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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 PROSPERO (CRD42017067795). 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.
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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-
analysis
Irene Bighelli
1*
, Maximilian Huhn
1
, Johannes Schneider-Thoma
1
, Marc Krause
1
, Cornelia Reitmeir
1
, Sofia Wallis
1
,
Felicitas Schwermann
1
, Gabi Pitschel-Walz
1
, Corrado Barbui
2
, Toshi A. Furukawa
3
and Stefan Leucht
1
Abstract
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
PROSPERO (CRD42017067795).
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 researchersallegiance. 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.bighelli@tum.de
1
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
https://doi.org/10.1186/s12888-018-1964-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
Schizophrenia is a severe disorder, and a leading cause of
disability with a dramatic burden on society [1]. 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 tomorrows science [4].
Among psychotherapies for schizophrenia, cognitive be-
havioural therapy (CBT) is the most studied, and it is cur-
rently recommended by guidelines [2]. 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 [5]. 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-
suredasstandardizedmeandifferencesofCBTin
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 [5].
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 [6]. 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
remains unclear.
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 [7]. 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 [5], 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.
Methods
Study design and participants
The protocol of the original review was registered in PROS-
PERO (number CRD42017067795) and published [8]. 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 [9], 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-
domizedcontrolledtrialsthatcomparedCBTwithother
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
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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 [12]). According to
equipercentile linking studies comparing PANSS/BPRS
scores with simultaneous CGI ratings [13], an improvement
of at least 20% corresponds approximately to minimally im-
provedas measured with the Clinical Global Impressions of
the raters, while 50% reduction from baseline means much
improved according to the CGI [1416].
In studies on psychological interventions, the number of
patients reaching responseis not often reported: only 12
out of 62 trials presented this information in our previous
review [5]. 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.[17] 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 [14]. 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.
Inthecasewhereascalehadapossibleminimumbaseline
score different from 0 (for example, PANSS rated as 17for
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
responders.
Data analysis
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 [20]. 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
intention-to-treat datasets.
Heterogeneity was assessed using the I-square stat-
istic (values > 50% were considered considerable het-
erogeneity) [23].
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, researchersallegiance (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.
Results
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
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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 439). 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 researchersallegiance.
There were no important other biases which would have
been relevant for our research question.
Response rates
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
2
=85%),
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
2
=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
2
= 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
2
=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
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Subgroup and meta-regression analyses (Table 1and
Table 2)
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
rateinstudiesinpatientsthatdidnotrespondtoa
previous treatment compared to studies in patients
that were not treatment resistant (33.4% vs 53.3%,
p= 0.0293).
Fig. 2 Response rates in overall symptoms.Pooled results for response rates calculated as 20% (a) and 50% (b) reduction from baseline in
overall symptoms
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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).
Researchersallegiance
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
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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).
Treatment duration
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
showninthetable).
Mean age
Response rates were not found to be associated with pa-
tientsmean 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 Eggers test for forest plot asymmetry (p= 0.4167) (see
Additional file 3).
Discussion
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 [14]. 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 patientscharacteristics of be-
ing treatment resistant, the severity at baseline, and the
clinicians factors of researchersallegiance 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
Researchersallegiance Yes 17 0.5113* 0.40; 0.62 4.38 0.04*
No 9 0.3275* 0.22; 0.46
Therapists expertise Expert 15 0.4853 0.37; 0.60 3.15 0.07
Trainee 3 0.3006 0.17; 0.47
*p< 0.05
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
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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 respondersrates
that are slightly higher than the ones that we found
(46 and 7% for the 20 and 50% PANSS total reduction of
symptoms, respectively) [24].
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
allegiance.
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 [14], and is importantly lower than the
one of patients enrolled in antipsychotics trials [27].
Some limitations should be considered in interpreting
our results.
First, it has been shown that the imputation method of
response data tends to overestimate very low values and to
underestimate extremely high values [18]. 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 17versionof
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-
cise calculations.
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 [30]. 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
behavioural therapy.
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-
sponse rates.
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 patientsprob-
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
schizophrenia.
Conclusions
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
symptoms.
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Additional files
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)
Abbreviations
BPRS: Brief Psychiatric Rating Scale; CBT: Cognitive Behavioural Therapy;
PANSS: Positive and Negative Syndrome Scale
Acknowledgements
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.
Funding
This study was funded by the European Unions 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://
www.psykl.mri.tum.de/node/69
Authorscontributions
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
not applicable
Consent for publication
not applicable
Competing interests
MH has received speakers 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.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar,
Technische Universität München, Munich, Germany.
2
WHO Collaborating
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.
3
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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... In the past few decades, psychological interventions have been shown to be effective when used in conjunction with pharmacological treatment (10,11). Psychoeducation, assertiveness training, family therapy, cognitive behavioral therapy, and cognitive remediation treatment programs have been developed and systematically studied and further improved (10)(11)(12)(13)(14)(15). ...
... In the past few decades, psychological interventions have been shown to be effective when used in conjunction with pharmacological treatment (10,11). Psychoeducation, assertiveness training, family therapy, cognitive behavioral therapy, and cognitive remediation treatment programs have been developed and systematically studied and further improved (10)(11)(12)(13)(14)(15). Current guidelines recognize their importance for treatment and outcome, correspondingly implementation early on in treatment is recommended, even in hospitalized patients (16)(17)(18)(19). ...
... Participants are also encouraged to continue participation after discharge. Although we consider that the completion of a treatment programme to be an important factor determining response, evidence suggests that response is not associated with treatment duration and number of sessions (10). ...
Article
Full-text available
Background: Schizophrenic psychoses are severe mental disorders. Despite advances in treatment, outcomes are still unsatisfactory. Pharmacological treatments are still limited, in particular regarding improvements in psychosocial functioning and neuro-cognitive impairment. In recent years new psychological therapies have been developed, demonstrating promising results. However, most of these interventions have been designed for and studied in outpatients; their efficacy and feasibility for patients requiring hospitalization is still unknown. Therefore, we have designed a clinical trial to compare a neuro-cognitive (Integrated Neuro-cognitive Treatment INT); a cognitive-behavioral (Integrated Psychological Therapy IPT); and a control (Cogpack CGP) intervention for patients with a schizophrenic psychosis hospitalized for treatment. Methods: In a three-parallel-arm, single-blind, randomized, controlled study, we compare INT, IPT, and CGP. Participants will take part in two weekly sessions of one intervention for at least 16 sessions. If due to randomization, participants are allocated to a treatment arm not suitable for them, they are allowed to switch intervention after four sessions. Based on a sample size calculation, recruitment will continue until 30 participants have completed the intervention for each treatment arm. Outcome Measurement: Primary outcomes are: change in symptom as measured by the Positive and Negative Syndrome Scale (PANSS), change in psychosocial functioning as assessed by the mini ICF-APP and neuro-cognitive performance, assessed by the Matrics Cognitive Consensus Battery (MCCB). Other outcomes of interest are the Brief Symptom Inventory (BSI) and the Health of the Nation Outcome Scales (HoNOS); together with prescribed medication, treatment retention and completion rates. Outcomes will be measured at baseline, 2 weeks into treatment (prior to a potential switch of intervention arm), post-treatment and at 6 and 12-month post-treatment follow-ups. Expected Outcomes: We expect an overall improvement; however, with differences in specific domains for each treatment arm, with those completing INT showing better outcomes than IPT and CGP, respectively. We anticipate that lower functioning participants will drift to CGP and higher functioning participants to INT. Conclusion: Due to the complexity of treatment for patients with a schizophrenic psychosis, we consider it crucial to compare different treatment options for those more severely affected, therefore, requiring inpatient treatment. Trial registration: www.clinicaltrials.gov (ID: NCT03316664; 17.10.2017).
... The heterogeneity in studies testing CBT in people with FEP was identified as high [16,18] which might underlie a different response to CBT of different patients [19]. A recent review shed some light on this, identifying that 44.5% of the patients reach a 20% (minimally improved) and 13.2% reach a 50% (much improved) reduction of overall symptoms [18]. ...
... The heterogeneity in studies testing CBT in people with FEP was identified as high [16,18] which might underlie a different response to CBT of different patients [19]. A recent review shed some light on this, identifying that 44.5% of the patients reach a 20% (minimally improved) and 13.2% reach a 50% (much improved) reduction of overall symptoms [18]. ...
Article
Purpose of review: Assessing recent evidence on psychosocial interventions for people with first episode psychosis (FEP). Recent findings: Family interventions (FI) reduce relapse rates, whilst cognitive behavioural therapy (CBT) shows a moderate effect in improving positive psychotic symptoms. Vocational interventions (VI) appear to be worthy of implementation within early intervention for psychosis (EIP) teams, but it is still unclear what is the most cost-effective strategy for their delivery. Promising interventions, which need more careful evaluation, focus on substance misuse, physical health comorbidities, improvement of social participation, peer support and the potential of new technologies. Summary: The first five years after the onset of psychotic symptoms are a 'critical period' in which psychosocial interventions can be particularly influential in determining prognosis. Traditional EIP interventions have different effectiveness profiles, i.e., FI reduce relapse rates, CBT has a moderate effectiveness on overall and positive symptoms and VI can improve educational and employment-related functioning. Newer interventions show promise on important targets for FEP treatment but require higher-quality evaluations. Decisions on which interventions to implement within EIP teams should be informed by high-quality evidence, but difficult choices will have to be made based on costs, professionals and technologies available, and local priorities.
... In patients with schizophrenia, psychotherapy as a treatment option has been largely neglected. Recently, however, it has gained recognition as an effective treatment when used in conjunction with pharmacotherapy [4,5]. Furthermore, current guidelines now recommend the early implementation of psychotherapy in the treatment process [6,7]. ...
... 3. I thought the system was easy to use. 4. I think that I would need the support of a technical person to be able to use this system. ...
Article
Full-text available
Background: Digital technologies have expanded the possibilities of Psychotherapy, especially for the treatment of Schizophrenia with the Avatar Therapy. Despite its vast possibilities, this treatment method is still not disseminated; the operability and functionality are unknow. Objective: We aim to study the usability of a therapeutic virtual reality human-human interface created in a game engine with psychiatric hospital staff. Methods: Participants introduced to the therapeutic platform in a "hands-on" mode. The System Usability Scale (SUS) was employed for the evaluation of the system. We will conduct descriptive statistics, chi-square test, an ANOVA, and multilevel factor analysis for statistical evaluation. Results: In total, 109 staff members were introduced to the therapeutic tool and completed the SUS. The mean SUS global score was 81.49±11.1. Among the professional groups, psychotherapists (86.44±8.79) scored significantly higher (F (2, 106) = 6.136; p = 0.003) than nursing staff (79.01±13.30) and administrative personnel (77.98 ± 10.72). A Multilevel Factorial Analysis (MLFA) shows a different factor structure for each profession. Conclusions: By different professions, the usability of a digital psychotherapeutic tool developed using a game engine achieves the benchmark for an excellent system, scoring even highest among the professional target group. The usability of the system, therefore, also depending on the professional background of the operator. With gaming technology and platforms, it is possible to create and customisation of novel therapeutic psychotherapeutic approaches. Clinicaltrial: Clinical Trial: ClinicalTrials.gov (NCT04099940).
... For psychotherapy, a response rate of 13% for overall symptoms and 25% for positive symptoms was found 139 (a reduction of symptoms of at least 50% was required). The response rate decreased considerably if researcher allegiance (authors evaluated the therapy that they developed) was taken into account (from 13% to 4.9%) 139 . ...
Article
Mental disorders represent a worldwide public health concern. Psychotherapies and pharmacotherapies are recommended as first line treatments. However, evidence has emerged that their efficacy may be overestimated, due to a variety of shortcomings in clinical trials (e.g., publication bias, weak control conditions such as waiting list). We performed an umbrella review of recent meta-analyses of randomized controlled trials (RCTs) of psychotherapies and pharmacotherapies for the main mental disorders in adults. We selected meta-analyses that formally assessed risk of bias or quality of studies, excluded weak comparators, and used effect sizes for target symptoms as primary outcome. We searched PubMed and PsycINFO and individual records of the Cochrane Library for meta-analyses published between January 2014 and March 2021 comparing psychotherapies or pharmacotherapies with placebo or treatment-as-usual (TAU), or psychotherapies vs. pharmacotherapies head-to-head, or the combination of psychotherapy with pharmacotherapy to either monotherapy. One hundred and two meta-analyses, encompassing 3,782 RCTs and 650,514 patients, were included, covering depressive disorders, anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder, somatoform disorders, eating disorders, attention-deficit/hyperactivity disorder, substance use disorders, insomnia, schizophrenia spectrum disorders, and bipolar disorder. Across disorders and treatments, the majority of effect sizes for target symptoms were small. A random effect meta-analytic evaluation of the effect sizes reported by the largest meta-analyses per disorder yielded a standardized mean difference (SMD) of 0.34 (95% CI: 0.26-0.42) for psychotherapies and 0.36 (95% CI: 0.32-0.41) for pharmacotherapies compared with placebo or TAU. The SMD for head-to-head comparisons of psychotherapies vs. pharmacotherapies was 0.11 (95% CI: –0.05 to 0.26). The SMD for the combined treatment compared with either monotherapy was 0.31 (95% CI: 0.19-0.44). Risk of bias was often high. After more than half a century of research, thousands of RCTs and millions of invested funds, the effect sizes of psychotherapies and pharmacotherapies for mental disorders are limited, suggesting a ceiling effect for treatment research as presently conducted. A paradigm shift in research seems to be required to achieve further progress.
... They are often associated with high levels of distress and can have a profound impact on everyday life, with typical content involving threats, commands, and abusive comments. Voices frequently persist for many years despite optimal pharmacotherapy, and the currently recommended psychological therapy for voices, cognitive behavioural therapy for psychosis (CBTp) is effective [3] but only for just over 50% of people [4]. CBTp also involves delivering a relatively lengthy treatment, which presents significant barriers to access [5]. ...
Article
Full-text available
Background AVATAR therapy is a novel intervention targeting distressing auditory verbal hallucinations (henceforth ‘voices’). A digital simulation (avatar) of the voice is created and used in a three-way dialogue between participant, avatar and therapist. To date, therapy has been delivered over 6 sessions, comprising an initial phase, focusing on standing up to a hostile avatar, and a second phase in which the avatar concedes and focus shifts to individualised treatment targets, including beliefs about voices. The first fully powered randomised trial found AVATAR therapy resulted in a rapid and substantial fall in voice frequency and associated distress that was superior to supportive counselling at 12 weeks. The main objective of this AVATAR2 trial is to test the efficacy of two forms of AVATAR therapy in reducing voice-related distress: AVATAR-brief (standardised focus on exposure, assertiveness and self-esteem) and AVATAR-extended (phase 1 mirroring AVATAR-brief augmented by a formulation-driven phase 2). Secondary objectives include the examination of additional voice, wellbeing and mood outcomes, the exploration of mediators and moderators of therapy response, and examining cost-effectiveness of both forms of therapy compared with usual treatment (TAU). Methods This multi-site parallel group randomised controlled trial will independently randomise 345 individuals to receive AVATAR-brief (6 sessions) plus TAU or AVATAR-extended (12 sessions) plus TAU or TAU alone (1:1:1 allocation). Participants will be people with a diagnosis of schizophrenia spectrum and other psychotic disorders who have heard distressing voices for more than 6 months. The primary outcome is the PSYRATS Auditory Hallucinations Distress dimension score at 16 and 28 weeks, conducted by blinded assessors. Statistical analysis will follow the intention-to-treat principle and data will be analysed using linear mixed models. Mediation and moderation analyses using contemporary causal inference methods will be conducted as secondary analyses. Service costs will be calculated, and cost-effectiveness assessed in terms of quality-adjusted life years accrued. Discussion This study will clarify optimal therapy delivery, test efficacy in a multi-site study and enable the testing of the AVATAR software platform, therapy training and provision in NHS settings. Trial registration ISRCTN registry ISRCTN55682735 . Registered on 22 January 2020. The trial is funded by the Wellcome Trust (WT).
... Cognitive behavioural therapy for psychosis (CBTp) is a structured, time-limited psychotherapy, that uses both cognitive and behavioural strategies to address unhelpful thought patterns, that has been successfully used in people with psychotic illnesses (Wykes et al., 2008). Though the effect size of CBTp on psychotic symptoms has been shown to be small among people with schizophrenia more generally (Bighelli et al., 2018;Jauhar et al., 2014), that small effect may be clinically meaningful in people with TRS on clozapine, where other treatment choices have been exhausted. Recent meta-analyses of CBTp have not focussed on people treated with clozapine (Jauhar et al., 2014;Turner et al., 2014). ...
Article
Background Cognitive behavioural therapy for psychosis (CBTp), an effective treatment for people with schizophrenia, may have a role in clozapine refractory schizophrenia. Aims A systematic-review and meta-analysis on the impact of CBTp on psychotic symptoms in people on clozapine. Methods We searched PubMed, Embase, PsycInfo, CINAHL and Cochrane for randomised control trials of CBTp as augmentation in people with treatment-refractory schizophrenia on clozapine and conducted pair-wise meta-analyses. Results Four studies met inclusion criteria. On pairwise meta-analyses, the primary outcome of total psychotic symptoms was not significantly altered by CBTp at either therapy endpoint or six to twelve months follow-up. Secondary outcomes showed that CBT improved positive symptoms at both therapy endpoint (SMD −0.33, 95%CI −0.50 to −0.16, p = 0.002, I² = 0%) and six to twelve months follow-up (SMD −0.20, 95%CI −0.38 to −0.02, p = 0.03, I² = 0%) though did not alter negative psychotic symptoms at either timepoint. Conclusions CBTp may lead to small benefits for positive symptoms refractory to clozapine. Given the low risks associated with CBTp, and the limited alternative options for clozapine refractory schizophrenia, this approach should be considered in this population.
... For each clinical measure, patients were categorized as either reaching a treatment response or not post-PBCT based on two cut-off levels. An improvement of at least 20% corresponded approximately to 'minimally improved', while a 50% reduction from baseline corresponded to 'much improved' (Bighelli et al., 2018). Overall findings are summarized as treatment response rates. ...
Article
Background: Person-based cognitive therapy (PBCT) was developed as a treatment for psychosis. The effectiveness of group PBCT was examined in the Mindfulness for Voices (M4V) randomized controlled trial and generated promising results. Group PBCT was implemented as a trans-diagnostic treatment for distressing voices within the Sussex Voices Clinic (SVC), a specialist secondary care mental health service. Aim: To conduct a service evaluation of engagement, outcomes and cost of group PBCT within SVC, and to compare engagement and outcomes from routine practice with the M4V trial. Secondary aims were to explore predictors of levels of engagement and change in group PBCT. Method: Service level data from 95 SVC patients were evaluated. Descriptive statistics, hypothesis tests and linear regression models were used. The primary clinical outcome was voice-related distress. Engagement levels and pre-post effect sizes were estimated; associated predictors were explored. Results: Fifty-nine per cent of patients completed group PBCT within SVC, compared with 72% within M4V. Completers within SVC had lower baseline depression scores compared with non-completers. There were significant improvements in voice-related distress (Cohen's d = -0.47; p = 0.001), subjective recovery (Cohen's d = 0.35; p = 0.001) and depression (Cohen's d = -0.20; p = 0.044); these outcomes were comparable to M4V. Higher baseline subjective recovery and lower depression both predicted improvement in voice-related distress. Therapy within SVC cost an average of £214 per patient. Conclusion: PBCT groups can be delivered trans-diagnostically in routine clinical practice. Engagement was lower when compared with an RCT, but outcomes were comparable. The low level of resources involved suggests that group PBCT can offer value for money.
... Training effects are rarely seen in the general outcome literature (Lambert, 2013), making the leader finding a surprise. However, our finding does replicate the results of a recent meta-analysis (Bighelli et al., 2018) of 33 studies where greater improvement for CBT delivered by expert therapists versus trainees was found with hospitalized schizophrenia patients. It may be that level of training is more important when treating patient populations such as schizophrenia. ...
Article
The effectiveness of group treatments for people with schizophrenia has not been examined on symptom-specific (positive and negative symptoms) outcomes, and the differential effects of the most popular group treatments remain unknown. We conducted a meta-analysis of randomized controlled trials that tested (a) the effectiveness of 7 frequently used group treatments on positive and negative symptoms and (b) if treatment-specific outcome improvement was associated with improvement on schizophrenia symptoms. Major databases were searched from 1990 to 2018 for randomized controlled trials of group treatment for people with schizophrenia, including first-episode psychosis. A random effects meta-analysis and meta-regression was conducted on 52 studies representing 4,156 individuals that produced a significant, small effect on symptom-specific outcomes (g = 0.30), with 4 group treatments (cognitive remediation, multifamily, psychoeducational, and social skills training) posting significant improvement. In addition, change on treatment-specific outcomes explained 16% of schizophrenia symptom and 44% of general functioning improvement. Results are discussed with respect to how they replicate past meta-analytic findings and possible revision of practice guidelines to incorporate evidence-based group treatments for schizophrenia. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Article
Background Psychomotor agitation is a common condition in patients with psychotic disorders. One treatment possibility is intramuscular (IM) second-generation antipsychotics. Yet their efficacy in this formulation and for this aim is unclear. This network meta-analysis aims to evaluate the efficacy of short-acting IM second-generation antipsychotic drugs, haloperidol and placebo in patients with diagnosis of schizophrenia and schizophrenia-like disorders that present acute agitation. Methods We searched the Cochrane Schizophrenia Group Controlled Trials Register, MEDLINE, EMBASE, PsycINFO, Cochrane Library, PubMed, BIOSIS, ClinicalTrials.gov and WHO ICTRP up to November 2018 and PubMed until March 2020. Study selection and outcome extraction were performed independently by two reviewers. Pairwise and network meta-analyses were conducted to compare the different IM second-generation antipsychotics among themselves and with IM haloperidol and placebo. The primary outcome was the number of responders at 2 h after the first injection. Responders at 24 h were also analysed. Results 10 studies with 1964 patients were included in the meta-analysis. Ziprasidone, olanzapine, aripiprazole and haloperidol were more efficacious than placebo in calming patients at 2 h after administration. Furthermore, olanzapine was superior to aripiprazole. The results at 24 h confirmed the superiority of aripiprazole, olanzapine and haloperidol over placebo, while for ziprasidone no data were available. Conclusions All second-generation antipsychotics available as intramuscular medications were effective in reducing agitation in people with schizophrenia. Olanzapine was somewhat more efficacious than aripiprazole.
Article
Aim The comparative study of childhood‐onset schizophrenia (COS) and adolescent‐onset schizophrenia (AOS) is scarce. This study aimed to examine the differences in clinical presentations and treatment efficacy between COS and AOS and further analyse the factors affecting the efficacy of early‐onset schizophrenia (EOS). Methods A total of 582 electronic medical records of inpatients with EOS (216 COS and 366 AOS inpatients) between 2012 and 2019 were retrospectively analysed. The positive and negative syndrome scale (PANSS) was used to assess psychotic symptoms. Logistic regression analysis was performed to analyse the predictors of efficacy. Results The mean age of onset of EOS was 12.87 ± 2.19 years. The importance of better diagnosing COS appeared in a longer illness course, more frequently insidious onset, less frequent delusions, more severe negative symptoms and bizarre behaviours than AOS. Besides, COS had more frequent visual hallucinations and impulsive behaviours than AOS. After hospitalization, the improvement rate of psychotic symptoms in COS and AOS were 38.3% and 47.8%, respectively. The difference of efficacy between the two groups was statistically significant. Days of hospitalization, age of onset, presence of flat affect, PANSS total and negative score at admission were predictors of treatment efficacy in EOS individuals. Conclusions COS inpatients suffer more obvious negative symptoms, bizarre behaviours, visual hallucinations and impulsive behaviours and worse efficacy than AOS inpatients. The severity of negative symptoms and age of onset seem the most noteworthy predictors of efficacy. These findings highlight the importance of early detection and early intervention.
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The revised edition of the Handbook offers the only guide on how to conduct, report and maintain a Cochrane Review. The second edition of The Cochrane Handbook for Systematic Reviews of Interventions contains essential guidance for preparing and maintaining Cochrane Reviews of the effects of health interventions. Designed to be an accessible resource, the Handbook will also be of interest to anyone undertaking systematic reviews of interventions outside Cochrane, and many of the principles and methods presented are appropriate for systematic reviews addressing research questions other than effects of interventions. This fully updated edition contains extensive new material on systematic review methods addressing a wide-range of topics including network meta-analysis, equity, complex interventions, narrative synthesis, and automation. Also new to this edition, integrated throughout the Handbook, is the set of standards Cochrane expects its reviews to meet. Written for review authors, editors, trainers and others with an interest in Cochrane Reviews, the second edition of The Cochrane Handbook for Systematic Reviews of Interventions continues to offer an invaluable resource for understanding the role of systematic reviews, critically appraising health research studies and conducting reviews.
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Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta‐analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add‐on to antipsychotics. On average, patients were moderately ill at baseline. The network meta‐analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=−0.29; 95% CI: –0.55 to −0.03), treatment as usual (SMD=−0.30; 95% CI: –0.45 to −0.14) and supportive therapy (SMD=−0.47; 95% CI: –0.91 to −0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers’ allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.
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Background: Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. Methods: We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual. Findings: From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event. Interpretation: At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. Funding: National Institute for Health Research Technology Assessment programme.
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Introduction There is rising awareness that we need multidisciplinary approaches integrating psychological treatments for schizophrenia, but a comprehensive evidence based on their relative efficacy is lacking. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs) to rank psychological treatments for schizophrenia according to their efficacy, acceptability and tolerability. Methods and analysis We will include all RCTs comparing a psychological treatment aimed at positive symptoms of schizophrenia with another psychological intervention or with a no treatment condition (waiting-list and treatment as usual). We will include studies on adult patients with schizophrenia, excluding specific subpopulations (eg, first-episode patients or patients with psychiatric comorbidities). Primary outcome will be the change in positive symptoms on a published rating scale. Secondary outcomes will be acceptability (dropout), change in overall and negative symptoms of schizophrenia, response, relapse, adherence, depression, quality of life, functioning and adverse events. Published and unpublished studies will be sought through database searches, trial registries and websites. Study selection and data extraction will be conducted by at least two independent reviewers. We will conduct random-effects NMA to synthesise all evidences for each outcome and obtain a comprehensive ranking of all treatments. NMA will be conducted in Stata and R within a frequentist framework. The risk of bias in studies will be evaluated using the Cochrane Risk of Bias tool and the credibility of the evidence will be evaluated using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation framework to NMA, recommended by the Cochrane guidance. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination No ethical issues are foreseen. Results from this study will be published in peer-reviewed journals and presented at relevant conferences. PROSPERO registration number CRD42017067795.
Article
Background: Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. Methods: We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. Findings: Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). Interpretation: A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. Funding: National Institute for Health Research.
Article
Background: Psychological treatments occupy an important place in evidence-based mental health treatments. Now is an exciting time to fuel treatment research: a pressing demand for improvements is poised alongside new opportunities from closer links with sister scientific and clinical disciplines. The need to improve mental health treatment is great; even the best treatments do not work for everyone, treatments have not been developed for many mental disorders, and the implementation of treatments needs to address worldwide scalability. Psychological treatments have yet to benefit from numerous innovations that have occurred in science, particularly those that have emerged in the past 20 years, and arguably vice versa. This Commission comprises ten parts that each outline an area in which we see substantial opportunity and scope for advancements that will move psychological treatments research forward. / Part 1: How do existing treatments work? Making the case for the mechanisms of psychological treatments Beyond knowing that an intervention is efficacious, research initiatives are needed that clarify the key mechanisms through which interventions work. An experimental psychopathological approach enables the identification of mechanisms. Research on these mechanisms has considerable scope to facilitate treatment innovation. / Part 2: Where can psychological treatments be deployed? Research to improve mental health worldwide We outline a number of factors to facilitate worldwide access to psychological treatments. Future research initiatives need to continue to develop and assess the efficacy of brief and flexible interventions that can be adapted to meet the needs of individuals across cultural contexts, and delivered and disseminated in a sustainable way. / Part 3: With what? The potential for synergistic treatment effects—using and developing cross-modal treatment approaches The combination of psychological and pharmacological treatments needs to be better understood, both in terms of the clinical effect and the underlying shared and different mechanisms. Efforts to develop and investigate the efficacy of novel cross-modal treatments could contribute to treatment innovation. / Part 4: When in life? Psychological science, prevention, and early intervention—getting the approach right from the start The social and economic tolls of mental health problems early in life make the development of effective prevention and early intervention approaches a priority. A preventive focus and a developmental approach are needed to identify risk factors for psychopathology, and identification of the optimal time at which to offer prevention approaches is needed to increase the likelihood of vulnerable young people growing up with positive mental health. / Part 5: Technology—can we transform the availability and efficacy of psychological treatment through new technologies? New technologies provide exciting and timely means by which to disseminate and extend the efficacy and global reach of evidence-based interventions. eHealth and mHealth approaches that use information technology (eg, the internet, virtual reality, serious gaming) and mobile and wireless applications (eg, text messaging, apps) are examples of how technology has been harnessed to innovate psychological treatments and their availability and evaluation. / Part 6: Trials to assess psychological treatments The findings of randomised controlled trials that assess psychological therapies inform policy and practice. Accordingly, the design and conduct of these trials warrants scrutiny and ongoing efforts for quality improvement (eg, reporting standards, specification of protocols, inclusion and exclusion criteria, choice of outcome measures, measurement of adverse effects, and prevention of bias in design and analysis). We outline several opportunities for further improvement that should enhance the credibility and quality of future trials. / Part 7: Training—can we cultivate a vision for interdisciplinary training across mental health sciences to improve psychological treatments? Early examples of collaboration between basic scientists and clinicians translated into historical steps in the innovation of psychological treatment. Such synergy has become less apparent in the past few years. The improvement in links between clinical psychology, psychiatry, and basic research has the potential to deliver more advances in psychological treatments. We propose opportunities to improve training in interdisciplinary mental health sciences. This training approach would be the first step toward forging links between scientists and clinicians in the next generation and bridging the gap between clinical practice and the basic research programmes that underpin psychological treatments. / Part 8: Whom should we treat, for what, and with what? Embracing the complexity of mental disorders from personalised models to universal approaches Mental disorders are inherently complex (eg, hetero-geneity in symptoms across disorders, high rates of comorbidity) and evidence-based treatments must address this complexity. Potential solutions include considering both highly individualised (ie, personalised) approaches and so-called universal or transdiagnostic approaches that target common mechanisms. A goal of future research will be to examine whether these approaches improve treatment effectiveness. / Part 9: Target: suicidal behaviour—protecting lives Suicidal behaviour is one of many areas in which advances are needed. Despite developments in the understanding of risk factors that predict the likelihood of suicide attempts, and the treatment and prevention of suicidal behaviour, many questions remain. We specify areas for future research—eg, use of new technologies, the role of culture, input from individuals with lived experience of suicidal behaviour, and using a team-based approach in the development, assessment, and dissem-ination of prevention efforts. / Part 10: Active innovation and scrutiny of future psychological treatments research The task of improving psychological treatments is an exciting prospect for scientists and clinicians with an interest in the so-called science of mental life. Clinicians, researchers, service users, carers, funders, commissioners, managers, policy planners, and change experts all have a part to play in improving psychological treatment. Some long-held ideas need examination, from the branding of psychological treatment types, to considering what people actually want treatment for. Scrutiny of new ideas should be rigorous and yet encourage innovation.
Article
It is often stated that first-episode patients tend to respond better to antipsychotics than chronic patients, but the exact numbers and moderators of response in this population are unclear. We, therefore, present the first systematic review on response rates of first episode patients with schizophrenia in randomized trials. We searched multiple databases for randomized-controlled trials of antipsychotics in acutely ill patients with a first episode of schizophrenia (last search: November 17, 2016). The outcomes were response rate based on two criteria, at least 50% PANSS or BPRS total score reduction from baseline and at least 20% reduction. Data were pooled in a single-group summary meta-analysis using Comprehensive Meta-Analysis software. Moreover, several potential moderators of response to antipsychotics were examined by meta-regression. We included 17 studies with a total of 3156 participants. On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively. Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naïve patients, in patients with a shorter illness duration and in open studies. Study duration and dosage were no significant moderators of response. Our finding suggest that more than 80% of first-episode patients achieved 20% PANSS/BPRS reduction from baseline and around 50% achieved a 50% PANSS/BPRS reduction. Several patient characteristics moderated response rates.