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DOI 10.1007/s40263-015-0308-1
SYSTEMATIC REVIEW
Abstract
Introduction Early-onset schizophrenia (EOS) is a serious debilitating disorder with considerable morbidity and a
reduced life expectancy; therefore, early diagnosis and
effective treatments are particularly important. Negative
symptoms are more prominent in adolescents and children
(compared with adults), and are key predictors of worse
functional and clinical outcomes in EOS. Therefore, this
study aimed to explore the relative efficacy of antipsychotics used in the treatment of EOS, with a focus on
studies reporting effectiveness using the Positive and
Negative Syndrome scale (PANSS), a scale that includes
an overall symptom measure, in addition to separate subscales for positive and, importantly, negative symptoms.
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Key Points
The analysis demonstrates positive outcomes in
terms of symptom control, using the Positive and
Negative Syndrome Scale outcome scale, although
there were no statistically significant results between
treatments for managing negative symptoms.
Rates for discontinuation and weight gain highlight a
need to balance treatment efficacy with side-effect
profiles.
Evidence for the comparative efficacy and safety of
antipsychotic use in the paediatric population is
limited; large randomised controlled trials are
needed to verify the results of indirect treatment
comparisons.
1 Introduction
Early-onset schizophrenia (age of onset before 18 years)
(EOS) is often a severe and debilitating psychotic disorder
with considerable impairments in psychological, social,
educational and occupational functioning and a reduced
life expectancy. Schizophrenia is estimated to affect
1.61.9 per 100,000 in the child population, with a steep
rise during adolescence [1, 2]. EOS poses a heavy burden
on the patient, family and health services, accounting for
24.5 % of all adolescent psychiatric admissions (with an
overall admission rate of 0.46 per 1000 for this age range in
England and Wales) [3].
EOS appears to be a more severe disorder than adult-onset
schizophrenia [4]. In particular, it has been linked to a higher
burden of negative symptoms, in addition to reduced cognitive functioning, lower educational attainment and poorer
response to treatment [5]. Furthermore, treatment can be
problematic in children and adolescents, although a recent
longitudinal study from Melbourne, with an early-intervention service, found advantageous outcomes with early
treatment [6]. Psychological interventions have a positive
impact if delivered before the onset of psychosis in individuals with attenuated or transient psychotic symptoms, and
are recommended as a first line of treatment for psychosis in
this age group [7, 8]. Antipsychotic (AP) medication is the
mainstay of treatment of psychosis; however, there is limited
evidence of efficacy for APs in this age group [8, 9]. Systematic reviews indicate efficacy, but with small effect sizes.
For second-generation antipsychotics (SGAs), there are
considerable problems with weight gain, metabolic and
cardiac effects, and a risk of diabetes mellitus [10]. Overall,
the risk of side effects associated with AP treatment for
R. C. Harvey et al.
29
Following database searches, primary screening was conducted by reviewers with titles and abstracts of all identified citations against a set of explicit eligibility criteria. For
citations that appeared to meet the inclusion criteria based
on abstract screening, full articles were obtained and
assessed against the full eligibility criteria. Two reviewers
independently conducted primary (title and abstract) and
secondary (full-text) screening before comparing results.
Any disagreements were discussed and settled with the
assistance of a third reviewer.
Eligibility studies (a) focused on patients aged 18
years and below with a diagnosis of schizophrenia,
schizoaffective disorder or schizophreniform disorder;
(b) conducted two or more arm trials in the disease area;
(c) reported mean (and standard deviation or error)
baseline and changes over time in PANSS symptom
scores (total, positive or negative), where reductions in
PANSS scores are indicative of symptom improvements;
and (d) reported data between 6- and 12-week endpoints
for comparisons to be justified. Where there was evidence that the studies reported results from the same
primary study, the paper reporting these data within the
most relevant time scale (i.e. closest to a 6-week endpoint for primary outcome data) was chosen, or if time
points were equal, the most recently published paper was
chosen, to avoid double counting the data.
Because of the paucity of randomised controlled trials
(RCTs) in this population, non-RCT designs were included
to allow for a broader treatment comparison. A sensitivity
analysis excluding non-randomised studies was planned at
the protocol stage.
30
R. C. Harvey et al.
Different doses of the same intervention were not distinguished in the analysis. For trials that consider the same
intervention at different doses, data were pooled, weighting
by the sample size in each treatment arm to estimate an
overall effect for this treatment within a study.
Sensitivity analyses were performed to exclude particular studies from the NMA based on any anomalies identified in the trial. This included the removal of the one nonrandomised trial that was identified to examine the impact
on results.
2.4.4 Inconsistency of Evidence
An underlying assumption of NMAs is that direct and
indirect sources of evidence are estimating the same
treatment effects. When this assumption is violated,
inconsistency may be present, which is a discrepancy
between direct and indirect evidence. Inconsistency can
only be checked where both direct and indirect data are
present for any pairs of treatments, i.e. closed loops exist
within the network (not arising from three-arm trials).
Potential inconsistency was evaluated using a node-splitting approach, which is only possible within a Bayesian
framework [26].
2.4.5 Presentation of Results
Results are presented in the form of forest plots showing
relative efficacy of all interventions vs placebo. Additionally, all pairwise treatment comparisons are presented
in tabular format within the supplementary material to
show the relative efficacy between all interventions
included in the network. Point estimates [mean difference (MD) for continuous outcomes, odds ratios (OR)
for binary outcomes] and 95 % credible intervals (CrI)
are presented. Because a reduction in PANSS scores
(total, positive and negative), lower discontinuation rates
and lower weight change are favourable, point estimates
lying to the right of the line of no difference favour the
intervention over placebo. When the 95 % CrI lies
exclusively to the left or right of this line of no difference, this indicates a statistically significant result vs
placebo. Treatment ranking probabilities are presented in
the form of rankograms, which show the probability of
attaining each possible rank. The vertical axis represents
the probability, and the horizontal axis shows the possible ranks in ascending order (equal to the number of
treatments in the network). Lines showing a decreasing
trend indicate more efficacious treatments as they indicate a reducing probability of being ranked lower. All
outcomes are displayed on one figure and are identified
by the line type.
3 Results
3.1 Search Results
In total, 1613 potentially relevant citations were identified
through database searches. Primary title and abstract
screening resulted in 1174 citations being excluded on the
basis that they clearly did not meet the eligibility criteria of
the review. Of the resulting 439 citations accessed in full,
11 were publications of studies meeting the inclusion criteria (Fig. 1).
3.2 Study Characteristics and Quality Assessment
Key characteristics of the included studies are presented in
Table 1. Generally, the studies were quite small, although
this varied, from 7 to 190 patients per treatment arm.
Baseline patient characteristics (such as age and proportion
31
Identification
Eligibility
Screening
eligibility (n=439)
(n=428)
Outcome (n=21)
Study design (n=26)
Included
Population (n=336)
Overlapping patient
population (n=8)
Duplicate (n=6)
Lack of detail (n=26)
Unable to access (n=5)
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R. C. Harvey et al.
Study type
Controlled trial
Time point
post-baseline
(week)
8
12
Treatment arm
(mg/day)
Age,
years
(mean)
Male
patients,
%
Baseline
total
PANSS
Haloperidol
(515)
17.1
71.4
86.1
Olanzapine
(1020)
17
16.8
68.4
71.6
Risperidone
(0.56)
15
17.0
52.9
90.2
Olanzapine
(2.520)
12
11.5
41.7
92.75
Risperidone
(0.254.5)
13
10.7
38.5
93.85
Aripiprazole (10)
99
15.6
45
93.6
Aripiprazole (30)
97
15.4
63.7
94.0
Placebo
98
15.4
61
94.6
Molindone
(10140)
Olanzapine
(2.520)
40
NR
58
99.7
35
NR
71
100.3
Risperidone
(0.56)
41
NR
66
103.3
Risperidone
(0.150.6)
Risperidone
(0.56)
131
NR
NR
96.4
124
NR
NR
93.3
Risperidone
(13)
54
15.7
30
95.4
Risperidone
(46)
Placebo
50
15.7
37
93
54
15.5
35
93.2
72
16.1
51
95.3
Kryzhanovskaya et al.
(2009) [33]
Olanzapine
(2.520)
Placebo
35
16.3
24
95.5
Quetiapine
(100800)
11
NR
NR
89
Risperidone
(0.56)
11
NR
NR
87.09
Paliperidone
(1.5)
54
15.1
30
91.6
Paliperidone
(36)
48
15.3
31
90.6
Paliperidone
(612)
47
15.5
33
91.5
Placebo
51
15.7
23
90.6
Quetiapine (400)
73
15.45
43
96.2
Quetiapine (800)
74
15.45
44
97.0
Placebo
Findling et al. (2013) [37]
Ziprasidone
(40160)
Placebo
73
15.34
42
96.7
190
15.24
56.48
88.9
88
15.43
68.69
87.4
33
arms [28, 33], while in the remaining three studies, this was
unclear [27, 32, 34].
3.3 Data Analysis
3.3.1 NMA Evidence Base
Eleven studies were included in the primary analysis
(change from baseline total PANSS scores) as shown by
the network of evidence (Fig. 2). All studies except Swadi
(2010) were included in the analyses of change from
baseline positive PANSS scores, negative PANSS scores
and weight change (denoted * in Fig. 2) [34]. All-cause
discontinuation was less frequently reported; seven studies
were included in this analysis (denoted ** in Fig. 2). For
all analyses except all-cause discontinuation, eight active
treatments and placebo were included within the network
of evidence (Fig. 2).
3.3.2 Assessment of Efficacy
Relative treatment effects vs placebo for change from
baseline to 6 weeks in total PANSS scores are shown by the
forest plot (Fig. 3a). There was evidence to suggest that
three interventions (molindone, olanzapine and risperidone)
were associated with a statistically significant reduction in
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R. C. Harvey et al.
Fig. 3 Forest plots for all outcomes. AE adverse events, CrI credible interval, MD mean difference, OR, odds ratio, PANSS Positive and
Negative Syndrome Scale
35
reduction in negative PANSS scores vs placebo, no comparison was statistically significant. Haloperidol and
molindone showed the greatest reduction in negative
PANSS scores vs placebo (MD = -3.42); however, the
respective 95 % CrIs spanned zero. Treatment ranking
probabilities (Fig. 4) show that haloperidol had the greatest
probability of being ranked the best treatment in the network for both positive and negative PANSS scores, with
probabilities of 0.85 and 0.40, respectively.
Relative treatment effects vs placebo for change from
baseline to 6 weeks in weight are shown by the forest plot
(Fig. 3d). Olanzapine, quetiapine and risperidone showed a
statistically significant weight gain vs placebo. Haloperidol, molindone and ziprasidone showed a trend of reduced
weight gain vs placebo; however, there was no statistically
significant difference between these treatments and placebo. The treatment ranking probabilities (Fig. 4) show
that haloperidol and molindone have the greatest probabilities of being the best treatments (prob = 0.50 and
prob = 0.45, respectively). All remaining treatments each
had probabilities of less than 0.03.
Odds ratios of all treatments vs placebo for all-cause
discontinuation are shown in the forest plot (Fig. 3e). One
treatment (risperidone) showed statistically significant
reduced odds of discontinuing treatment because of any
reason vs placebo. All treatments showed a trend of lower
odds of discontinuing because of any reason vs placebo; for
risperidone, this is a statistically significant result
[OR = 0.48, 95 % CrI (0.25, 0.84)]. The treatment with
the lower odds vs placebo was haloperidol. However, there
is much uncertainty around this estimate [OR = 0.19,
95 % CrI (0.01, 2.42)]. The treatment ranking probabilities
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R. C. Harvey et al.
Total
residual
deviance
26.1
24
20.6
22
20.8
20.0
22
22
All-cause discontinuation
16.0
15
19.9
22
4 Discussion
This study, using an NMA, aimed to provide a comparison
of the efficacy profiles of different AP medications for the
treatment of EOS, with data from both direct and indirect
trial comparisons. Changes in PANSS scores can demonstrate the efficacy of a treatment in maintaining symptom
control; however, rather than looking at total PANSS
scores, we chose to first analyse the positive and negative
symptom scores. These are useful clinical indicators, particularly in view of the poor treatment response for negative symptoms to date. While acknowledging the
uncertainty in the results, haloperidol showed a trend of
being the most efficacious intervention for reducing
conducted in the adult population was much more comprehensive and included 212 trials, with data for 43,049
participants, which is considerably more than the 11
studies and 1714 participants available here. This highlights, once again, the poor evidence base for APs in the
adolescent population. However, the interesting suggestion coming from both studies is to consider broadening
the range of medications used, depending on the clinical
needs of the patient, rather than limiting choice to the
dichotomous classification of APs into first- and secondgeneration groupings.
There are a number of limitations to the study. The
usefulness of existing trials completed in the paediatric
population is often restricted by their quality, small sample
numbers and heterogeneity among the study populations
[43]. Trials demonstrate efficacy of symptom control;
however, there is a paucity of data on the side effects of
treatment and longer-term health impacts, demonstrating a
need for more research. The potential bias identified in the
studies reduces the reliability of the data used to form the
network, and some of the bias (e.g. signs of selective bias
and differences in baseline characteristics) may lead to
incorrect interpretations around treatment effect. Small
sample numbers in the trials may be due to hesitation (in
particular ethical considerations) in conducting clinical
trials in a younger populations [44]. The literature search
was not restricted to RCTs, acknowledging the lack of data
in this population, and thus widened the evidence base,
which places the study at a higher risk of bias. Additionally, NMAs are susceptible to publication bias, with
detrimental effects of publication bias being identified in
previous psychiatric studies [45].
There is considerable uncertainty in the relative treatment effects, most likely because of the limited number of
studies included in the network. Many of the treatment
comparisons are informed by only one trial. It has previously been noted that there is often a substantial response
in the placebo arm of trials for psychiatric interventions,
which may therefore limit the reliability of NMA results
[45]. Additionally, a non-RCT was included in the analysis
to allow comparisons to be made with haloperidol. Inclusion of the study (Gothelf et al.) enabled relative effects vs
haloperidol to be estimated [27]. While a sensitivity analysis excluding this study was performed, with results
remaining consistent, NMAs do rely upon the synthesis of
RCTs only. Another limitation with the evidence base is
the assumption that risperidone (0.150.6 mg) is equivalent
to placebo. This assumption was made so this trial could be
included within the analyses, thus providing more evidence
on the higher dose of risperidone, given the paucity of data
in this evidence base. In addition, as the typical starting
dose is 0.5 mg, it is stated that this low dose is seen as a
pseudo-placebo [46].
37
The study also includes few outcomes owing to limitations in the data (a lack of reporting of all possible
outcomes) and research constraints. An increase in the
number of studies available should report a greater
number of outcomes (e.g. EPSE), which will allow for
more in-depth research. In addition, this review focused
on the PANSS outcome scale for assessing response to
treatment as this allowed us to differentiate between the
positive and negative symptoms in schizophrenia. However, this meant that some treatments could not be
included because trials studying these treatments did not
use PANSS as the tool to measure symptom control, and
they therefore did not meet the inclusion criteria (e.g. a
trial was identified with clozapine, but had to be
excluded as the outcome was not reported using
PANSS). There are a number of other scales, including
the Brief Psychiatric Rating Scale and the Clinical
Global Impression. To widen the scope of the research,
it would have been possible to widen the criteria and to
make assumptions around the relationship between outcome measures. However, this would have prevented the
separate analysis of the positive and negative subscales,
and would have relied on using the standardised MD,
which also has limitations (e.g. outcome measures would
need to be deemed similar enough to combine and
interpretability of results could be challenging). As it
stands, decision makers need to carefully consider the
treatments available in their locality and whether the
study is reflective of the commonly used treatments.
Finally, this study focuses on pharmacological treatments. There is an emerging evidence base for the effectiveness of psychological interventions, although no studies
were identified during the review that focused on these
alternative treatments.
5 Conclusion
Evidence for the comparative efficacy and safety of AP use
in the paediatric population is limited, and results should be
interpreted cautiously. The evidence does demonstrate
favourable outcomes in terms of symptom control, using
the PANSS outcome scale; however, it does also highlight
a lack of statistically significant effects on negative
symptoms, increased weight gain and a lack of quantifiable
data to assess the risk of other side effects of treatment
more comprehensively.
Clinical strategy will involve a trade-off between the
efficacy of an AP and the likely side effects resulting from
treatment. This has to be seen as a major consideration, not
only because of the serious side effects seen with SGAs
(predominantly weight gain and associated metabolic
effects), and with FGAs (EPSE, including tardive
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R. C. Harvey et al.
dyskinesia), but also because of the high rate of discontinuation rates for APs in general.
Acknowledgments We thank Rachel Brown, a Clinical Lead
Pharmacist, for advising on the dosing of interventions included in the
analyses.
Author contributions G E. Shields and R. C. Harvey designed and
carried out the research, with A. C. James providing clinical validation. G. E. Shields undertook the systematic review, with R. C. Harvey acting as the second reviewer. R. C. Harvey undertook the
statistical analysis. G. E. Shields, R. C. Harvey and A. C. James wrote
the first draft of the manuscript. All authors contributed to and have
approved the final manuscript.
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