R E S E A R C H A R T I C L E Open Access
Response rates in patients with
schizophrenia and positive symptoms
receiving cognitive behavioural therapy: a
systematic review and single-group meta-
, Maximilian Huhn
, Johannes Schneider-Thoma
, Marc Krause
, Cornelia Reitmeir
, Sofia Wallis
, Gabi Pitschel-Walz
, Corrado Barbui
, Toshi A. Furukawa
and Stefan Leucht
Background: Cognitive behavioural therapy has been used for schizophrenia, but to which extent it is effective is
still controversial. Results of existing meta-analyses are of difficult interpretation, because they mainly present effect
sizes in the form of standardized mean differences between intervention and control groups based on rating scales,
which are of unclear clinical meaning. No meta-analysis has considered the number of patients responding to
treatment yet. Based on this ground, we present the first meta-analysis examining the response rates of patients
with schizophrenia and positive symptoms to cognitive behavioural therapy.
Methods: We searched multiple databases for randomized controlled trials on psychological interventions of
schizophrenia including patients with positive symptoms, and included for this analysis the studies on cognitive
behavioural therapy (last search: January 2018). We applied a validated imputation method to calculate the number of
responders from rating scales for the outcomes overall symptoms and positive symptoms, based on two criteria, at
least 20% and at least 50% reduction from baseline on PANSS or BPRS total scores. Data were pooled in a single-group
summary meta-analysis using R software. Additionally, several potential moderators of response to cognitive
behavioural therapy were examined by subgroup and meta-regression analyses. The protocol has been registered in
Results: We included 33 studies with a total of 1142 participants receiving cognitive behavioural therapy. On average,
44.5 and 13.2% of the patients reached a 20% (minimally improved) and 50% (much improved) reduction of overall
symptoms. Similarly, 52.9 and 24.8% of the patients reached a 20%/50% reduction of positive symptoms. Subgroup
and meta-regression analyses revealed a better treatment response in overall symptoms for patients that were not
treatment resistant and in studies with researchers’allegiance. Of borderline significance was the better response in
studies employing expert therapists and in patients that were more severely ill at baseline. Blinding of outcome
assessor, number of sessions, treatment duration, age and gender were not significant moderators of response.
Conclusions: Our findings suggest that adding cognitive behavioural therapy to pharmacotherapy brings about a
minimal improvement in overall symptoms among 44.5% of its recipients. Several study and patients characteristics
can moderate response rates.
Keywords: Schizophrenia, Cognitive behavioural therapy, Meta-analysis, Response rate
* Correspondence: Irene.email@example.com
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar,
Technische Universität München, Munich, Germany
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Bighelli et al. BMC Psychiatry (2018) 18:380
Schizophrenia is a severe disorder, and a leading cause of
disability with a dramatic burden on society . Psycho-
logical interventions for schizophrenia have been developed
to address several aspects of the disorder, and in agreement
with guidelines from the National Institute for Health and
Care Excellence in the UK and the Schizophrenia Patient
Outcomes Research Team in the USA, are widely regarded
as necessary interventions [2,3]. The importance of re-
search advancements in the field of psychological treat-
ments has been also recently pointed out by the
constitution of the Lancet Psychiatry Commission on psy-
chological treatments research in tomorrow’s science .
Among psychotherapies for schizophrenia, cognitive be-
havioural therapy (CBT) is the most studied, and it is cur-
rently recommended by guidelines . In a recent
systematic review and network meta-analysis by our group,
which considered all psychological interventions for schizo-
phrenia, 41 out of 53 included randomized controlled trials
(RCTs) examined CBT . Results revealed that CBT is ef-
ficacious for treating patients with schizophrenia who
present positive symptoms, which had a significant benefit
from the treatment when compared to patients receiving
usual care, supportive therapy and inactive control condi-
tions such as befriending. In particular, effect sizes mea-
comparison with usual care were −0.38 (95% CI -0.56 to −
0.20) for overall symptoms, −0.30 (95% CI -0.30 to −0.14)
for positive symptoms and −0.16 (95% CI -0.29 to −0.03)
for negative symptoms .
However, efficacy measured with rating scales is difficult to
interpret. The clinical meaning of results is especially unclear
when different measures are used in different studies, and a
standardized mean difference is employed as effect size.A
pragmatic outcome like response to treatment would make
the results easier to interpret. Moreover, meta-analyses pro-
vide the relative treatment effects in comparison to an alter-
native intervention, while, from a clinical point of view, it is
important to know the absolute treatment effect that can be
expected from a certain therapy.
Nonetheless, the number of patients who improve with a
treatment is rarely reported in the studies, and very heteroge-
neous criteria are used to define it. Probably for that reason,
not one of the existing pairwise meta-analyses on CBT for
schizophrenia presented data on response rates. The only ex-
ception is represented by a Cochrane review by Jones et al.,
in which the authors pooled response rates from seven trials
under the label of “reliable change”,pointingoutthatthese
trials applied different definitions of response . They pre-
sented a pooled relative effect size that did not inform on the
absolute treatment effect of cognitive behavioural treatment.
As a result, the extent to which patients with schizo-
phrenia and positive symptoms may benefit from CBT
A possible strategy to deal with this issue was applied by
Zhu and colleagues, who calculated response rates from con-
tinuous outcomes in the field of antipsychotic medication for
patients with first episode schizophrenia . Thus, we de-
cided to apply the same methodology to calculate response
rates from studies on CBT that were included in the previ-
ous review , in order to provide an easy-to-interpret meas-
ure of treatment effect.
Goals for present meta-analysis are: i) calculating how
well patients with schizophrenia and positive symptoms
respond to cognitive behavioural therapy; ii) examining
the determinants of response to cognitive behavioural
therapy in this population.
Study design and participants
The protocol of the original review was registered in PROS-
PERO (number CRD42017067795) and published . We
included studies in adult individuals with a diagnosis of
schizophrenia or related disorders (such as schizophreniform
or schizoaffective disorders), presenting current positive
symptoms, as defined by inclusion criteria of the trial, with
no restrictions on setting, gender or ethnicity. We excluded
studies on patients with predominant negative symptoms or
concomitant medical or psychiatric illness, and patients at
different stages of illness (first episode, at risk of psychosis).
Studies were included if at least 80% of the patients had
schizophrenia or related disorders (such as schizophreniform
or schizoaffective disorders). Following the rules of the
Cochrane Schizophrenia group we included trials regardless
of the diagnostic criteria used , in order to increase repre-
sentativeness and generalizability.
Intervention, comparator and outcome
For the current analysis, unlike our previous review, we
considered only studies on cognitive behavioural therapy,
compared with any non-pharmacological intervention or
control condition. Among the included studies cognitive
behavioural therapy was administered usually in addition
to standard care, which typically included pharmacological
treatment. Studies were included in the analysis if they
provided data for overall symptoms and/or positive symp-
toms measured with validated rating scales.
Search strategy and inclusion criteria
We searched Embase, MEDLINE, PsycINFO, PubMed,
WHO International Clinical Trials Registry Platform (ICTRP),
ClinicalTrials.gov and Cochrane Collaboration Controlled Tri-
als Register for reports published up to January 2018 for ran-
psychological treatments or with a non-pharmacological con-
trol condition in patients with schizophrenia currently pre-
senting positive symptoms. We applied no restrictions for
language or publication period. Previous reviews on CBT
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 2 of 10
were also inspected to determine if some studies met our in-
clusion criteria as well.
Screening and data extraction
Two reviewers among IB, CR, SW and FS independently
inspected all abstracts identified in the searches based on the
inclusion criteria. Disagreements were resolved by discussion,
and in case of doubts the full paper was retrieved for further
inspection. Full articles were obtained for all eligible papers,
and were again independently assessed by two reviewers.
Disagreements were resolved by discussion, and in case of
need, by contacting study authors for further information.
Two of IB, CR, SW and FS independently extracted data
from the selected studies, considering main reports, second-
ary publications and supplementary materials, entered the
relevant information into a Microsoft-Access database cre-
ated especially for this study and assessed risk of bias using
the Cochrane risk of bias tool [10,11]. We contacted authors
of included studies published in the last 30 years for missing
or additional information about their studies.
Definitions of response
Response is defined typically in schizophrenia trials as a
minimum percentage reduction of the PANSS/BPRS total
score from baseline to endpoint. Different cut-offs have been
used in the literature to define response (for example at least
20, 25, 30, 40% or 50% improvement ). According to
equipercentile linking studies comparing PANSS/BPRS
scores with simultaneous CGI ratings , an improvement
of at least 20% corresponds approximately to ‘minimally im-
proved’as measured with the Clinical Global Impressions of
the raters, while 50% reduction from baseline means much
improved according to the CGI [14–16].
In studies on psychological interventions, the number of
patients reaching “response”is not often reported: only 12
out of 62 trials presented this information in our previous
review . In trials included in the present analysis this in-
formation was reported in 10 out of 33 studies. Moreover,
when number of responders is provided, they are often de-
fined with very heterogeneous criteria, that would not be
comparable. In order to obtain a reliable measure of the re-
sponse rate that could be comparable across studies, we
calculated the rate of responders from the scores on con-
tinuous scales, using the imputationmethodproposedori-
ginallybyFurukawaetal. and replicated [7,18]. We
used this method to estimate number of patients who
reached at least 20 and 50% reduction from baseline of rat-
ing scales measuring overall symptoms (mainly PANSS and
BPRS), based on means and standard deviations at end-
point or change scores from baseline. Our primary outcome
was the reduction of at least 20% from baseline in overall
symptoms scale, that corresponds to a minimal improve-
ment . Since the efficacy of CBT had already been estab-
lished in our previous network meta-analysis, we wanted
now to determine how many patients benefited from the
treatment, and even a small decrease in symptoms was
regarded as relevant. Additionally, given the focus on patients
with positive symptoms, we also calculated response rates
from positive symptoms scales, again for 20 and 50% cut-offs.
score different from 0 (for example, PANSS rated as 1–7for
each item), the application of this method would result in an
underestimation of response rates [12,19]. Therefore, we sub-
tracted the minimum score of the scales (for example 30 in
the case of PANSS total) before imputing the number of
Unlike from most meta-analyses focusing on comparisons be-
tween interventions, the aim of the current meta-analysis was
to examine the response rate in a population of patients with
schizophrenia receiving CBT. Accordingly, in this case the
index is not a between-group difference, but rather, a single-
group summary, that uses in essence the same meta-analytic
calculations . To obtain an average response rate, we per-
formed a single-group summary meta-analysis in R using the
metaprop function in the meta package [21,22]. Analyses
were conducted separately for both outcomes (reduction in
overall and positive symptoms), for both cutoffs (at least 20%
and at least 50% reduction from baseline), and using the
Heterogeneity was assessed using the I-square stat-
istic (values > 50% were considered considerable het-
In order to explore which study characteristics might ex-
plain heterogeneity, we performed subgroup (dichotomous
variables) and meta-regression analyses (continuous variables)
for the primary outcome response rate at 20% reduction in
overall symptoms. When the analysis revealed a possible role
for a specific moderator, we investigated further on the num-
ber of responders calculated with a 50% reduction in overall
symptoms threshold. The following moderators were chosen
a priori: blinding of outcome assessor, treatment resistant pa-
tients, researchers’allegiance (whether study authors also de-
veloped the investigational intervention of the study), expertise
of the therapist, number of sessions, treatment duration, base-
line severity, mean age, gender ratio and percentage of partici-
pants taking antipsychotic medication. We assessed small-
study effects by visual examination of funnel plots.
Description of included studies
We identified 21,772 unique references through the literature
search (last update January 2018), of which 2754 were consid-
ered eligible after screening of title and abstract. After inspec-
tion of full-text, we included 62 randomised controlled trials,
of which 33 had usable data and were included in the analyses,
with a total of 1142 participants in the CBT arms. The
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 3 of 10
PRISMA flow-chart is presented in Fig. 1. Characteristics and
detailed references of included studies are presented in
Additional file 1.
For 26 studies it was possible to calculate number of re-
sponders from an overall symptoms scale, while for 29 stud-
ies it was possible to calculate number of responders from a
scale measuring positive symptoms.
Twelve studies enrolled treatment-resistant patients. Treat-
ments were generally delivered by expert therapists (20 stud-
ies), while three studies employed therapists in training. The
median number of sessions was 12.95, and the median treat-
ment duration 23 weeks (range 4–39). In 21 studies CBT was
delivered by a psychologist, in 12 studies by a nurse, and in 7
studies by a psychiatrist. Twelve studies involved different pro-
fessional figures to deliver CBT, while 6 studies did not pro-
vide any information on the professional background of the
therapist. In 23 studies the therapists received a specific train-
ing for the CBT protocol used in the trial.
The mean age of participants was 37.34 years, and the
mean percentage of male participants in each study was
61.1%. The mean baseline severity (PANSS equivalents)
was 70.55. Figures illustrating risk of bias assessment are
presented in Additional file 2. Overall, the reports often
did not provide details on randomization procedures
and allocation concealment. As expected in studies on
psychological treatments, patients and personnel were
never blind to treatment allocation, but twenty-six studies
employed a blind rater to assess the outcome. Attrition bias
was high in most of the studies, with intention-to-treat data
used rarely for analysis. In 21 studies the authors evaluated
the efficacy of a treatment that they had developed or man-
ualized, being rated as high risk for researchers’allegiance.
There were no important other biases which would have
been relevant for our research question.
The pooled response rate for the cutoff at least 20% reduc-
tion from baseline in overall symptoms was 44.5% (26
RCTs, 1000 participants, 95% CI 35.5 to 53.9%, I
and the pooled response rate for the cutoff of at least 50%
reduction from baseline was 13.2% (26 RCTs, 1000 partici-
pants, 95% CI 8.5 to 20.0%, I
=81%) (Fig. 2). When con-
sidering positive symptoms scales, the pooled response rate
for the 20% cutoff was 52.9% (29 RCTs, 1020 participants,
95% CI 46.7 to 59%, I
= 68%), and the pooled response rate
for the 50% cutoff was 24.8% (29 RCTs, 1020 participants,
95% CI 19.1 to 31.5%, I
=75%) (Fig. 3). All the analyses re-
vealed a considerable heterogeneity in the response rates be-
tween the different studies, which we explored in subgroup
and meta-regression analyses.
Fig. 1 Study selection process
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 4 of 10
Subgroup and meta-regression analyses (Table 1and
Blinded vs open label studies
The test for subgroup differences of response rate be-
tween rater-blinded studies and open-label studies was
not statistically significant (42.6% vs 50.9%, p= 0.6238).
Treatment-resistant vs other patients
We found a statistically significant lower response
previous treatment compared to studies in patients
that were not treatment resistant (33.4% vs 53.3%,
Fig. 2 Response rates in overall symptoms.Pooled results for response rates calculated as 20% (a) and 50% (b) reduction from baseline in
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 5 of 10
When looking at a 50% symptom reduction cutoff, we
found that treatment-resistant patients had a 6.5% re-
sponse rate, compared to the others who responded in
18.8% of cases (p= 0.0553, not shown in the table).
We found a statistically significant higher response rate
in studies in which authors evaluated the therapy that
they developed (51.1% vs 32.8%, p= 0.0363).
Also when considering the 50% threshold, researchers’
allegiance had a significant impact on the responders
rate (20.7% vs 4.9%, p= 0.0026, not shown in the table).
Expertise of the therapist
The response rate in studies that employed expert thera-
pists was 48.5%, while in studies allowing trainees as ther-
apists it was 30%. However, this difference was only of
borderline significance (p= 0.0758). We further examined
Fig. 3 Response rates in positive symptoms. Pooled results for response rates calculated as 20% (a)and50%(b) reduction from baseline in positive symptoms
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 6 of 10
the effect of this moderator on the percentage of patients
who obtained a 50% reduction of symptoms, and found a
significant effect difference between the two groups (re-
sponders rate with expert therapists 18.9%, with trainees
4.5%, p= 0.0056, not shown in the table).
Number of sessions
Response rate was not found to be associated with num-
ber of sessions (p= 0.6690).
We did not find a role of study duration in moderating
response rates (p= 0.6530).
Baseline severity –Overall symptoms
We found that baseline severity could have a role in
moderating response rates, even if of borderline sig-
nificance (p= 0.0552). When further investigating the
effect of baseline severity on the percentage of pa-
tients who obtained a 50% reduction of symptoms,
there was no effect for this moderator (p= 0.174, not
Response rates were not found to be associated with pa-
tients’mean age (p= 0.1581).
Percentage male participants
Response rates were not found to be associated with per-
centage of males (p= 0.1952).
Percentage of participants taking antipsychotics
Information about number of patients actually receiving
medication with antipsychotics was very seldom given in the
trials, and never separately for the different arms. Therefore,
it was not possible to investigate the role of concurrent anti-
psychotic medication as a moderator of response.
Small study effects
There was no obvious asymmetry in the funnel plot that
would have indicated small-study effects. This was confirmed
by Egger’s test for forest plot asymmetry (p= 0.4167) (see
Additional file 3).
To the best of our knowledge, this is the first systematic
review that informs on how well patients with schizo-
phrenia and current positive symptoms respond to cog-
nitive behavioural therapy in randomized trials.
Our main findings were that 44.5% of patients who re-
ceived CBT reached an at least 20% reduction from base-
line in overall symptoms, and can be considered at least
minimally improved, while 13.2% of patients reached an at
least 50% reduction from baseline in overall symptoms,
being considered much improved . A decrease in posi-
tive symptoms of at least 20%/50% occurred in 52.9%/24.8%
of patients, respectively. The observed improvement in posi-
tive symptomatology might be explained with the fact that
CBT for psychosis actively addresses the thoughts and cogni-
tions related to delusions and hallucinations.
We also found that the patients’characteristics of be-
ing treatment resistant, the severity at baseline, and the
clinician’s factors of researchers’allegiance and expertise
could have a role as determinants of response to cogni-
tive behavioural therapy.
Table 1 Subgroup analyses (dichotomous moderators) –20% overall symptoms reduction
Test for subgroup differences
Moderator N Responders rate 95% CI Q P-value
Blinding of outcome assessment Blind 22 0.4263 0.33; 0.53 0.24 0.62
Open 3 0.5086 0.23; 0.79
Treatment resistant Yes 11 0.3338* 0.22; 0.47 4.75 0.03*
No 15 0.5327* 0.42; 0.64
Researchers’allegiance Yes 17 0.5113* 0.40; 0.62 4.38 0.04*
No 9 0.3275* 0.22; 0.46
Therapist’s expertise Expert 15 0.4853 0.37; 0.60 3.15 0.07
Trainee 3 0.3006 0.17; 0.47
Table 2 Meta-regression analyses (continuous moderators) -
20% overall symptoms reduction
Moderator Coefficient 95% CI Z value P-value
Number of sessions 0.0059 −0.02; 0.03 0.43 0.67
Treatment duration 0.0022 −0.007; 0.01 0.45 0.65
Baseline severity 0.0113 −0.0003; 0.0228 1.92 0.05
Mean age 0.0117 −0.005; 0.03 1.41 0.16
Male percentage 0.3081 −0.16; 0.77 1.29 0.20
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 7 of 10
The response rates were lower in treatment-resistant
patients, who failed to benefit from a previous treatment.
This finding may be explained by the fact that
treatment-resistant symptoms are more difficult to treat,
and therefore a CBT intervention can bring only a lower
improvement compared to that of other patients. A trial
on clozapine-resistant patients receiving CBT, published
after the date of our search, reported responders’rates
that are slightly higher than the ones that we found
(46 and 7% for the 20 and 50% PANSS total reduction of
symptoms, respectively) .
We found a borderline significance for higher response
rates in more severely ill patients. This is consistent with
previous findings, in which more severely ill patients at
baseline had a higher response rate with antipsychotics
than less severely ill patients [25,26].
A reason for the higher response rates in studies con-
ducted by researchers testing the efficacy of their own
treatments could be that they might have a vested inter-
est in showing better results for cognitive behavioural
therapy. In order to assess the role of this factor, studies
should always report information on researchers’
We also found that patients treated by expert therapists
had higher response rates, especially when considering the
50% reduction from baseline threshold. The expertise of
the therapist might play a more important role when aim-
ing to achieve a greater symptom reduction.
We did not find a role for the other variables that we
investigated as possible moderators (blinding type, num-
ber of sessions, treatment duration, age and gender).
It must be noted that, on average, patients in the in-
cluded studies were only moderately ill, with a baseline
PANSS total of 70.55, that corresponds to a CGI be-
tween 3 and 4 , and is importantly lower than the
one of patients enrolled in antipsychotics trials .
Some limitations should be considered in interpreting
First, it has been shown that the imputation method of
response data tends to overestimate very low values and to
underestimate extremely high values . In the case of the
present analysis, we adopted a conservative approach in
our calculations and subtracted the minimum scores only
where it was explicitly declared that the 1–7versionof
PANNS and BPRS was used. This may have led to a certain
degree of imprecision in calculating the response rates. Fu-
ture studies should always clearly report which version of
BPRS / PANSS was employed in order to allow more pre-
Second, patients in the included studies were also
receiving standard care, which usually included anti-
psychotics, so that cognitive behavioural therapy was
delivered as add-on to the pharmacological treatment.
However, detailed information on antipsychotic medication
was usually not provided in the studies. As a result, it
is not possible to ascertain the respective role of cog-
nitive behavioural therapy and medication on the out-
come, neither to evaluate the adequacy of the
pharmacotherapy provided in combination with CBT.
Moreover, administration of CBT to patients with
schizophrenia without concomitant antipsychotic
medication is a debated issue: some studies have been
conducted by Morrison et al. in patients receiving CBT
without medication [24,28,29], but other authors have
claimed this to be unethical . We argue that the
situation in the studies included in the present review
resembles real-life clinical practice settings, where pa-
tients, in general, receive antipsychotics in addition to
CBT, making our results more generalizable to the clin-
ical context. We claim that future trials should provide
detailed information on antipsychotic medication, such
as number of patients who actually received antipsy-
chotics and dosages, so that the role of medication can
be assessed and differentiated from the role of cognitive
A further weakness of these results is the high hetero-
geneity that we found across different studies. However,
we found possible explanations in the role of different
moderators as possible sources for heterogeneity in re-
This study also presents some strengths. First, the study
was planned carefully in agreement with PRISMA guide-
lines, and followed a sound methodology that was a-priori
published in the protocol, including a comprehensive
search and the evaluation of quality of studies with the
Cochrane Risk of Bias tool. Second, results presented as
response rates are easy to interpret for clinicians, and can
provide, at first glance, information on the patients’prob-
ability of receiving a benefit from CBT. This information,
together with the relative effect sizes coming from com-
parison of CBT with control conditions, can provide a
more complete picture to be considered in the decision
making process of treatment strategies for patients with
We conclude that adding CBT to pharmacotherapy
brings about a minimal improvement in overall symp-
toms among 44.5% of its recipients, and a considerable
improvement among 13.2%. This seems to be particu-
larly relevant for patients that are not treatment resist-
ant, who are more severely ill at baseline and when
the treatment is provided by expert therapists. Clini-
cians can expect a benefit within this order of magni-
tude when considering offering cognitive behavioural
therapy to patients with schizophrenia and positive
Bighelli et al. BMC Psychiatry (2018) 18:380 Page 8 of 10
Additional file 1: Included studies (PDF 461 kb)
Additional file 2: Risk of bias assessment (PDF 766 kb)
Additional file 3: Small study effect and publication bias (PDF 402 kb)
BPRS: Brief Psychiatric Rating Scale; CBT: Cognitive Behavioural Therapy;
PANSS: Positive and Negative Syndrome Scale
The authors thank Samantha Roberts for help in the literature search, Patricia
Kratochwill for help in full text acquisition and proof reading, Yikang Zhu for
help with screening and data extraction from Chinese studies.
This study was funded by the European Union’s Horizon 2020 Research and
Innovation Programme, Marie Skłodowska-Curie (701717). The funder had no
role in study design, data collection, analysis, or interpretation, writing of the
report or decision to submit the paper for publication.
Availability of data and materials
The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request. More information
about this project is available at the project website: https://
SL and IB designed the study; GPW provided substantial clinical advice in the
conception of the work. IB and MH set up the database. IB, CR, SF and FS
screened the literature search, acquired reports of relevant trials, selected
included studies and extracted data. IB and FS contacted trial investigators for
additional information. IB performed all statistical analyses; IB, MH, JST, MK, TAF,
CB and SL analyzed and interpreted the data. IB and SL wrote the draft and the
final version of the manuscript. All authors critically reviewed the report for
important intellectual content and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
MH has received speaker’s honoraria from Janssen and Lundbeck. TAF has
received lecture fees from Janssen, Meiji, Mitsubishi-Tanabe, Merck Sharp &
Dohme, and Pfizer; and research support from Mitsubishi-Tanabe. SL has re-
ceived honoraria for consulting from LB Pharma, Lundbeck, Otsuka, TEVA,
Geodon Richter, Recordati, LTS Lohmann, and Boehringer Ingelheim; and for
lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis, and Servier. All
other authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar,
Technische Universität München, Munich, Germany.
Centre for Research and Training in Mental Health and Service Evaluation,
Department of Neuroscience, Biomedicine and Movement Sciences, Section
of Psychiatry, University of Verona, Verona, Italy.
Department of Health
Promotion and Human Behavior, Kyoto University Graduate School of
Medicine/School of Public Health, Kyoto, Japan.
Received: 23 August 2018 Accepted: 27 November 2018
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