/L)
ARI vs. RIS Final HDL 2/240 RE MD = 0.06 [− 0.03; 0.14] (p = 0.19) i2 = 0.0% (p = 0.43) NR Lowd, f
cholesterol
(mmol/L)
ARI vs. RIS Increase blood 5/358 RE RR = 0.28 [0.09; 0.82] (p = 0.021) i2 = 0.0% (p = 0.98) NR Lowd, h
glucose
(short term)
ARI vs. ZIP Weight gain 3/232 RE RR = 4.01 [1.10; 14.60] (p = 0.035) i2 = 0.0% (p = 0.52) NR Lowd, h
ARI vs. OLA Weight gain 9/1538 RE RR = 0.25 [0.15; 0.43] (p < 0.00001) i2 = 30.0% (p = 0.18) NR Moderated
ARI vs. OLA Body weight (kg) 2/656 RE MD = − 3.03 [− 7.35; 1.29] (p = 0.17) i2 = 84.0% (p = 0.01) NR Lowd, f
ARI vs. OLA Final body 3/242 RE MD = − 7.43 [− 9.21; − 5.65] i2 = 0.0% (p = 0.73) NR Lowd, i
weight (kg) (p < 0.00001)
ARI vs. OLA Total cholesterol 2/789 RE MD = − 15.37 [− 21.62; − 9.11] i2 = 0.0% (p = 0.59) NR Moderated
(mg/dL) (p < 0.0001)
Table 3 (continued)

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity or Publication Quality of
measure patientsa model [95.0% CI or CrI] incosistencyc bias evidence
(P value)b

ARI vs. OLA Final total 2/182 RE MD = − 1.00 [− 1.44; − 0.56] i2 = 0.0% (p = 1.0) NR Lowd, i
cholesterol (p < 0.00001)
(mmol/L)
ARI vs. OLA Increase blood 3/227 RE RR = 0.12 [0.03; 0.44] (p = 0.0014) i2 = 0.0% (p = 0.97) NR Lowd, h
glucose
ARI vs. OLA Blood glucose 2/883 RE MD = − 3.39 [− 7.98; 1.19] (p = 0.15) i2 = 0.0% (p = 0.70) NR Lowd, f
(mg/dL)
Klemp et al., ARI vs. PLB Weight gain 18/5463 FE RR = 4.57 [3.07; 6.54] (p < 0.05) NR NR Very lowd, e, g, k
2011 [19]
Leucht et al., ARI vs. HAL, Body weight (kg) 3/1892 RE SMD = 0.19 [− 0.60; 0.97] (p = 0.64) NR NR Very lowd, f, g
2009 [22] PER, PLB
ARI vs. HAL Body weight (kg) 2/1598 RE SMD = 0.60 [− 0.10; 1.20] (p = 0.071) NR NR Lowd, f, l
Leucht et al., PBL vs. ARI Body weight (kg) NR/NR NR SMD = − 0.17 [− 0.28; − 0.05] (p < 0.05) NS NR Moderated
2013 [23] HAL vs. ARI Body weight (kg) NR/NR NR SMD = − 0.08 [− 0.21; 0.05] (NS) NS NR Lowd, f
ZIP vs. ARI Body weight (kg) NR/NR NR SMD = − 0.07 [− 0.21; 0.08] (NS) NS NR Lowd, f
LUR vs. ARI Body weight (kg) NR/NR NR SMD = − 0.07 [− 0.23; 0.10] (NS) NA NR Lowd, f
ARI vs. AMI Body weight (kg) NR/NR NR SMD = − 0.03 [− 0.21; 0.15] (NS) NA NR Lowd, f
ARI vs. ASE Body weight (kg) NR/NR NR SMD = − 0.06 [− 0.25; 0.12] (NS) NA NR Lowd, f
ARI vs. PAL Body weight (kg) NR/NR NR SMD = − 0.21 [− 0.37; − 0.06] (p < 0.05) NA NR Moderated
ARI vs. RIS Body weight (kg) NR/NR NR SMD = − 0.25 [− 0.38; − 0.12] (p < 0.05) NS NR Moderated
ARI vs. QUE Body weight (kg) NR/NR NR SMD = − 0.26 [− 0.41; − 0.12] (p < 0.05) NS NR Moderated
ARI vs. SER Body weight (kg) NR/NR NR SMD = − 0.37 [− 0.55; − 0.19] (p < 0.05) NA NR Moderated
ARI vs. CPZ Body weight (kg) NR/NR NR SMD = − 0.38 [− 0.62; − 0.15] (p < 0.05) NA NR Moderated
ARI vs. ILO Body weight (kg) NR/NR NR SMD = − 0.45 [− 0.61; − 0.28] (p < 0.05) NA NR Moderated
ARI vs. CLO Body weight (kg) NR/NR NR SMD = − 0.49 [− 0.83; − 0.13] (p < 0.05) NA NR Moderated
ARI vs. ZOT Body weight (kg) NR/NR NR SMD = − 0.55 [− 0.81; − 0.28] (p < 0.05) NA NR Moderated
ARI vs. OLA Body weight (kg) NR/NR NR SMD = − 0.57 [− 0.70; − 0.45] (p < 0.05) NS NR Moderated
Majer et al., ARI IM vs. PLB Weight gain 5/3224 FE OR = 2.24 [1.22; 3.96] (p < 0.05) NR NR Lowd, g
2015 [24] ARI Oral vs. PLB Weight gain 5/3224 FE OR = 3.24 [1.64; 6.14] (p < 0.05) NR NR Lowd, g
Oya et al., ARI IM vs. PLB Weight gain 2/1138 RE RR = 1.58 [0.92; 2.73] (p = 0.10) i2 = 46.0% (NR) NR Lowd, f
2015 [26] ARI IM vs. PLB Body weight (kg) 2/734 RE SMD = 0.41 [0.18; 0.64] (p = 0.0005) i2 = 57.0% (NR) NR Very lowd, l, j
ARI IM vs. ARI Oral Weight gain 2/986 RE RR = 0.97 [0.46; 2.06] (p = 0.94) i2 = 68.0% (NR) NR Very lowd, f, l
ARI IM vs. ARI Oral Body weight (kg) 2/847 RE SMD = − 0.16 [− 0.29; − 0.02] (p = 0.02) i2 = 0.0% (NR) NR Low a,g
Rummel-Kluge et al., ARI vs. OLA Body weight (kg) 2/656 FE MD = − 3.90 [− 6.19; − 1.62] (p = 0.0008) i2 = 37.0% (p = 0.21) NR Moderated
2010 [27] ARI vs. RIS Body weight (kg) 2/383 FE MD = − 0.54 [− 1.24; 0.15] (p = 0.12) i2 = 0.0% (p = 0.89) NR Lowd, f
ARI vs. OLA 2/789 RE i2 = 0.0% (p = 0.59) NR Moderated
Eur J Clin Pharmacol
Table 3 (continued)

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity or Publication Quality of
measure patientsa model [95.0% CI or CrI] incosistencyc bias evidence
(P value)b
Eur J Clin Pharmacol

Total cholesterol MD = − 15.35 [− 21.62; − 9.08]

(mg/dL) (p < 0.0001)
ARI vs. OLA Blood glucose (mg/dL) 3/1487 RE MD = − 4.13 [− 6.58; − 1.68] i2 = 0.0% (p = 0.86) NR Moderated
(p = 0.0009)

P value < 0.05 is considered statistically significant

AMI amisulpride, ARI aripiprazole, ASE asenapine, CLO clozapine, CPZ chlorpromazine, FE fixed effects, HAL haloperidol, ILO iloperidone, IM intramuscular, LUR lurasidone, MD mean difference, NR
not related, NS not significant, OLA olanzapine, OR odds ratio, PAL paliperidone, PER perphenazine, PLB placebo, QUE quetiapine, RE random effects, RIS risperidone, RR relative risk, SER sertindole,
SMD standardized mean difference, ZIP ziprasidone, ZOT zotepine
a
Network meta-analyses: all the studies that compose the network of evidence are presented
b
Bayesian network meta-analysis: the combined effect is presented with its respective credibility interval (CrI)
c
Network meta-analysis: only the consistency of closed-loop comparisons is evaluated
d
Most trials with unclear or inadequate random sequence generation and/or allocation concealment
e
The assumption of transitivity cannot be assessed
f
Imprecision, 95% CI or CrI includes both benefit and harm
g
Impossible to assess the heterogeneity of the direct meta-analysis and/or inconsistency
h
Imprecision, total number of the events < 100
i
Imprecision, total population size < 400 patients
j
Imprecision, did not report minimal clinically important difference but overlapped the threshold for appreciable benefit (MD or SMD ± 0.5)
k
Literature search does not comprehensive with possible publication bias
l
Statistical heterogeneity was not measured but there is a clear direction of effect

clozapine (low quality). No significant difference was detect-
ed between the risk of agitation associated with aripiprazole
and other atypical antipsychotic drugs [18, 28] (Table 4).
Parkinsonism and the use of antiparkinsonian medication
As can be seen in Table 4, Khanna et al. [18] reported no
significant difference between aripiprazole and olanzapine in
the induction of parkinsonism. About the use of
antiparkinsonian medication, two reviews [17, 23] found no
significant difference, when comparing aripiprazole to place-
bo administration. Compared to risperidone, lurasidone, and
zotepine, aripiprazole significantly reduced the use of
antiparkinsonian drugs [23] (moderate quality). On the other
hand, aripiprazole significantly increased the use of
antiparkinsonian drugs, compared with clozapine (moderate
quality) [23]. Two reviews showed that aripiprazole was asso-
ciated with the use of antiparkinsonian medication to a signif-
icantly lower extent than were atypical antipsychotics (mod-
erate quality evidence) [22, 23].
Risk of bias in systematic reviews
The assessment of the risk of bias in systematic reviews based
on the ROBIS tool is showed in Table 5. Domain 1 of phase 2
assessed the specification of eligibility criteria, and ten studies
[15–18, 21–24, 26, 27] were characterized as of Blow^ risk of
bias. Studies classified as Bunclear^ [25] or Bhigh^ [19, 20,
28] risk of bias did not show details of the eligibility criteria,
such as specifications and restrictions. Domain 2 assessed the
methods used for the identification and selection of studies,
and four reviews [16–18, 25] reached a Blow^ risk of bias.
Studies classified as having Bunclear^ [15, 21, 23, 26, 27] or
Bhigh^ [19, 20, 22, 24, 28] risk of bias had not reported the
complete search strategy, neither the terms used, and had not
provided detailed restrictions on the date, format, and lan-
guage of the incorporated publications. Domain 3 assessed
the methods used to collect data and appraise studies, and
six reviews [15–18, 23, 24] achieved a Blow^ risk of bias.
Systematic reviews classified as of Bunclear^ [20–22,
26–28] or Bhigh^ [19, 25] risk of bias had not presented the
quality assessment of the RCTs, using appropriate criteria or
failed to minimize the error of this evaluation. Six studies
[15–18, 21, 23] achieved a Blow^ risk of bias classification
in domain 4, which assessed the synthesis and findings.
Studies categorized as having Bunclear^ [20, 22, 24, 26–28]
or Bhigh^ [19, 25] risk of bias had not provided information on
the pre-defined protocol. Phase 3 assessed the overall risk of
bias in the systematic reviews, and five studies were classified
as Blow^ risk [15–18, 23], five as Bunclear^ risk [21, 22, 24,
26, 27], and four were categorized as Bhigh^ risk of bias [19,
20, 25, 28].
Eur J Clin Pharmacol
Discussion
Main findings
The present overview identified 14 systematic reviews with
meta-analysis that studied the efficacy and/or safety of
aripiprazole for the treatment of schizophrenia. The efficacy
of the antipsychotic drugs was evaluated using the PANSS
scale, whereas safety was estimated by the reported metabolic
changes and EPSE. Despite superior efficacy in total, positive,
and negative PANSS, when compared to placebo,
aripiprazole’s performance was similar to that of the typical
antipsychotics, on these same scales. Among the atypical an-
tipsychotic drugs, aripiprazole was inferior to olanzapine and
amisulpride, in total PANSS, and did not show significant
differences in comparison to the atypical antipsychotics for
positive and negative PANSS. In this sense, if a patient with
schizophrenia presents a good clinical response on
aripiprazole, the most relevant factor for choosing it would
be its safety profile.
While aripiprazole induces body weight gain, it usually
causes less weight gain than other atypical drugs (except for
lurasidone, ziprasidone, amisulpride, and asenapine) and does
not show a significant difference in relation to typical antipsy-
chotics. Given that weight gain is multifactorial in patients
with schizophrenia, aripiprazole has the benefit of causing less
weight gain within its class (atypical drugs), and its effects are
similar to those of typical antipsychotics. Weight gain is an
adverse event that increases mortality, produces somatic se-
quelae, and jeopardizes medication adherence, as well as stig-
matization and deterioration in quality of life [29]. In this
sense, aripiprazole could be a valuable option for patients
prone to weight gain.
Regarding the metabolic changes caused by atypical anti-
psychotics, aripiprazole was the one that caused the lowest
increase in blood glucose and cholesterol levels.
Schizophrenia is a risk factor for glucose intolerance and for
the development of type 2 diabetes mellitus [30, 31].
Consequently, individuals with schizophrenia who need anti-
psychotic drug treatment and bear other risk factors for diabe-
tes (i.e., genetic and environmental predisposition) could ben-
efit from the use of aripiprazole. In addition, high cholesterol
levels contribute substantially to the development of coronary
artery disease [32]; thus, aripiprazole may be the drug-of-
choice for schizophrenic patients with high cardiovascular
risk.
EPSE are attributed to dopaminergic block in certain brain
areas. Therefore, the first-generation (typical) antipsychotics
are associated with an elevated risk of EPSE, since their main
mechanism of action is the dopamine receptor blockade. This
risk is usually higher than that of atypical antipsychotics, shar-
ing other mechanisms of action beyond dopaminergic block
[33, 34]. In this overview, aripiprazole was shown to cause
Table 4 Extrapyramidal side effects results of systematic reviews on aripiprazole use in schizophrenia

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity Publication Quality
measure patientsa model [95.0% CI or CrI] or incosistencyc bias of evidence
(p value)b
Eur J Clin Pharmacol

Bai et al., 2017 [15] CLO vs. ARI EPSE 20/2210 FE OR = 0.02 [0.00; 3.13] (NS) NA NR Very lowd, e, f, g, h
OLA vs. ARI EPSE 20/2210 FE OR = 0.09 [0.00; 2.08] (NS) NA Very lowd, e, f, g, h
QUE vs. ARI EPSE 20/2210 FE OR = 0.44 [0.03; 8.94] (NS) NA Very lowd, e, f, g, h
PAL vs. ARI EPSE 20/2210 FE OR = 0.79 [0.06; 10.28] (NS) NA Very lowd, e, f, g, h
ARI vs. ZIP EPSE 20/2210 FE OR = 0.67 [0.05; 8.91] (NS) NA Very lowd, e, f, g, h
ARI vs. RIS EPSE 20/2210 FE OR = 0.39 [0.07; 1.89] (NS) NA Very lowd, e, f, g, h
ARI vs. AMI EPSE 20/2210 FE OR = 0.23 [0.01; 2.89] (NS) NA Very lowd, e, f, g, h
Belgamwar et al., ARI vs. PLB Akathisia 5/1595 FE RR = 1.78 [1.16; 2.74] (p = 0.0088) i2 = 0.0% (p = 0.60) NR Lowd, e, i
2011 [16] ARI vs. PLB EPSE 4/1298 FE RR = 0.83 [0.47; 1.45] (p = 0.51) i2 = 5.0% (p = 0.37) NR Lowd, e, g
ARI vs. PLB Anxiety 3/1035 FE RR = 0.83 [0.62; 1.12] (p = 0.23) i2 = 2.0% (p = 0.36) NR Lowd, e, g
ARI vs. PLB Use of antiparkinson 4/1043 FE RR = 0.83 [0.61; 1.14] (p = 0.26) i2 = 0.0% (p = 0.81) NR Lowd, e, g
medication
ARI vs. PLB Agitation 3/980 FE RR = 0.61 [0.40; 0.92] (p = 0.02) i2 = 0.0% (p = 0.89) NR Lowd, e, j
Bhattacharjee et al., ARI vs. HAL. PERF EPSE 3/968 RE RR = 0.46 [0.25; 0.87] (p = 0.016) i2 = 69.0% (p = 0.04) NR Moderatee, k
2008 [17] ARI vs. HAL. PERF Akathisia 3/903 RE RR = 0.39 [0.25; 0.60] (p = 0.00002) i2 = 0.0% (p = 0.54) NR Lowe, j
ARI vs. HAL. PERF Agitation 3/955 RE RR = 0.99 [0.63; 1.54] (p = 0.95) i2 = 0.0% (p = 0.96) NR Lowe, g
ARI vs. HAL. PERF Anxiety 2/608 RE RR = 0.95 [0.65; 1.40] (p = 0.80) i2 = 0.0% (p = 0.64) NR Lowe, g
Khanna et al., ARI vs. CLO Anxiety (short term) 11/732 RE RR = 2.62 [1.21; 5.70] (p = 0.015) i2 = 25.0% (p = 0.21) NR Lowd, e, j
2014 [18] ARI vs. CLO Akathisia (short term) 13/916 RE RR = 1.21 [0.54; 2.68] (p = 0.65) i2 = 53.0% (p = 0.01) NR Very lowd, e, g.i
ARI vs. CLO Dystonia (short term) 5/374 RE RR = 3.24 [1.29; 8.12] (p = 0.012) i2 = 0.0% (p = 0.54) NR Lowd, e, j
ARI vs. CLO EPSE (short term) 8/520 RE RR = 1.91 [0.75; 4.85] (p = 0.18) i2 = 33.0% (p = 0.16) NR Lowd, e, g
ARI vs. CLO Use of antiparkinson 2/ 140 RE RR = 2.84 [0.07; 117.07] (p = 0.58) i2 = 86.0% (p = 0.01) NR Very lowd, e, g.i
medication (short term)
ARI vs. QUE Agitation (short term) 5/423 RE RR = 1.29 [0.27; 6.27] (p = 0.75) i2 = 25.0% (p = 0.26) NR Lowd, e, g
ARI vs. QUE Anxiety (short term) 2/168 RE RR = 2.18 [0.51; 9.35] (p = 0.29) i2 = 0.0% (p = 0.82) NR Lowd, e, g
ARI vs. QUE Akathisia (short term) 7/571 RE RR = 1.15 [0.49; 2.70] (p = 0.75) i2 = 23.0% (p = 0.25) NR Lowd, e, g
ARI vs. QUE Dystonia (short term) 2/145 RE RR = 0.47 [0.06; 3.53] (p = 0.46) i2 = 0.0% (p = 0.41) NR Lowd, e, g
ARI vs. QUE EPSE (short term) 4/348 RE RR = 2.80 [0.64; 12.31] (p = 0.17) i2 = 53.0% (p = 0.09) NR Lowd, e, g
ARI vs. RIS Anxiety (short term) 9/744 RE RR = 1.81 [1.12; 2.94] (p = 0.015) i2 = 0.0% (p = 0.54) NR Lowd, e, j
ARI vs. RIS Agitation (short term) 26/2038 RE RR = 1.26 [0.86; 1.84] (p = 0.23) i2 = 0.0% (p = 1.00) NR Lowd, e, g
ARI vs. RIS Akathisia (short term) 42/3501 RE RR = 0.60 [0.48; 0.74] (p < 0.00001) i2 = 15.0% (p = 0.20) NR Moderated, e
ARI vs. RIS Dystonia (short term) 32/2640 RE RR = 0.35 [0.25; 0.49] (p < 0.00001) i2 = 19.0% (p = 0.17) NR Moderated, e
ARI vs. RIS EPSE (short term) 31/2605 RE RR = 0.39 [0.31; 0.50] (p < 0.00001) i2 = 44.0% (p = 0.005) NR Moderated, e, k
ARI vs. ZIP Agitation (short term) 2/150 RE RR = 1.00 [0.11; 9.42] (p = 1.00) i2 = 0.0% (p = 0.34) NR Lowd, e, g
ARI vs. ZIP Akathisia (short term) 3/423 RE RR = 0.80 [0.25; 2.61] (p = 0.71) i2 = 47.0% (p = 0.15) NR Lowd, e, g
ARI vs. ZIP EPSE (short term) 2/120 RE RR = 0.77 [0.37; 1.62] (p = 0.50) i2 = 0.0% (p = 0.74) NR Lowd, e, g
ARI vs. ZIP Use of antiparkinson 2/ 140 RE RR = 2.84 [0.07; 117.07] (p = 0.58) i2 = 86.0% (p = 0.01) NR Very lowd, e, g.i
medication
(short term)
ARI vs. OLA Anxiety 2/778 RE RR = 1.23 [0.79; 1.90] (p = 0.36) i2 = 0.0% (p = 0.39) NR Lowd, e, g
ARI vs. OLA Akathisia 6/1320 RE RR = 1.56 [0.67; 3.60] (p = 0.30) i2 = 63.0% (p = 0.02) NR Lowd, e, g
ARI vs. OLA EPSE 4/667 RE RR = 0.99 [0.62; 1.59] (p = 0.97) i2 = 0.0% (p = 0.36) NR Lowd, e, g
ARI vs. OLA Parkinsonism 3/618 RE RR = 0.80 [0.46; 1.38] (p = 0.42) i2 = 0.0% (p = 0.57) NR Lowd, e, g
ARI vs. outros APC Anxiety 2/1361 FE RR = 1.33 [0.94; 1.90] (p = 0.11) i2 = 0.0% (p = 0.66) NR Lowd, e, g
ARI vs. outros APC Akathisia 2/1361 RE RR = 2.77 [1.28; 5.99] (p = 0.01) i2 = 25.0% (p = 0.25) NR Lowd, e, j
Table 4 (continued)

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity Publication Quality
measure patientsa model [95.0% CI or CrI] or incosistencyc bias of evidence
(p value)b

Klemp et al., ARI vs. PLB EPSE 20/5910 FE RR = 1.34 [1.06; 1.65] (p < 0.05) NR NR Very lowe, f, m, n
2011 [19]
Leucht et al., ARI vs. HAL. Use of antiparkinson 5/2049 RE RR = 0.49 [0.36; 0.66] (p = 0.000) NR NR Moderatee, o
2009 [22] PER. PLB medication
ARI vs. HAL Use of antiparkinson 4/1794 RE RR = 0.45 [0.32; 0.64] (p < 0.0001) NR NR Moderatee, o
medication
Leucht et al., ARI vs. PBL Use of antiparkinson NR/NR NR OR = 1.20 [0.73; 1.85] (NS) NS NR Lowd, e, g
2013 [23] medication
ARI vs. HAL Use of antiparkinson NR/NR NR OR = 0.25 [0.15; 0.39] (p < 0.05) NS NR Moderated, e
medication
ARI vs. ZIP Use of antiparkinson NR/NR NR OR = 0.78 [0.41; 1.34] (NS) NA NR Lowd, e, g
medication
ARI vs. LUR Use of antiparkinson NR/NR NR OR = 0.51 [0.26; 0.91] (p < 0.05) NA NR Moderated, e
medication
AMI vs. ARI Use of antiparkinson NR/NR NR OR = 1.40 [0.66; 2.61] (NS) NA NR Lowd, e, g
medication
ASE vs. ARI Use of antiparkinson NR/NR NR OR = 1.46 [0.64; 2.90] (NS) NA NR Lowd, e, g
medication
PAL vs. ARI Use of antiparkinson NR/NR NR OR = 1.59 [0.82; 2.82] (NS) NA NR Lowd, e, g
medication
RIS vs. ARI Use of antiparkinson NR/NR NR OR = 1.83 [1.08; 2.94] (p < 0.05) NS NR Moderated, e
medication
QUE vs. ARI Use of antiparkinson NR/NR NR OR = 0.89 [0.48; 1.51] (NS) NS NR Lowd, e, g
medication
SER vs. ARI Use of antiparkinson NR/NR NR OR = 0.71 [0.35; 1.31] (NS) NA NR Lowd, e, g
medication
CPZ vs. ARI Use of antiparkinson NR/NR NR OR = 2.33 [1.00; 4.66] (p < 0.05) NA NR Moderated, e
medication
ILO vs. ARI Use of antiparkinson NR/NR NR OR = 1.39 [0.43; 3.47] (NS) NA NR Lowd, e, g
medication
CLO vs. ARI Use of antiparkinson NR/NR NR OR = 0.26 [0.09; 0.59] (p < 0.05) NA NR Moderated, e
medication
ZOT vs. ARI Use of antiparkinson NR/NR NR OR = 2.64 [1.06; 5.57] (p < 0.05) NA NR Moderated, e
medication
OLA vs. ARI Use of antiparkinson NR/NR NR OR = 0.88 [0.50; 1.42] (NS) NS NR Lowd, e, g
medication
Majer et al., ARI IM vs. PLB EPSE 5/3289 FE OR = 1.68 [1.07; 2.55] (p < 0.05) NR NR Lowe, n
2015 [24] ARI Oral vs. PLB EPSE 5/3289 FE OR = 1.43 [0.83; 2.33] (NS) NR NR Very lowe, g, n
Moteshafi et al., ARI vs. Control Akathisia 8/2264 RE EER = 0.05 [0.03; 0.09] (p < 0.05) NR NR Moderatee, f, o
2012 [25]
Oya et al., 2015 [26] ARI IM vs. PLB Anxiety NR RE RR = 0.87 [0.51; 1.47] (NS) NR NR Very lowe, g, p
ARI IM vs. PLB EPSE NR RE RR = 1.63 [0.64; 4.15] (NS) NR NR Very lowe, g, p
ARI IM vs. PLB Akathisia 2/592 RE SMD = 0.22 [− 0.24; 0.68] (p = 0.34) i2 = 85.0% (NR) NR Very lowe, g, l
ARI IM vs. PLB Dystonia 2/592 RE SMD = 0.00 [− 0.17; 0.17] (p = 1.00) i2 = 0.0% (NR) NR Lowe, g
ARI IM vs. ARI Oral Akathisia 2/680 RE SMD = 0.25 [− 0.24; 0.74) (p = 0.31) i2 = 90.0% (NR) NR Very lowe, g, l
Eur J Clin Pharmacol
Table 4 (continued)

Authors. year Comparisons Outcome No of RCT/ Statistical Pooled effect Heterogeneity Publication Quality
measure patientsa model [95.0% CI or CrI] or incosistencyc bias of evidence
(p value)b
Eur J Clin Pharmacol

ARI IM vs. ARI Oral Dystonia 2/680 RE SMD = − 0.06 [− 0.38; 0.26] (p = 0.73) i2 = 85.0% (NR) NR Very lowe, g, l
Thomas et al., ARI vs. PLB. Akathisia 12/3772 FE RR = 1.52 [1.20; 1.91] (p = 0.0004) i2 = 0.0% (p = 0.57) NR Moderatee
2015 [28] OLA. RIS. ZIP
ARI vs. OLA. Akathisia 8/2440 FE RR = 1.49 [1.13; 1.99] (p = 0.006) i2 = 0.0% (p = 0.61) NR Moderatee
RIS. ZIP
ARI vs. PLB Akathisia 4/1332 FE RR = 1.55 [1.05; 2.29] (p = 0.03) i2 = 29.0% (p = 0.24) NR Lowe, i
ARI vs. PLB. Agitation 6/NR FE RR = 1.02 [0.83; 1.26] (p = 0.83) i2 = 43.0% (NR) NR Low b.d
OLA. RIS. ZIP
ARI vs. OLA. Agitation 4/NR FE RR = 1.21 [0.89; 1.65] (p = 0.23) i2 = 0.0% (NR) NR Lowe, g
RIS. ZIP
ARI vs. PLB. Anxiety 10/NR FE RR = 1.02 [0.87; 1.20] (p = 0.81) i2 = 5.0% (NR) NR Lowe, g
OLA. RIS. ZIP
ARI vs. OLA. Anxiety 6/NR FE RR = 1.09 [0.88; 1.35] (p = 0.43) i2 = 0.0% (NR) NR Lowe, g
RIS. ZIP
ARI vs. PLB. Dystonia 2/NR FE RR = 0.40 [0.12; 1.31] (p = 0.14) i2 = 0.0% (NR) NR Lowe, g
OLA. RIS. ZIP
ARI vs. OLA. Dystonia 2/NR FE RR = 0.29 [0.07; 1.23] (p = 0.09) i2 = 67.0% (NR) NR Very lowe, g, l
RIS. ZIP

P value < 0.05 is considered statistically significant

AMI amisulpride, APC antipsychotics, ARI aripiprazole, ASE asenapine, CLO clozapine, CPZ chlorpromazine, EER event rate ratio, EPSE extrapyramidal side effects, FE fixed effects, HAL haloperidol,
ILO iloperidone, IM intramuscular, LUR lurasidone, NR not related, NS not significant, OLA olanzapine, OR odds ratio, PAL paliperidone, PER perphenazine, PLB placebo, QUE quetiapine, RE random
effects, RIS risperidone, RR relative risk, SER sertindole, SMD standardized mean difference, ZIP ziprasidone, ZOT Zotepine
a
Network meta-analysis: all the studies that compose the network of evidence are presented
b
Bayesian network meta-analysis: the combined effect is presented with its respective credibility interval (CrI)
c
Network meta-analysis: only the consistency of closed-loop comparisons is evaluated
d
Most trials with unclear or lack of blinding of participants and personnel
e
Most trials with unclear or inadequate random sequence generation and/or allocation concealment
f
The assumption of transitivity cannot be assessed
g
Imprecision, 95% CI or CrI includes both benefit and harm
h
Impossible to assess the heterogeneity of the direct meta-analysis and/or inconsistency
i
Imprecision, does not reach the optimum information size (OIS)
j
Imprecision, total number of the events < 100
k
High heterogeneity, but with clear direction of effect
l
High unexplained heterogeneity
m
Literature search does not comprehensive with possible publication bias
n
Impossible to assess the heterogeneity of direct meta-analysis and/or inconsistency
o
Statistical heterogeneity was not measured but there is a clear direction of effect
p
Statistical heterogeneity was not measured and it is not possible to assess the direction of effect
 Eur J Clin Pharmacol

Table 5 Quality assessment of the included systematic reviews based on Risk of Bias in Systematic Reviews (ROBIS) tool
Phase 2 Phase 3
2.
1. Study Identification 3. Data collection Risk of bias in
Authors, year 4. Synthesis
eligibility and and the
and findings
criteria selection of study appraisal review
studies
Bai et al., 2017 [15] ?

Belgamwar et al., 2011 [16]

Bhattacharjee et al., 2008 [17]

Khanna et al., 2014 [18]

Klemp et al., 2011 [19]

Kunitomi et al., 2014 [20] ? ?

Leucht et al., 2009 [21] ? ? ?

Leucht et al., 2009 [22] ? ? ?

Leucht et al., 2013 [23] ?

Majer et al., 2015 [24] ? ?

Moteshafi et al., 2012 [25] ?

Oya et al., 2015 [26] ? ? ? ?

Rummel-Kluge et al., 2010[27] ? ? ? ?

Thomas et al., 2015 [28] ? ?

= low risk; = high risk; = unclear risk

less general EPSE, compared to typical antipsychotics, and
exhibited no significant difference in relation to the other atyp-
ical drugs.
Akathisia is described by motor restlessness, accompanied
by the subjective feeling of inner tension and discomfort, prin-
cipally of the upper and lower limbs. It may coexist with
parkinsonism; however, it can be more common, and its
symptoms more distressing, leading to poor medication adher-
ence [35]. In contrast, acute dystonia is a sustained condition
of abnormal postures or muscle spasms, developed within
7 days after the initiation of treatment. The drug-induced acute
dystonia is considered secondary and usually occurs after the
use of anti-dopaminergic drugs, such as antipsychotics [36,
37]. The findings of our overview indicate that aripiprazole
causes akathisia in fewer cases than do typical antipsychotics
and risperidone and dystonia in fewer cases than does risper-
idone. Nevertheless, dystonia was caused by aripiprazole in
more cases than by clozapine. Given the debilitating nature of
akathisia and dystonia, the related high risk of poor medica-
tion adherence, and the difficulty of managing treatment-
Eur J Clin Pharmacol
related adverse events, aripiprazole appears as an alternative
associated with a low risk of EPSE.
Drug-induced parkinsonism is a condition that includes the
presence of resting tremor, muscular rigidity, akinesia, or bra-
dykinesia, developing within few weeks after starting or rais-
ing the dosage of a medication, typically neuroleptic [1].
Therefore, individuals with schizophrenia bearing risk factors
for parkinsonism—e.g., elderly, females, with familial predis-
position, severe unexplained hyposmia, concomitant brain
damage and atrophy, dementia, and high dose of inducing
medication [38]—should choose drugs that do not target do-
pamine receptors or do not induce parkinsonism. Current ev-
idence shows that patients taking aripiprazole require
antiparkinsonian medication to a lesser degree than do those
taking typical drugs and most other atypical antipsychotics,
with the exception of clozapine.
Aripiprazole showed no significant difference about anxi-
ety and agitation, compared to typical antipsychotic drugs or
regarding agitation, compared to atypical antipsychotics. In
contrast, aripiprazole was shown to cause anxiety to a signif-
icantly greater extent than did clozapine and risperidone.
Negative symptoms are a major problem in schizophrenia,
since they directly affect the patient’s quality of life and par-
ticipation in the society. Primary negative symptoms are in-
trinsic to schizophrenia, while secondary negative symptoms
occur in association with, or presumably are caused by posi-
tive symptoms, affective symptoms, medication adverse ef-
fects, environmental deprivation, or other treatment- and
disease-related factors [39]. Given that anxiety is a relevant
source of secondary negative symptoms [40], its control is
essential for the improvement of the patient’s quality of life.
Risk of bias in systematic reviews
According to our knowledge, this is the first schizophrenia-
based study to apply the ROBIS tool to evaluate the risk of bias
in systematic reviews. The ROBIS tool was chosen for quality
assessment of the systematic reviews because it was recently
published, have fair reliability and good construct validity, and
requires a more detailed assessment of the methodology
employed for the systematic review [14, 41, 42]. Although
AMSTAR tool is widely used and has showed acceptable reli-
ability and validity [43], studies have reported limitations relat-
ed to the interpretation of the items and their instructions [44,
45]. In addition, there is overlap in the items considered by
ROBIS and AMSTAR and a strong correlation between both
tools [41, 42]. Most reviews (nine studies), included in this
overview, were characterized as having Bunclear^ or Bhigh^
risk of bias. Many studies did not detail the eligibility criteria
(prior protocol), did not report the complete search strategy, and
did not assess the quality of the RCTs, using appropriate
criteria. Importantly, domain 4 in phase 2 is an easy tool for
the evaluation of direct evidence in systematic reviews with
meta-analysis. However, for indirect or mixed comparisons,
there is little guidance in the ROBIS tool on how to classify
systematic reviews on study variability (heterogeneity) and ro-
bustness of the data (sensitivity analysis). In addition, important
aspects in indirect or mixed comparison are not addressed in
this tool, such as the principle of transitivity and inconsistency.
Opportunities for future research
Most systematic reviews, included in this overview, involved
hospitalized patients with schizophrenia or related well-
defined disorders, with limited physical and psychical comor-
bidities. However, this population is minority in everyday life
of the medical clinic, since most patients are not hospitalized,
have other associated pathologies (e.g., substance abuse and
depression), and use other concomitant medications [40],
which may affect the effectiveness of pharmacotherapy of
schizophrenia. In addition, most studies evaluated short-term
treatment (usually up to 12 weeks), making difficult the un-
derstanding of the long-term efficacy and of the safety profile
of aripiprazole—patients with schizophrenia usually require
prolonged pharmacotherapy. In addition, most studies includ-
ed in the overview were classified as having Bhigh^ or
Bunclear^ risk of bias, according to the ROBIS tool. Many
reviews did not detail eligibility criteria (prior protocol), com-
plete search strategy to be replicated, and did not assess the
quality of primary studies.
Given the debilitating nature of schizophrenia—affecting
not only the patient but also the family—pharmacotherapy
needs to be better studied and documented through RCTs of
high methodological quality, with reduced risk of bias, includ-
ing a larger number and diversity of patients, and with a longer
follow-up period. Thus, it is expected that new and more ro-
bust scientific evidence will be available to health profes-
sionals and guide improved decision-making.
Limitations of the overview
The present overview has some limitations. Firstly, the risk of
bias in the GRADE approach was judged based on the risk
assessment of original trials made by the review authors. In
addition, the exclusion of three potential systematic reviews
due to failure in obtaining the full-text articles—even though
they were requested from the corresponding author via
ResearchGate and/or by e-mail—may have generated publi-
cation bias. Also, we did not search unpublished reviews,
either in thesis repositories or in proceedings of scientific
events. Furthermore, our a priori decision to exclude reviews
not presenting a meta-analysis might have led to the exclusion
of important reviews on this theme, because in some cases
statistical pooling was not appropriate. We could not conduct
a quantitative analysis owing to the heterogeneity of popula-
tions, interventions, and outcomes in the included reviews.

Conclusion
The findings of this overview showed that aripiprazole is effec-
tive for the reduction in the total PANSS and has efficacy sim-
ilar to that of typical and atypical (with the exception of
olanzapine and amisulpride) antipsychotics. Given the high
occurrence of metabolic effects among atypical antipsychotics,
aripiprazole—in spite of provoking them—is related to lower
weight gain and lower change in glucose and cholesterol levels,
compared to clozapine, risperidone, or olanzapine. Although
typical antipsychotics do not usually cause metabolic effects,
they tend to cause movement disorders. Aripiprazole caused
less general EPSE, need for antiparkinsonian medication, and
akathisia, compared to typical antipsychotic drugs and risperi-
done. On the other hand, it caused more anxiety than that
caused by risperidone, in addition to more dystonia, anxiety,
and need for antiparkinsonian medication than did clozapine.
Therefore, individuals with a good clinical response to
aripiprazole and with predisposition for certain EPSE, weight
gain, hyperglycemia, or hyperlipidemia may be the main ben-
eficiaries of this therapy. However, it is important to note that
these results were based mostly on Blow^ or Bvery low^ quality
evidence and were derived from systematic reviews mostly
with Bhigh^ or Bunclear^ risk of bias.
Author’s contributions E.L.A.R. and P.M.A. planned the study. E.L.A.R.
and T.M.L. performed the literature search and the qualitative analysis,
supervised by P.M.A. E.L.A.R. wrote the first draft, and T.M.L.,
M.E.B.V., S.S., and P.M.A. reviewed the manuscript. All authors contrib-
uted to and have approved the final manuscript.
Compliance with ethical standards
Conflict of interest The authors have no potential conflicts of interest
relevant to disclose. The research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit sectors.
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