Cochrane Database of Systematic Reviews

Non-clozapine antipsychotic combinations for treatment-

resistant schizophrenia (Protocol)

Yow A, Jayaram MB

Yow A, Jayaram MB.

Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia.
Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD012523.
DOI: 10.1002/14651858.CD012523.

www.cochranelibrary.com

Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol) i

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Non-clozapine antipsychotic combinations for treatment-

resistant schizophrenia

Alex Yow1 , Mahesh B Jayaram1

1 Department of Psychiatry, Melbourne Neuropsychiatry Centre, Melbourne, Australia

Contact address: Alex Yow, Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne,
Australia. wyow@student.unimelb.edu.au.

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: New, published in Issue 1, 2017.

Citation: Yow A, Jayaram MB. Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia. Cochrane Database
of Systematic Reviews 2017, Issue 1. Art. No.: CD012523. DOI: 10.1002/14651858.CD012523.

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects (benefits and harms) of non-clozapine antipsychotic combinations for people with treatment-resistant schizophrenia.

BACKGROUND other often accepted operational definition of TRS used in clinical

Description of the condition
Schizophrenia is a chronic, relapsing and debilitating neuropsy-
chiatric disorder. Antipsychotic medication remains the mainstay
of treatment, however of those on adequate antipsychotic therapy,
about one third fail to respond, and persist with positive symptoms
such as hallucinations and delusions, and negative symptoms such
as apathy or poor social functioning (Meltzer 1997). These pa-
tients are often described as having treatment-resistant schizophre-
nia (TRS). Despite the concept being clinically intuitive, attempts
at operationalising the criteria for TRS have yielded disparate defi-
nitions. Most are iterations of the definition endorsed by the World
Federation of Societies of Biological Psychiatry, which defines TRS
as the lack of significant improvement of psychopathology and/
or target symptoms despite treatment with two different antipsy-
chotics from at least two different chemical classes (at least one
should be an atypical antipsychotic) at the recommended dosages
for a period of at least 2 to 8 weeks per drug (Hasan 2012). An-
Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
trials is one to three failed antipsychotic attempts, with each hav-
ing a duration of more than 4 to 6 weeks at the dose equivalent to
400 to 1000 mg of chlorpromazine, which is similar to the Kane
criteria based on his landmark clozapine trial (Kane 1988; Suzuki
2012).
TRS affects about 7.8 million people worldwide, with clozapine
refractory TRS affecting about 4.68 million (Eaton 2008; Kane
1988). Its significance cannot be understated, with close to 60%
of people with schizophrenia failing to achieve response after 23
weeks of antipsychotic therapy, and mean quality of life about
20% lower than that of patients in remission (Kennedy 2014).
A recent published Global Burden of Disease Study placed it in
the top 20 diseases for mean years lost to disability (YLD), with a
significant jump of 52% from the 1990s baseline (Global Burden
2015). Patients experiencing TRS can continue to hear voices
or contend with ongoing delusional beliefs. Whilst the positive
symptoms are easier to elicit, persistence of negative symptoms
and cognitive deficits are harder to elicit and most patients do not
spontaneously report these unless specifically looked for. These,
1
however, lead to significant decline in functional outcomes. A re-
cent survey in Australia - the Survey of High Impact Psychosis
(SHIP) demonstrated that more than 40% of patients who were
adequately treated remained symptomatic, and life expectancy is
reduced by at least 10 years due to risk of suicide alone, not with-
standing the devastating effects of smoking and metabolic syn-
drome (Morgan 2012). Patients with TRS showed the poorest
achievements in functional milestones of everyday living compared
to those with other chronic psychiatric conditions, with most be-
ing unemployed, unable to live independently, and lacking any
sentimental relationships (Iasevoli 2015). TRS is also very costly,
costing 3 to 11 times more per patient for care than other patients
with schizophrenia (Kennedy 2014).
Description of the intervention
For patients with TRS, when clozapine is either not an option or
has not worked, the common alternatives considered are combina-
tion antipsychotics. This usually involves combining a first-gener-
ation antipsychotic (FGA) with a second-generation antipsychotic
(SGA), followed by other combinations such as FGA + FGA, then
SGA + SGA (Correll 2012). One of the hypotheses for this ra-
tionale is to combine serotonin blocking agents with dopamine
blockers. A recent review documented 19 studies on SGA + SGA,
4 studies on FGA + FGA, 3 studies on SGA + FGA and 2 studies
on FGA + SGA, excluding clozapine for the treatment of patients
with schizophrenia (Galling 2016). Commonly used SGA + SGA
in that review were aripiprazole plus risperidone and sulpiride plus
olanzapine. With no single accepted non-clozapine antipyschotic
combination therapy (NCCAT) demonstrating significant and
sustained benifit, different combinations are often trialled and
tried in patients with schizophrenia. For example, aripiprazole has
been combined with either quetiapine or risperidone and studied
for efficacy and tolerability in patients with schizophrenia (Kane
2009). Another study compared aripiprazole plus haloperidol to
haloperidol alone, showing amelioration of prior hyperprolactine-
mia (Shim 2007). Other studies have combined olanzapine with
ziprasidone where there was no significant improvement observed
for fasting glucose, insulin resistance, hyperlipidaemia and obe-
sity, compared to clozapine plus ziprasidone (Henderson 2009).
Seven different combinations were reported in case studies for a
review, including amisulpiride plus olanzapine, olanzapine plus
risperidone, and quetiapine plus risperidone (Chan 2007). Given
the broad chemical and pharmacological heterogeneity of antipsy-
chotic agents, many different NCCAT are used in clinical studies
and in practice.
How the intervention might work
The lack of any pharmacological rationale for combining antipsy-
chotics with the same putative antipsychotic dopamine D2 recep-
Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
tor blockade has been criticised (Correll 2012). However, the ef-
ficacy of clozapine in spite of its modest D2 blockade and the ac-
tivity of different antipsychotics on a variety of non-D2 receptors
suggest the possibility that efficacy of antipsychotic combination
treatment may relate to a more optimal suite of action on such a
spectrum of receptors. Moreover, employing lower doses of two
antipsychotics may mitigate unpleasant or harmful side effects,
given the different side-effect profile of the antipsychotics. For ex-
ample, the addition of either amisulpride or risperidone to olanza-
pine or quetiapine may result in improvement in the D2 receptor
antagonism but with a better side-effect profile, as olanzapine or
quetiapine have a reduced tendency to cause extrapyramidal side
effects or prolactin elevation (Chan 2007).
Why it is important to do this review
The current mainstay treatment for TRS is the antipyschotic cloza-
pine (Hasan 2012). However, 40% to 70% of TRS patients are re-
sistant to clozapine (Chakos 2001). In addition, of those on cloza-
pine, 17% discontinue due to intolerance to clozapine’s side effects
(Young 1998). For those who have been challenged again with
clozapine after life-threatening adverse effects, failure rate remains
high for agranulocytosis and myocarditis (Manu 2012). It is also
contraindicated in patients with multiple comorbidities such as ac-
tive liver disease and pre-existing cardiovascular diseases, which are
common in people with schizophrenia (Chwastiak 2014; Naheed
2001). The mandatory, frequent haematological monitoring in
some countries can also cause much inconvenience to some pa-
tients (Alvir 1994).
Clinicians then need to consider NCCAT as a last-line solution
for TRS.
Indeed, the fact that antipsychotic combination treatment has
been estimated to be prescribed to 10% to 50% of patients (Hasan
2012), is testament to both the prevalence of TRS and the inade-
quacy of monotherapy. Furthermore, clozapine displays both par-
tial dopaminergic antagonism and serotonergic antagonism which
are postulated to be implicated in its efficacy in TRS (Meltzer
1989). Thus NCCAT can be employed for patients who are intol-
erant to, contraindicated or who have refused clozapine, by opti-
misation of the two neurotransmission pathways, leading to better
efficacy and reduced side effects.
Reviews to date have largely focused on clozapine antipsychotic
combination treatments in TRS (Cipriani 2009) or antipsy-
chotic combination treatments in schizophrenia in general (Correll
2012). Consequently, there is a lack of good quality evidence re-
garding the efficacy or tolerability of non-clozapine combinations
in TRS. This review will address this gap.
OBJECTIVES
2
To assess the effects (benefits and harms) of non-clozapine Primary outcomes
antipsychotic combinations for people with treatment-resistant
schizophrenia.
1. Leaving the study early

METHODS
2. Global state
2.1 Clinically-important change in global state - as defined by each
of the studies
Criteria for considering studies for this review 2.2 Relapse - as defined by each of the studies

Secondary outcomes
Types of studies
All relevant randomised controlled trials. If a trial is described as
’double blind’ but implies randomisation, we will include such 1. Global state
trials in a sensitivity analysis (see Sensitivity analysis). We will ex-
clude quasi-randomised studies, such as those allocating by alter- 1.1 Any change in global state
nate days of the week. 1.2 Average endpoint/change score in global state scale

Types of participants
Adults, aged over 18 years, however defined, with treatment-resis-
tant schizophrenia.
We are interested in making sure that information is as relevant to
the current care of people with schizophrenia as possible, and aim
to highlight the current clinical state (acute, early post-acute, par-
tial remission, remission), and the stage (prodromal, first episode,
early illness, persistent) of participants. We also aim, where possi-
ble, to highlight studies with people having a particular problem
(for example, negative symptoms).
Types of interventions
2. Mental state
2.1 Clinically-important change in mental state - as defined by
individual studies
2.2 Any change in mental state - as defined by individual studies
2.3 Average endpoint/change score in mental state scales
2.4 Clinically-important change in positive symptoms - as defined
by individual studies
2.5 Average endpoint/change score in positive symptoms scales
2.6 Clinically-important change in negative symptoms - as defined
by individual studies
2.7 Average endpoint/change score in negative symptoms scales
2.8 Clinically-important change in aggression/agitation symptoms
- as defined by individual studies
2.9 Average endpoint/change score in aggression/agitation symp-
toms scales

1. Intervention
3. Service use
Antipsychotic combination: treatment that involves more than
one antipsychotic medication, none of which is clozapine: any 3.1 Hospital admission
dose, any route of delivery. 3.2 Days in hospital
3.3 Change in hospital status

2. Comparator
Treatment with either placebo or one or more antipsychotic medi-
cations with or without additional placebo medications: any dose,
any route of delivery.
Types of outcome measures
We aim to divide outcomes into short term (less than 6 months),
medium term (7 to 12 months) and long term (over 1 year).
4. Behaviour
4.1 Clinically-important change in behaviour - as defined by in-
dividual studies
4.2 Any change in behaviour - as defined by individual studies
4.3 Average endpoint/change score in behaviour scales
4.4 Specific behaviours
4.4.1 Employment status during trial (employed/unemployed)
4.4.2 Occurrence of violent incidents (to self, others, or property)
4.4.3 Level of substance abuse

Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol) 3

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5. Social functioning
5.1 Clinically-important change in social functioning - as defined
by individual studies
5.2 Any change in social functioning - as defined by individual
studies
5.3 Average endpoint/change score in social functioning scales
6. Adverse effects
6.1 Any serious adverse events
6.2 Adverse events requiring hospitalisation
6.3 Specific adverse effects
6.3.1 Allergic reactions
6.3.2 Blood dyscrasia such as agranulocytosis
6.3.3 Central nervous system (ataxia, nystagmus, drowsiness, fits,
diplopia, tremor)
6.3.4 Death (suicide and non-suicide deaths)
6.3.5 Endocrinological dysfunction (hyperprolactinaemia)
6.3.6 Weight gain
6.3.7 Movement disorders (extrapyramidal side effects)
7. Quality of life
7.1 Clinically-important change in quality of life - as defined by
individual studies
7.2 Any change in quality of life - as defined by individual studies
7.3 Average endpoint/change score in quality of life scales
8. Economic (cost of care)
8.1 Direct costs
8.2 Indirect costs
’Summary of findings’ table
We will use the GRADE approach to interpret findings (
Schünemann 2011) and will use GRADE profiler (GRADEPRO)
to import data from RevMan 5 (Review Manager) to create ’Sum-
mary of findings’ tables. These tables provide outcome-specific
information concerning the overall quality of evidence from each
included study in the comparison, the magnitude of effect of the
interventions examined, and the sum of available data on all out-
comes we rated as important to patient care and decision making.
We aim to select the following main outcomes for inclusion in the
’Summary of findings’ table.
1. Leaving the study early.
2. Global state: clinically-important change - as defined by
individual studies.
3. Global state: relapse - as defined by individual studies.
4. Mental state: clinically-important change - as defined by
individual studies.
5. Adverse effects - any serious adverse event.
Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6. Adverse effects - specific: movement disorders.
7. Quality of life - clinically-important change - as defined by
individual studies.
Search methods for identification of studies
Electronic searches
Cochrane Schizophrenia Group’s Study-Based Register of
Trials
The information specialist will search the Cochrane Schizophrenia
Group’s Study-Based Register of Trials using the following search
strategy:
*Treatment Resistant* in Healthcare Conditions of STUDY
In such a study-based register, searching the major concept re-
trieves all the synonym keywords and relevant studies because all
of the studies have already been organised based on their interven-
tions and linked to the relevant topics.
The Cochrane Schizophrenia Group’s Register of Trials is com-
piled by systematic searches of major resources (including AMED,
BIOSIS, CINAHL, Embase, MEDLINE, PsycINFO, PubMed,
and registries of clinical trials) and their monthly updates, hand-
searches, grey literature, and conference proceedings (see Group’s
Module). There are no language, date, document type, or publi-
cation status limitations for inclusion of records into the register.
Searching other resources
1. Reference searching
We will inspect references of all included studies for further rele-
vant studies.
2. Personal contact
We will contact the first author of each included study for infor-
mation regarding unpublished trials. We will note the outcome of
this contact in the tables ’Characteristics of included studies’ or
’Characteristics of studies awaiting classification’.
Data collection and analysis
Selection of studies
AY will independently inspect all citations from the searches and
identify relevant abstracts. A random 20% sample will be inde-
pendently inspected by MJ to ensure reliability. Where disputes
4
arise, we will acquire the full report for more detailed scrutiny.
AY will obtain and inspect full reports of the abstracts meeting
the review criteria. Again, MJ will also inspect a random 20% of
these reports in order to ensure reliable selection. Where it is not
possible to resolve disagreement by discussion, we will attempt to
contact the authors of the study for clarification.
Data extraction and management
1. Extraction
AY will extract data from all included studies. In addition, to en-
sure reliability, MJ will independently extract data from a ran-
dom sample of these studies, comprising 10% of the total. Again,
we will discuss and document any disagreement and, if necessary,
will contact authors of studies for clarification. With remaining
problems MJ will help clarify issues and we will document these
final decisions. We will attempt to extract data presented only in
graphs and figures whenever possible. We will attempt to contact
authors through an open-ended request in order to obtain missing
information or for clarification whenever necessary. If studies are
multicentre, where possible, we will extract data relevant to each
component centre separately.
2. Management
2.1 Forms
We will extract data onto standard, simple forms.
2.2 Scale-derived data
We will include continuous data from rating scales only if:
a) the psychometric properties of the measuring instrument have
been described in a peer-reviewed journal (Marshall 2000); and
b) the measuring instrument has not been written or modified by
one of the trialists for that particular trial.
Ideally the measuring instrument should either be i. a self-report
or ii. completed by an independent rater or relative (not the thera-
pist). We realise that this is not often reported clearly. In ’Descrip-
tion of studies’, we will note if this is the case or not.
2.3 Endpoint versus change data
There are advantages of both endpoint and change data. Change
data can remove a component of between-person variability from
the analysis. On the other hand calculation of change needs two
assessments (baseline and endpoint) which can be difficult in un-
stable and difficult-to-measure conditions such as schizophrenia.
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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We have decided to primarily use endpoint data, and only use
change data if the former are not available. We will combine end-
point and change data in the analysis as we prefer to use mean dif-
ferences (MD) rather than standardised mean differences (SMD)
throughout (Higgins 2011b).
2.4 Skewed data
Continuous data on clinical and social outcomes are often not
normally distributed. To avoid the pitfall of applying parametric
tests to non-parametric data, we aim to apply the standards de-
scribed below to all data before inclusion.
Please note, we will enter data from studies of at least 200 partic-
ipants, in the analysis irrespective of the following rules, because
skewed data pose less of a problem in large studies. We will also
enter change data, as when continuous data are presented on a
scale that includes a possibility of negative values (such as change
data), it is difficult to tell whether data are skewed or not. We will
present and enter change data into statistical analyses.
For endpoint data N < 200:
a) when a scale starts from the nite number zero, we will subtract
the lowest possible value from the mean, and divide this by the
standard deviation. If this value is lower than one, it strongly sug-
gests a skew and we will exclude such data. If this ratio is higher
than one but below two, there is suggestion of skew. We will en-
ter these data and test whether their inclusion or exclusion would
change the results substantially. Finally, if the ratio is larger than
two we will include these data because skew is less likely (Altman
1996; Higgins 2011b);
b) if a scale starts from a positive value (such as the Positive and
Negative Syndrome Scale (PANSS; Kay 1986) which can have
values from 30 to 210), we will modify the calculation described
above to take the scale starting point into account. In these cases
skew is present if 2 SD > (S-S min), where S is the mean score and
’S min’ is the minimum score.
2.5 Common measure
To facilitate comparison between trials, we aim to convert variables
that can be reported in different metrics, such as days in hospital
(mean days per year, per week or per month) to a common metric
(e.g. mean days per month).
2.6 Conversion of continuous to binary
Where possible, we will make efforts to convert outcome measures
to dichotomous data. This can be done by identifying cut-off
points on rating scales and dividing participants accordingly into
’clinically improved’ or ’not clinically improved’. It is generally
assumed that if there is a 50% reduction in a scale-derived score
such as the Brief Psychiatric Rating Scale (BPRS; Overall 1962)
or the PANSS (Kay 1986), this could be considered as a clinically-
significant response (Leucht 2005a; Leucht 2005b). If data based
5
on these thresholds are not available, we will use the primary cut-
off presented by the original authors.
2.7 Direction of graphs
Where possible, we will enter data in such a way that the area
to the left of the line of no effect indicates a favourable outcome
for non-clozapine combination therapy. Where keeping to this
makes it impossible to avoid outcome titles with clumsy double-
negatives (e.g. ’Not un-improved’) we will report data where the
left of the line indicates an unfavourable outcome, and note this
in the relevant graphs.
Assessment of risk of bias in included studies
AY and MJ will assess risk of bias by using criteria described in the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011a). This set of criteria is based on evidence of associations
between overestimate of effect and high risk of bias of the study
in domains such as sequence generation, allocation concealment,
blinding, incomplete outcome data and selective reporting.
If the raters disagree, we will make the final rating by consensus.
Where inadequate details of randomisation and other characteris-
tics of trials are provided, we will contact authors of the studies in
order to obtain further information. We will report non-concur-
rence in ’Risk of bias’ assessment, but if disputes arise as to which
rating a trial is to be allocated, again, we will resolve by discussion.
We will note the level of risk of bias in both the text of the review
and in the ’Summary of findings’ table.
Measures of treatment effect
1. Binary data
For binary outcomes we will calculate a standard estimation of
the risk ratio (RR) and its 95% confidence interval (CI). It has
been shown that RR is more intuitive (Boissel 1999) than odds
ratios (ORs) and that ORs tend to be interpreted as RRs by clin-
icians (Deeks 2000). For binary data presented in the ’Summary
of findings’ table/s, where possible, we will calculate illustrative
comparative risks.
2. Continuous data
For continuous outcomes, we will estimate mean difference (MD)
between groups. We prefer not to calculate effect size measures
(SMD). However, if scales of very considerable similarity are used,
we will presume there is a small difference in measurement, and
we will calculate effect size and transform the effect back to the
units of one or more of the specific instruments.
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Unit of analysis issues
1. Cluster trials
Studies increasingly employ ’cluster randomisation’ (such as ran-
domisation by clinician or practice), but analysis and pooling of
clustered data poses problems. Firstly, authors often fail to account
for intra-class correlation in clustered studies, leading to a ’unit
of analysis’ error (Divine 1992) whereby P values are spuriously
low, confidence intervals unduly narrow and statistical significance
overestimated. This causes type I errors (Bland 1997; Gulliford
1999).
Where clustering is not accounted for in primary studies, we will
present data in a table, with a (*) symbol to indicate the presence
of a probable unit of analysis error. We will contact authors of such
studies to obtain intra-class correlation coefficients (ICCs) for their
clustered data and to adjust for this by using accepted methods
(Gulliford 1999). Where clustering has been incorporated into the
analysis of primary studies, we will present these data as if from a
non-cluster randomised study, but adjust for the clustering effect.
We have obtained statistical advice that the binary data as presented
in a report should be divided by a ’design effect’. This is calculated
using the mean number of participants per cluster (m) and the
ICC [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC
is not reported we will assume it to be 0.1 (Ukoumunne 1999).
If cluster studies have been appropriately analysed taking into ac-
count ICCs and relevant data documented in the report, synthesis
with other studies will be possible using the generic inverse vari-
ance technique.
2. Cross-over trials
A major concern of cross-over trials is the carry-over effect. It oc-
curs if an effect (e.g. pharmacological, physiological or psycho-
logical) of the treatment in the first phase is carried over to the
second phase. As a consequence, on entry to the second phase
the participants can differ systematically from their initial state,
despite a wash-out phase. For the same reason cross-over trials are
not appropriate if the condition of interest is unstable (Elbourne
2002). As both effects are very likely in severe mental illness, we
will only use data of the first phase of cross-over studies.
3. Studies with multiple treatment groups
Where a study involves more than two treatment arms, if relevant,
we will present the additional treatment arms in comparisons. If
data are binary we will simply add these and combine within the
two-by-two table. If data are continuous we will combine data fol-
lowing the formula in section 7.7.3.8 (Combining groups) of the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011). Where the additional treatment arms are not relevant, we
will not use these data.
6
Dealing with missing data
1. Overall loss of credibility
At some degree of loss of follow-up, data must lose credibility (Xia
2009). If for any particular outcome, more than 50% of data are
unaccounted for, we will not reproduce these data or use them
within analyses. If, however, more than 50% of those in one arm
of a study are lost, but the total loss is less than 50%, we will
address this within the ’Summary of findings’ table/s by down-
grading quality. Finally, we will also downgrade quality within the
’Summary of findings’ table/s should loss be 255 to 50% in total.
2. Binary
In the case where attrition for a binary outcome is between 0 and
50% and where these data are not clearly described, we will present
data on a ’once-randomised-always-analyse’ basis (an intention-
to-treat analysis). Those leaving the study early are all assumed to
have the same rates of negative outcome as those who completed,
with the exception of the outcome of death and adverse effects.
For these outcomes we will use the rate of those who stay in the
study - in that particular arm of the trial - for those who did
not. We will undertake a sensitivity analysis testing how prone the
primary outcomes are to change when data only from people who
complete the study to that point are compared to the intention-
to-treat analysis using the above assumptions.
3. Continuous
3.1 Attrition
In the case where attrition for a continuous outcome is between 0
and 50%, and data only from people who complete the study to
that point are reported, we will reproduce these.
3.2 Standard deviations
If standard deviations are not reported, we will first try to obtain
the missing values from the authors. If not available, where there
are missing measures of variance for continuous data, but an exact
standard error and confidence intervals available for group means,
and either P value or t value available for differences in mean, we
can calculate them according to the rules described in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011):
When only the standard error (SE) is reported, standard deviations
(SDs) are calculated by the formula SD = SE * square root (n).
Chapters 7.7.3 of the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011) present detailed formula for estimat-
ing SDs from Pvalues, t or F values, confidence intervals, ranges
or other statistics. If these formula do not apply, we will calcu-
late the SDs according to a validated imputation method which is
Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
based on the SDs of the other included studies (Furukawa 2006).
Although some of these imputation strategies can introduce error,
the alternative would be to exclude a given study’s outcome and
thus to lose information. We nevertheless will examine the valid-
ity of the imputations in a sensitivity analysis excluding imputed
values.
3.3 Assumptions about participants who left the trials early
or were lost to follow-up
Various methods are available to account for participants who left
the trials early or were lost to follow-up. Some trials just present
the results of study completers, others use the method of last ob-
servation carried forward (LOCF), while more recently methods
such as multiple imputation or mixed effects models for repeated
measurements (MMRM) have become more of a standard. While
the latter methods seem to be somewhat better than LOCF (Leon
2006), we feel that the high percentage of participants leaving the
studies early and differences in the reasons for leaving the stud-
ies early between groups is often the core problem in randomised
schizophrenia trials. We will therefore not exclude studies based on
the statistical approach used. However, we will preferably use the
more sophisticated approaches. For example, we will prefer to use
MMRM or multiple imputation to LOCF and will only present
completer analyses if some kind of ITT data are not available at
all. Moreover, we will address this issue in the item ’incomplete
outcome data’ of the ’Risk of bias’ tool.
Assessment of heterogeneity
1. Clinical heterogeneity
We will consider all included studies initially, without seeing com-
parison data, to judge clinical heterogeneity. We will simply in-
spect all studies for clearly outlying people or situations which we
had not predicted would arise. When such situations or partici-
pant groups arise, we will fully discuss these.
2. Methodological heterogeneity
We will consider all included studies initially, without seeing com-
parison data, to judge methodological heterogeneity. We will sim-
ply inspect all studies for clearly outlying methods which we had
not predicted would arise. When such methodological outliers
arise we will fully discuss these.
3. Statistical heterogeneity
3.1 Visual inspection
7
We will visually inspect graphs to investigate the possibility of
statistical heterogeneity.
3.2 Employing the I2 statistic
We will investigate heterogeneity between studies by considering
the I2 method alongside the Chi2 P value. The I2 provides an
estimate of the percentage of inconsistency thought to be due to
chance (Higgins 2003). The importance of the observed value of I
2
depends on: i. magnitude and direction of effects and ii. strength
of evidence for heterogeneity (e.g. P value from Chi2 test, or a
confidence interval for I2 ). We will interpret an I2 estimate greater
than or equal to around 50% accompanied by a statistically sig-
nificant Chi2 value, as evidence of substantial levels of hetero-
geneity (Section 9.5.2, Higgins 2011b). When substantial levels of
heterogeneity are found in the primary outcome, we will explore
reasons for heterogeneity (Subgroup analysis and investigation of
heterogeneity).
Assessment of reporting biases
1. Protocol versus full study
Reporting biases arise when the dissemination of research findings
is influenced by the nature and direction of results. These are de-
scribed in section 10.1 of the Cochrane Handbook for Systematic
Reviews of Interventions (Sterne 2011). We will try to locate pro-
tocols of included randomised trials. If the protocol is available,
we will compare outcomes in the protocol and in the published
report. If the protocol is not available, we will compare outcomes
listed in the methods section of the trial report with the results
that were actually reported.
2. Funnel plot
Reporting biases arise when the dissemination of research findings
is influenced by the nature and direction of results (Egger 1997).
These are again described in Section 10 of the Cochrane Handbook
for Systematic Reviews of Interventions (Sterne 2011). We are aware
that funnel plots may be useful in investigating reporting biases
but are of limited power to detect small-study effects. We will
not use funnel plots for outcomes where there are ten or fewer
studies, or where all studies are of similar sizes. In other cases,
where funnel plots are possible, we will seek statistical advice in
their interpretation.
Data synthesis
We understand that there is no closed argument for preference for
use of fixed-effect or random-effects models. The random-effects
method incorporates an assumption that the different studies are
estimating different, yet related, intervention effects. This often
Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol)
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
seems to be true to us and the random-effects model takes into
account differences between studies even if there is no statistically
significant heterogeneity. There is, however, a disadvantage to the
random-effects model. It puts added weight onto small studies
which often are the most biased ones. Depending on the direction
of effect these studies can either inflate or deflate the effect size.
We will use the random-effects model for all analyses.
Subgroup analysis and investigation of heterogeneity
1. Subgroup analyses
1.1 Primary outcomes
• Dose of antipsychotic
• Choice of comparison
• Setting
1.2 Clinical state, stage or problem
We propose to undertake this review and provide an overview
of the effects of antipsychotic combinations for people with
schizophrenia in general. In addition, however, we will try to re-
port data on subgroups of people in the same clinical state, stage
and with similar problems.
2. Investigation of heterogeneity
We will report if inconsistency is high. First we will investigate
whether data have been entered correctly. Second, if data are cor-
rect, we will visually inspect the graph and successively remove
studies outside of the company of the rest to see if homogeneity
is restored. For this review we have decided that should this occur
with data contributing to the summary finding of no more than
around 10% of the total weighting, we will present data. If not,
we will not pool data, and will discuss relevant issues. We know of
no supporting research for this 10% cut off but are investigating
use of prediction intervals as an alternative to this unsatisfactory
state.
When unanticipated clinical or methodological heterogeneity are
obvious we will simply state hypotheses regarding these for future
reviews or versions of this review. We do not anticipate undertaking
analyses relating to these.
Sensitivity analysis
1. Implication of randomisation
We aim to include trials in a sensitivity analysis if they are de-
scribed in some way as to imply randomisation. For the primary
8
outcomes if inclusion of their data does not result in a substan-
tive difference, they will remain in the analyses. If their inclusion
does result in important clinically significant but not necessarily
statistically significant differences, we will not add the data from
these lower quality studies to the results of the better trials, but
will present such data within a subcategory.
2. Assumptions for lost binary data
Where assumptions have to be made regarding people lost to fol-
low-up (see Dealing with missing data) we will compare the find-
ings of the primary outcomes when we use our assumption/s and
when we use data only from people who complete the study to
that point. If there is a substantial difference, we will report results
and discuss them but will continue to employ our assumption.
Where assumptions have to be made regarding missing SDs (see
Dealing with missing data), we will compare the findings of the
primary outcomes when we use our assumption/s and when we
use data only from people who complete the study to that point.
A sensitivity analysis will be undertaken testing how prone results
are to change when completer-only data only are compared to the
imputed data using the above assumption. If there is a substantial
difference, we will report results and discuss them but will continue
to employ our assumption.
3. Risk of bias
We will analyse the effects of excluding trials that are judged to be
at high risk of bias across one or more of the domains of randomi-
sation (implied as randomised with no further details available,
allocation concealment, blinding and outcome reporting) for the
primary outcome. If the exclusion of data from trials at high risk
of bias does not substantially alter the direction of effect or the
precision of the effect estimates, then these data from these trials
will be included in the analysis.
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∗
Indicates the major publication for the study

CONTRIBUTIONS OF AUTHORS
AY adapted Cochrane Schizophrenia’s standard protocol to the current topic.
MJ coordinated and provided general advice on the protocol.

DECLARATIONS OF INTEREST
Alex Yow: none known
Mahesh B Jayaram: none known

SOURCES OF SUPPORT

Internal sources
• University of Melbourne, Department of Psychiatry (Melbourne Neuropsychiatry Centre), Australia.
Employs review author Mahesh Jayaram and Alex Yow is a medical student at this university.

External sources
• No sources of support supplied

Non-clozapine antipsychotic combinations for treatment-resistant schizophrenia (Protocol) 12

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.