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Application for a Systematic Review
1.
SYNOPSIS
APPLICANT
Prof. Dr. med. Stefan Leucht, editor, Cochrane Schizophrenia Group,
Vice chairman, Psychiatrische Klinik der Technischen Universität
München, Ismaningerstr. 22, D-81675 München, Tel.: +49-89-41404249, Fax: (-4888), e-mail: [email protected]
TITLE OF REVIEW
Do antipsychotics increase the risk for sudden death and serious
adverse events, and what are risk factors?
CONDITION
Schizophrenia and other severe mental disorders
OBJECTIVE(S)
To examine whether antipsychotic drugs increase the risk for death
(including sudden cardiac death) and serious adverse events, to find
out which serious adverse events are increased and whether there
are patient or treatment related factors that are associated with their
occurence.
TYPE OF REVIEW
Systematic review and meta-analysis comparing the class of
antipsychotics with placebo across indications. There will be special
methodological attention to the problem of rare events.
INTERVENTION (S)
Experimental intervention: Antipsychotic drugs.
Control intervention: Placebo.
STUDY SELECTION
Population (of patients): Schizophrenia, bipolar disorder, major
depressive disorder, dementia, off-label indications
Comparator(s): antipsychotic drugs versus placebo
Outcomes: Death due to any reason (primary), due to natural causes,
due to suicide; other serious adverse events according to ICP-GCP:
Life-threatening adverse events, hospitalization, disability, congenital
anomaly, requires intervention to prevent permanent damage, other
Design of primary studies: Double-blind, placebo controlled RCTs
SEARCH STRATEGY
Several electronic databases, pharmaceutical companies
manufacturing the antipsychotic drugs, personal contact of study
authors; previous reviews, FDA, EMA, clinical trial databases
QUALITY ASSESSMENT
Study quality in terms of sequence generation, allocation
concealment, blinding, the completeness of outcome data, selective
reporting, and other biases will be assessed with the Cochrane
Collaboration risk of bias tool.
DATA EXTRACTION
All data will be extracted independently by two reviewers. Doubts will
be resolved in a discussion with a third reviewer or by written request
to the authors. Data entry will be checked by double data entry in
Covidence software.
DATA SYNTHESIS
Pairwise meta-analyses within a Bayesian framework will be used to
estimate the summary comparative effect sizes. All outcomes will be
dichotomous and be primarily analysed as odds ratios, supplemented
by NNT/NNH. Special statistical attention in terms of data synthesis
and heterogeneity assessment will be paid to the fact that events will
be rare. Predefined subgroups analyses will address: diagnostic
subgroup, age, gender, antipsychotic drug used, antipsychotic
combinations, dose. Publication bias will be examined with funnelplot methods, recommendations will be made with GRADE.
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SAMPLE SIZE
Approximately 250 included RCTs with 50000 participants.
COOPERATING CENTERS
Georgia Salanti, PhD, Dept. of Hygiene and Epidemiology, University
of Ioannina, Greece
Cochrane Schizophrenia Group, Nottingham, United Kingdom
DURATION
20 months
APPLICATION HISTORY
This is the first application for this project.
1.1 KEY WORDS
Severe mental disorder, meta-analysis, antipsychotic drugs, death, serious adverse events, mortality
2.
RELEVANCE
Antipsychotics are very frequently used drugs. They are the mainstay of treatment of schizophrenia,
some of them have official indications for bipolar disorder, major depressive disorder and behavioural
disturbances of people with dementia, and they are clinically often used “off-label” for sleep
disturbances, anxiety disorders, for personality disorders and other indications. Careless, nonevidence based combinations of antipsychotics and excessive dosing are frequent [1, 2] and there is a
lot of controversy around antipsychotic drugs (e.g. [3]
or Peter Goetzsche in
www.madinamerica.com/2013/11/peter-gotzsche-2/). Much of this controversy has to do with the
side-effects of antipsychotics. The frequent ones such as movement disorders (extrapyramidal sideeffects), weight gain, sedation or prolactin increase are well understood and systematic reviews are
available (e.g. [4]). But there is also a discussion as to whether antipsychotics increase the risk for
(sudden) death due to rare, but serious adverse effects such as cardiac arrhythmias, cardiac
infarctions, stroke, thromboembolism, seizures, hyperglycaemic coma, malignant neuroleptic
syndrome and others. In practice, these deaths occur suddenly and often already early after initiating
treatment. The evidence of large, observational studies on this question is partly conflicting, because
there are many confounders which make it impossible to establish causal relationships (see 3.1
Evidence below). For example, people with schizophrenia often have unhealthy life styles in terms of
higher fat and less fiber diets [5], approximately 70% smoke [6], and co-morbid substance abuse is
frequent which can also cause excess mortality. We therefore plan a large systematic review and
meta-analysis of randomised trials comparing antipsychotic drugs with placebo across indications,
similar to influential reviews that have been published on selective serotonin reuptake inhibitors versus
placebo (e.g. [7]). The questions/objectives are: a) to find out whether (sudden) death and other
serious adverse events occur more frequently under treatment with antipsychotics compared to
placebo, b) which these adverse events are and c) to identify patient related factors (e.g. age,
diagnosis, comorbidity) or treatment related factors (e.g. specific drug, dose, combination treatment)
that increase the risk. The question whether the side-effects of antipsychotics outweigh their efficacy is
a research priority according to a consensus of patients and care givers published in Nature [8]. And
rare, severe adverse events often get overlooked by single RCTs. If a meta-analysis identified the
exact factors, preventive measures could be taken.
2.1
PREVALENCE, INCIDENCE, MORTALITY
The socioeconomic burden of the disorders for which all or some antipsychotic drugs have official
indications is extreme. The life morbid risk for schizophrenia is approximately 1% (mean/median 11/7
per 1000), the median point prevalence per 1000 is 4.6 (10, 90 percent quantiles 1.9, 10.0), and the
median yearly incidence per 100.000 is 15.2 (10, 90 percent quantiles 7.7, 43.0)[9]. Approximately 6%
of people with schizophrenia commit suicide [10] and standardized mortality ratios (SMRs) show a
2.58 times higher all-cause mortality compared to the general population [11]. Bipolar disorder is
comparably severe (bipolar spectrum: life time prevalence 2.4%, 12-month prevalence 1.5%, 16%
attempt suicide within one year [12]). Some antipsychotics also have an official indication for major
depressive disorder (life time prevalence 16.2%, point prevalence 5.6%, incidence per year 2445/100000, 4% of patients with at least one hospitalization die from suicide [13]), and they are also
frequently used to treat agitation in (Alzheimer) dementia (total prevalence in those elder than 65
years 5-9%, range of total incidence rates in the elderly population 1.4%-2.4%, 2-3 times increased
mortality compared to non-demented people of same age [14]), and they are used off-label for many
other psychiatric disorders [15]. All severe mental disorders are associated with substantially higher
mortality compared to the general population [16]. It has been shown, in schizophrenia, that the
excess mortality (leading to a shortened life-span by approximately 15 years [17]) is not only due to
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unnatural causes such as suicide (median SMR 7.5), but also due to a large number of natural causes
(median SMR 2.41), and that the excess has increased over the last decades [11]. The recently
introduced “atypical”, second-generation antipsychotic drugs which will be the target of our review
have been blamed as a cause, because many of them do not only produce weight gain and its longterm consequences [11], they can also lead to sudden death due to QTc prolongation and subsequent
torsades de pointe, thromboembolism, hyperglycemic coma, seizures, neuroleptic malignant
syndrome and falls due to postural hypotension. But which adverse events exactly explain a potentially
increased risk for (sudden) death, which drugs are most dangerous (e.g. second-generation, “atypical”
antipsychotics or first-generation, “typical” antipsychotics), what the risk factors are is unclear and the
observational literature is subject to confounders and partly contradictory (see 3.1 Evidence).
2.2
BURDEN OF DISEASE
The burden for patients, relatives and society just of the psychiatric disorders for which antipsychotics
have an official indication is dramatic. According to the 2010 global burden of disease report,
schizophrenia ranks 16th, bipolar disorder 18th, major depressive disorder 2nd and Alzheimer’s disease
24th in terms of years lived with disability (YLDs) overall [18]. In Germany schizophrenia, bipolar
disorder and major depressive disorder rank 16th, 17th, and 2nd in terms of DALYs in the 15-49 age
group,
and
Alzheimer’s
disease
ranks
5th
in
the
age
group
over
70
(http://www.healthmetricsandevaluation.org/gbd/visualizations/gbd-arrow-diagram). The total cost of
these four indications for antipsychotics have been estimated 312 billion EURO per year making them
among the most expensive diseases in the EU [19], exceeding the costs of widespread diseases such
as cardiovascular disorders [20]. The reasons for these costs are high hospitalisation rates and high
rates of unemployment and loss of productivity for the disorders which mainly start in the second or
third decade of life (schizophrenia, bipolar disorder, depression) leading to an enormous loss of
productivity and very early disease-related premature retirements, while the main cost driver of
dementia are the high care giving costs [14]. Finally, the antipsychotic drugs which will be investigated
by our systematic review are a market that has been estimated to be 14.8 billion USD worldwide in
2014 (http://www.bccresearch.com/report/antipsychotic-drugs-markets-phm063a.html).
2.3
NEED FOR THE SYSTEMATIC REVIEW
That there is excess mortality of schizophrenia and other severe mental illnesses compared to the
general population has been clearly established [11, 16], but whether and if how much antipsychotic
drugs contribute to it is not clear. A MEDLINE search with the terms “antipsychotic* AND (death OR
mortality), publication type review OR meta-analysis” (search date 25.3.2014) showed that a
systematic review of all randomised controlled trials of antipsychotic drugs compared to placebo on
mortality or other serious adverse events does not exist. It does also not exist on the major single
indications of antipsychotics (schizophrenia, bipolar disorder) except for the use of antipsychotics for
behavioural disturbances associated with dementia, in which a significantly increased mortality has
indeed been documented [21]. There is a systematic review of 12 observational studies on our
question [22]. Meta-analytic pooling was not possible because the studies varied substantially in
methodology. The review suggested an excess risk, but it also made it clear that the observational
evidence can be contradictory. E.g. a study using Finnish national registers published in the Lancet
found a decrease of mortality of people with schizophrenia on antipsychotic drugs compared to those
on no treatment [23], while the US study by Ray et al. [24] and the UK study by Murray-Thomas et al.
[25] found an increase of mortality of users compared to non-users. Moreover, there is debate which
antipsychotics are the most risky ones (e.g. first-generation antipsychotics or second-generation
antipsychotics, and which exact drugs [25, 26]), whether there is an association with dose [22], and
whether the risk increases when antipsychotics are combined (so called polypharmacy, at least one
influential study counterintuitively found that polypharmacy decreased the mortality risk [27]) is
unclear.
Finally, it is well-known that it is difficult to draw causal conclusions from observational studies due to
multiple problems such as indication bias, or unknown confounders that cannot be ruled out without
randomisation. Therefore a systematic review of RCTs comparing antipsychotics with placebo is
necessary. As a systematic review that showed that selective serotonin reuptake inhibitors increase
suicide risk compared to placebo [7] the review will have to be across diagnoses/ indications of
antipsychotics to increase the statistical power.
The review can have a substantial impact on evidence-based practice in Germany. Antipsychotics are
currently used very irrationally and often not very carefully. For example, combinations of
antipsychotics with other psychotropic drugs instead of the guideline recommended monotherapy are
rather the rule than the exception [1], although there isn’t hardly any evidence that such combinations
are effective [28]. Such combinations can lead to drug-drug interactions which are sometimes fatal.
Moreover, antipsychotics are used a lot “off-label” for indications they have not been approved for, and
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where they might do more harm than good [15]. If the frequency, causes and risk factors for sudden
death and serious adverse events were better understood, preventive measures could be undertaken
to avoid them.
The major significance for further clinical research that could result from the project is an obligation to
better report in subsequent clinical trials, because we have an impression that death and serious
adverse events are not consistently reported in paper publications so that we will also go back to the
manufacturers. Finally, the review may to some extent contribute to methodological progress in the
field of systematic reviews because we will have to pay special statistical attention to the problem of
rare events (see 5. Statistical Analysis).
2.4
PATIENT PARTICIPATION
A consensus of patients and care givers organised by The James Lind Organisation and published in
Nature lists the question as to whether the efficacy of antipsychotics outweighs their side-effects as
one of 10 research priorities in schizophrenia [8]. One of the 10 questions is whether the efficacy of
antipsychotics outweighs their side-effects. Efficacy and frequent, “milder” side-effects are well
understood, among others by previous reviews of our group [4]. Death is the worst “adverse event”
that can occur, and ICP-GCP defined other serious adverse events will be secondary outcomes in our
review. Therefore, we feel that we address a priority concern of patients. Moreover, we contacted a
German patient organization (Münchner Psychiatrie-Erfahrene (MüPE) e.V.) and discussed with the
Secretary, Mr. G. Wörishofer, that we will involve the organization at a protocol stage to assure that
the review will be relevant for patients.
3.
THE MEDICAL PROBLEM
3.1
EVIDENCE
There are many reviews on the effects of single antipsychotics compared to placebo in various
disorders (e.g. [4]), but death was usually not an outcome in them, in part because the authors were
probably aware that if they looked at the effects of single drugs the data would be underpowered.
Exceptions are reviews from the Cochrane Schizophrenia Group on single antipsychotics which as
expected did not find significant differences as they were underpowered. Only a meta-analysis on
behavioral disturbances in dementia documented an increased mortality associated with
antipsychotics [21]. These findings support our proposal in that a large systematic review across
indications might demonstrate an increased risk for mortality and other serious adverse events to be
associated with antipsychotics also in younger people and in other disorders than dementia.
As explained under “Evidence” (point 2.3 above), the non-randomised, observational evidence on
whether antipsychotics increase mortality, which ones have the most increased risk and whether there
are other risk factors (e.g. polypharmacy, dose, age) is in part contradictory and there are many
unknown confounders which can only be controlled for by randomisation. As (sudden) death is a rare
outcome in (often short-term) antipsychotic drug trials a systematic review across indications is
needed, which will be accompanied by subgroup analyses of different diagnoses, drugs and effect
modifiers such as age (e.g. different indications, combinations, see below). Similar reviews across
indications have already been successfully conducted on SSRIs and demonstrated an age related
suicidality risk [7]. In addition, we will also examine other serious adverse events according to “Good
Clinical Practice” (GCP) for a broader appraisal of severe side-effects.
The clinical relevance of the findings is that psychiatrists currently often use antipsychotics in an
irrational, potentially dangerous way (e.g. not evidence-based combinations being the rule rather than
the exception [1], frequent off-label use etc., also see 2.3 above) which can even increase mortality.
Rare, but sometimes serious, adverse events can get overlooked by single RCTs. The proposed large
scale, class-review of antipsychotics could help to understand the reasons for death and other serious
adverse events better, so that preventive measures could be taken and harm be avoided.
3.2
STRATEGIES FOR THE DISSEMINATION OF RESULTS
We will produce a very large review with approximately 50000 participants. The research question is a
priority for patients with schizophrenia and it is important for many other psychiatric patient groups for
which antipsychotics have indications or are used “off-label”. Therefore, it is likely that we will be able
to publish the results in a general medicine journal with high visibility such as the BMJ or the Lancet in
which other reviews of our group have already been published [29, 30, 31, 32]. It can be expected that
our findings will be rapidly implemented in national and international treatment guidelines. For
example, Stefan Leucht is a member of the group producing the schizophrenia and depression
guidelines of the German national psychiatric association (DGPPN) and of the British Association of
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Psychopharmacology, and he is leading the schizophrenia guideline group of the Collegium
Internationale Psychopharmacologicum (CINP). The relevance for patients decision making can for
example be that they might want to be especially careful if they have risk factors and then prefer drugs
that are safer than others. The economic impact is that antipsychotic drugs are a 14.8 billion USD
worldwide market (http://www.bccresearch.com/report/antipsychotic-drugs-markets-phm063a.html)
[33] and that they are often used off-label which might be restricted in case of demonstrated increased
risks.
4.
JUSTIFICATION OF DESIGN ASPECTS
4.1
POPULATION
The main indication of antipsychotic drugs is schizophrenia, but some of these drugs also have official
indications for bipolar disorder, major depressive disorder and behavioral disturbances in Alzheimer’s
disease (risperidone), and they have been examined by RCTs in multiple off-label indications such as
anxiety, sleep problems, obsessive compulsive disorder or PTSD [15]. As our primary outcome death
is rare in randomised antipsychotic drug trials, we need a large sample size. And to look at the effects
of antipsychotics on death and other serious adverse events across classes is justifiable, because in
contrast to efficacy, adverse effects, especially objective ones such as death, do not depend so much
on the disorder examined. We will therefore include any disorder in the review. There will also be no
restrictions in terms of age, gender, racial origin or other factors. For example, antipsychotic drugs are
used for all age groups, including children with schizophrenia and elderly, and it will be one aim of the
review to examine whether mortality and other serious adverse events are associated with age, as it
was for example the case in suicide risk associated with SSRIs in a similar systematic review across
diagnoses [7]. To include all patients across indications to some extent also increases generalizability
(the risk for (sudden) death of antipsychotics “in general”), but obviously we will also look at important
subgroups such as diagnosis, age, or specific antipsychotic drug, and we will record the diagnostic
codes according to ICD-10 or the DSM-III to V classifications accordingly.
4.2
INTERVENTION
We will include all so-called second-generation (“atypical”) antipsychotic drugs available in the Europe
or the US (amisulpride, aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine,
paliperidone, quetiapine, risperidone, sertindole, ziprasidone), and all first-generation (“typical”)
antipsychotic drugs that were used as additional active arms in comparisons of the second-generation
antipsychotic drugs versus placebo. The reasons why we will focus on this group of drugs are: 1.
Second-generation antipsychotics are in many countries such as the US or Germany nowadays the
most frequently prescribed compounds. 2. Several of them may be associated with side-effects that
may cause (sudden) death such as QTc prolongation, hyperglycemic coma, thromboembolism,
seizures etc. 3. As there is a debate whether there is a difference between second-generation and
first-generation antipsychotics in this regard we will also include first-generation drugs that were used
as additional active arms in these trials (usually haloperidol [4], the most frequently used firstgeneration antipsychotic in Germany [34]). 4. Importantly, the introduction of these second-generation
antipsychotics in the early 1990s was accompanied by a change in the way randomised schizophrenia
trials are conducted. Previously studies were often conducted by academics, they were single center
and usually small [35]. To obtain data on mortality from these old studies, which might not have been
reported properly in the original publications would be difficult. In contrast, the second-generation
antipsychotics were examined in a wave of large-scale, placebo-controlled trials (placebo-control is
recommended by the FDA and by the EMA in this area) organized by the pharmaceutical industry.
These trials followed stringent protocols and the recording of serious adverse events was a legal
obligation by ICP-GCP rules. We will include all these antipsychotics irrespective of their formulation,
including oral, intravenous and depot formulations, because our research question is not restricted to
oral preparations of these drugs. We will also include any doses, and both fixed-dose and flexibledose designs.
4.3
COMPARATOR(S)
The comparator will be placebo or ‘no treatment’. We would include open RCTs that use ‘no treatment’
as a comparator rather than placebo, because the primary outcome mortality is an objective one for
which blinding is not so important [36], but it is clear that there will be few such trials, the vast majority
will be placebo-controlled.
4.4
OUTCOMES
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1. Death due to any reason (primary outcome)
The primary outcome will be death due to any reason (i.e. including natural causes of death but also
suicides and accidents. This is the worst outcome that can happen and there is conflicting evidence
from observational data that antipsychotics could increase mortality [22]. On the other hand
antipsychotics could also reduce suicide. Despite its importance it has not been used much so far,
because it is a rare event so that reviews that look at individual drugs were underpowered.
2. Death due to natural causes
The criticism of antipsychotics is that they might be associated with (sudden) unexpected death due to
cardiac arrhythmias, thromboembolism, strokes and other factors. The specific reasons of death will
be recorded, and requested from the pharmaceutical companies.
3. Death due to suicide
It is possible that antipsychotics reduce suicide risks [23], but they could also increase the risk, e.g. by
antipsychotic induced depression.
4. Serious adverse events
It is mandatory by the guideline for Good Clinical Practice from the The International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICHGCP, http://www.ich.org/) to record and report serious adverse events from pharmacological trials. We
learned in a personal communication from Thomas Laughren, MD, who has previously led the
neuroscience division of the FDA, that in the US these rules have been in practice for more than 30
years. Therefore, information on these important outcomes will be available, because even if not in the
original publications, pharmaceutical companies who will in almost all occasions have conducted the
clinical trials in question, will have them recorded. These are:
a) Death (already covered, see above)
b) Life-threatening adverse events. In addition to the number of participants with “any lifethreatening adverse events” we will also analyse the single SAEs separately, e.g. arrhythmias,
stroke, pulmonary embolism, neuroleptic malignant syndrome, diabetic ketoacidosis, severe
allergic reactions etc.
c) Hospitalization (initial or prolonged). We will attempt to obtain the reasons for hospitalisation,
because hospitalisations can be due to exacerbations of the psychiatric disorder (disease
related adverse event) or due to side-effects (drug related adverse event). The latter are the
ones of interest of our review.
d) Disability - significant, persistent, or permanent change, impairment, damage or disruption in
the patient's body function/structure, physical activities or quality of life.
e) Congenital anomaly. This outcome will be extremely rare, because women are only included
in such trials if they use contraception. We include it only for consistency with the concept of
severe adverse events.
f) Requires Intervention to Prevent Permanent Impairment or Damage (Devices)
g) Other Serious Adverse Events (Important Medical Events): events that do not fit the other
outcomes, but may jeopardize the patient and may require medical or surgical intervention
(treatment) to prevent one of the other outcomes.
If not available, we will ask the study authors/manufacturers for descriptions of these serious adverse
events which will enable us to classify them correctly. If possible, we will record time of occurrence of
the adverse events which can be important for their understanding. E.g. it could be that certain
adverse events occur soon after initiation of treatment while others occur only with a substantial delay.
5. Drop-out due any reason, adverse events and inefficacy of treatmet
These are the major reasons why participants discontinue trials prematurely. Information on them will
also be needed for risk of bias assessment (see 4.7).
To better understand the risk for death and other serious adverse events associated with antipsychotic
drugs will be important for patients, clinicians and guideline makers. Antipsychotics have many other
“milder” side-effects (e.g. movement disorders, weight gain) which have already been addressed by
systematic reviews and are well understood (e.g. [4]). But the rare, serious adverse events have to
date been neglected by reviews. Death is the worst possible outcome, and the other serious adverse
events follow right after it. As many people are treated with antipsychotic drugs, even numerically
small differences would be important.
4.5
DESIGN OF PRIMARY STUDIES
All randomized trials that compared antipsychotic drugs with placebo or no treatment. Studies whose
sequence generation was at high risk of bias (e.g. randomization by the date of birth) or where
allocation was clearly not concealed will be excluded. As the primary outcome death is objective
blinding is less important [36], but from all the experience we have with antipsychotic drug trials it is
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likely that most studies will be double-blind and placebo-controlled. If unblinded trials exist, they will be
excluded in a sensitivity analysis. We will also include studies in which antipsychotic drugs were added
to another antipsychotics as long as there is a randomised placebo group. In the case of cross-over
studies we will use only the first cross-over phase to avoid the problem of carry-over effects which are
very likely in schizophrenia [37]. We will exclude cluster randomized trials due to the unit-of-analysisproblems associated with this design (it is anyhow unlikely that such studies on our question exist)
[38]. A systematic review of observational trials already exists but meta-analytic pooling was not
possible because the designs were too heterogeneous, and the results were partly contradictory. We
will, therefore, not use observational evidence. We will rather produce a large systematic review of
RCTs across indications of antipsychotics similar to the ones which have already been successfully
conducted on SSRIs (e.g. [7]).
Study quality will be assessed with the risk of bias tool described in the Cochrane Collaboration
Handbook [36]. This tool encourages consideration of how the sequence was generated, how
allocation was concealed, the integrity of blinding, the completeness of outcome data, selective
reporting and other biases. There will be no minimum duration because we also want to include trials
in which antipsychotics were given for short-term sedation. However, very short-term studies (up to
five days, usually on intramuscular or intravenous formulations), short-term results (up to 3 months)
and longer term results (more than 3 months) will also be analysed separately, and if possible we will
record the time of occurrence of the adverse events as described in section 4.4 above.
4.6
SEARCH STRATEGIES
1. We will run electronic searches in the databases MEDLINE, EMBASE, Cochrane Central Register
of Randomised Trials (CENTRAL), BIOSIS, CINAHL, Dissertation Abstracts, LILACS, PSYNDEX,
PsycINFO). Search terms will include the generic names of the second-generation antipsychotics of
interest, terms for randomization and terms for placebo/no treatment control. The exact search
phrases will be detailed with an experienced librarian (Samantha Roberts, who has been for a long
time been the trial search coordinator of the Cochrane Schizophrenia Group). This search will also
include the clinical trial registers clinicaltrials.gov and the WHO’s International Clinical Trials Registry
Platform (ICTRP).
2. We will contact the Cochrane Review Groups in psychiatry to run additional searches in their
registers. So that we can bridge the delay with which these groups forward their material to CENTRAL.
3. We will search the databases of the Food and Drug Administration (FDA) and of the European
Medical Association (EMA). Due to the Freedom of Information Act, the submission dossiers (usually
called “medical reviews”) of the pharmaceutical companies are freely available on the internet. We are
in contact with Philipp Kronstein, the current leader of the neuroscience section of the FDA.
4. We will search the websites of pharmaceutical companies and we will contact them directly by email and telephone. We will ask them to provide the necessary data for all their placebo-controlled
antipsychotic drug trials. It is a legal requirement by ICP-GCP and by the FDA (in the United States it
has been in place for more than 30 years) that Serious Adverse Events must be recorded. Therefore,
the data should be retrievable. Several manufacturers of antipsychotic drugs (EliLilly,
Janssen/Johnson and Johnson, Roche, Glaxo SmithKline) have already officially declared that they
will make data available to the field. Due to the “all trials campaign” (http://www.alltrials.net/) and
similar initiatives pharmaceutical companies are nowadays more open to share their data, and several
of them have sent us data in the past so that we are confident that they will be ready to collaborate
again. Our review is not an individual patient data meta-analysis, but approaching the FDA, EMA and
individual pharmaceutical companies will be important.
5. We will contact the first-authors of all individual included trials for our outcomes of interest, we will
search other systematic reviews such as those of the Cochrane Schizophrenia Group and our own
ones [4] for relevant trials and data, and we will inspect the references of all identified studies for more
trials.
As the abstract books of major conferences are regularly hand searched for the registers of the
Cochrane review groups who forward their results to CENTRAL, an extra hand search will not be
necessary for this review. There will be no language restriction applied concerning the literature
search to avoid a ‘language bias’ [39]. The exclusion of non-English publications would therefore
overestimate the effects [39]. As an exception we will exclude Chinese studies which often do not use
appropriate randomization procedures and do not report their methods so that it is impossible to check
on these issues [40]. Moreover, in Chinese studies there would be an opposite language bias,
because we found that Chinese studies more frequently find significant findings than international
ones [31].
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We estimate from existing reviews that the following numbers of studies and participants will be
available. In schizophrenia, two reviews on acute and maintenance treatment, included 105 studies
with 21238 participants and 65 RCTs with 6493 participants, respectively [4, 30]. A review on acute
treatment of bipolar disorder included 42 placebo-controlled antipsychotic drug trials with at least
11023 participants ([41], Table 1), and another one on maintenance treatment had seven RCTs with
2068 participants [42]. Other relevant reviews are antipsychotic drugs versus placebo for dementia (15
RCTs with 5110 participants [21]), antipsychotic drugs versus placebo for major depressive disorder
(14 RCTs with 3549 participants [43], and a review on RCTs on off-label use of antipsychotic drugs
with 162 RCTs (many studies of which were placebo-controlled [15]). We thus expect that our review
will be based on approximately 250 RCTs with 50000 participants.
4.7
DATA EXTRACTION
We will use the Covidence.org software which has been developed (in part by members of the
Cochrane Collaboration) to ensure high quality of study selection and data extraction.
1. Selection of trials
Two reviewers will independently inspect all abstracts identified in the literature searches.
Disagreement will be resolved by discussion, and where doubt still remains, we will acquire the full
article for further inspection. Once the full articles are obtained, at least two reviewers will
independently decide whether the studies meet the review criteria. If disagreement cannot be clarified
by discussion, we will resolve it with a third reviewer or seek further information from the study
authors.
2. Data extraction
At least two reviewers will independently extract data from all selected trials on simple, standard forms
(prepared for the Covidence Software) which will be piloted on a random sample of ten RCTs. When
disagreement arises we will resolve it by discussion with a third reviewer. Where this is not possible
we will contact the study authors.
3. Risk of bias assessment
Again working independently, two reviewers will assess risk of bias using the tool described in the
Cochrane Handbook for Systematic Reviews of Interventions [36]. This tool encourages consideration
of how the sequence was generated, how allocation was concealed, the integrity of blinding at
outcome, the completeness of outcome data, selective reporting, and other biases.
4. Data entry
The quality of data entry will be assured by independently entering the data by two reviewers in the
Covidence.org software, the software automatically detects discrepancies which will be resolved as
explained above.
5.
STATISTICAL ANALYSES
The statistical analysis has been planned by Georgia Salanti, PhD, University of Ioannina, who is CoConvenor of the Cochrane Statistical Methods Group.
1. Effect size measures:
All our outcomes will be dichotomous. The effect size measure will be the odds ratio (OR) and its 95%
confidence intervals (CIs) for its better mathematical properties; note that for infrequent events OR and
risk ratio are expected to be similar. We will calculate the number needed to treat to provide benefit /to
induce harm, and its 95% confidence interval (CI) for all outcomes with the software Grade Pro which
will also be used to produce a Summary of Findings Table (see below). Analyses will be carried out in
accordance to the ‘intention-to-treat’ principal when possible (‘once randomized always analyze’).
Everyone allocated to the intervention will be counted whether they completed the follow up or not. As
all outcomes of interest (serious adverse events) are rare we will assume for those who have been lost
to follow-up that they will not have had the outcome (unless it occurred before dropping out), because
other strategies would overestimate the risk because the outcomes are rare.
2. Data synthesis in the context of rare events:
Death and other severe adverse events are likely to be infrequent and individual trials may have few or
no events, a situation often referred to as rare events. Conventional meta-analysis methods rely on
large sample approximation and hence are inappropriate for rare outcomes and may produce unstable
estimates as a result of difficult-to-estimate variance [44]. Methods that add minimal information to
zero events and enable variance calculations been suggested (e.g. the “empirical continuity
correction” or the “reciprocal of the opposite arm size”) and their application will allow the inclusion of
studies with zero events in one of the arms in meta-analysis [45] However, such methods are not
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recommended for studies with zero events in both arms, which are typically excluded from the metaanalysis despite the fact that they provide information about the lack of adverse events.
We will therefore apply Bayesian approaches which provide a natural framework for handling sparse
data events and which have been advocated in a recent Institute of Medicine report for evaluating
safety issues of marketed pharmaceutical products [46]. In a Bayesian framework, we will use the
binomial likelihood to model the number of events, which accommodates zero events in one or both
study arms and bypasses computational problems with the estimation of the study variance.
We will primarily use a random effects model when pooling the data, but we will examine in a
sensitivity analysis whether a fixed effects model leads to essentially different results. In case they are
substantially different, we will explore whether small studies yield different results from larger studies
and we will consider a meta-regression model for small study effects using a function of the sample
size as covariate. We will use non-informative priors for location parameters and informative priors for
the heterogeneity parameter (see next section).
4. Assessment of heterogeneity
Another problem with rare events is the difficulty to estimate heterogeneity. The uncertainty is large
and it has been shown that conventional tests for heterogeneity have very low power while some
methods to estimate the between-study variance perform better than other [47]. To improve estimation
we will use informative priors for heterogeneity as recently derived in a large empirical study [48].
5. Subgroup analyses
We will primarily examine the effects of antipsychotic drugs across indications, drugs and age groups.
The following subgroup analyses will be conducted to explore reasons for heterogeneity and to identify
patients most at risk.
a) Diagnostic subgroups: schizophrenia, bipolar disorder, depression, dementia, other
b) Individual antipsychotic drugs, and first-generation versus second-generation antipsychotics
c) Age groups: Children and adolescents (e.g. up to 17 years, adults 18-65 years, elderly >65 years)
d) Antipsychotic doses in olanzapine equivalents according to Gardner et al. [49]
e) Studies in which antipsychotics were combined or added to other drugs versus monotherapy
studies (the risk may be higher in the former)
6. Sensitivity analyses
The following sensitivity analyses of the primary outcome are planned a priori: a) random-effects
instead of fixed effects model, b) exclusion of open RCTs, c) exclusion of studies that used doses
higher than in the official labels (“off-label doses”).
7. Summary of findings table
We anticipate including the following main outcomes in a summary of findings table using the software
GRADEpro : 1. All cause mortality. 2. Death due to natural causes. 3. Suicide. 4. Any life-threatening
adverse events. 5. Adverse events leading to disability. 6. Hospitalisation, 7. Other serious adverse
events. GRADE will also be used to calculate the numbers needed to treat to provide benefit /to
induce harm, and its 95% confidence interval (CI) and its 95% confidence interval (CI).
8. Publication bias
We will examine potential publication bias by ‘contour enhanced funnel-plots’ [50]. The problem of
conventional statistical tests to analyze funnel-plot asymmetry such as that by Egger et al. 1997 is that
they cannot distinguish between asymmetry that is due to publication bias and asymmetry that is due
to other factors such as heterogeneity or lower quality of small trials. In ‘contour enhanced funnelplots’ contour lines representing conventional significance levels (e.g. p-values <0.01, <0.05) are
drawn in the funnel plot. If missing studies are found in areas of statistical non-significance this
indicates that the source of funnel plot asymmetry is publication bias rather than other possible factors.
We will need to adapt the funnel plots for studies with zero events (for which the variance is difficult to
estimate) by using a) various continuity correction factors to estimate the study variance b) a function
of the total sample size as a proxy to study precision
9. Statistical software
The analysis will be performed using WinBUGS (MRC Biostatistics Unit, Cambridge, U.K.,
http://www.mrcbsu cam.ac.uk/bugs/winbugs/contents.shtml).
6.
#
EXPERTISE
Name
Affiliation
Prof. Dr. med.
Stefan Leucht (and
team: Dr. Myrto
Samara, Dr.
Clinical expertise (consultant psychiatrist
Klinikum rechts
responsible for a schizophrenia ward) and
der Isar der TUmethodological expertise (SL is associate
München
editor to the Cochrane Schizophrenia Group
Version 09.04.2013
Role
Signature
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Markus Dold,
Maximilian Huhn,
Dr. Claudia Leucht)
Samantha Roberts
University of
Nottingham
and has published numerous systematic
reviews). Has a working group of four people
with experience in systematic reviews.
Librarian, was the trial search coordinator of
the Cochrane Schizophrenia Group for
years.
Department of
Statistical expertise (PhD statistician
Hygiene and
Georgia Salanti,
specialized in meta-analysis, Co-convenor of
Epidemiology,
PhD
Cochrane Collaboration Statistical Methods
University of
Group)
Ioannina
Prof. Dr. Stefan Leucht is a consultant psychiatrist and an editor of the Cochrane Schizophrenia Group
[51]. Several members of his working group have experience in meta-analysis (Dr. Markus Dold,
Magdolna Tardy, MSc, Maximilian Huhn, Dr. Claudia Leucht). His team has published over 30
systematic (Cochrane) reviews in the field of psychiatry in renowned journals, among others four in the
Lancet [29, 30, 31, 32] and several in the Cochrane Library. He has also co-directed the “Service
Centre Cochrane Meta-analyses” within the Network of Competence Schizophrenia sponsored by the
BMBF. He has successfully led his team to conduct the following systematic reviews funded by the
BMBF: Head-to-head comparisons of second-generation antipsychotics for schizophrenia (Project
number: 01KG0606), Maintenance treatment with antipsychotic drugs for schizophrenia (Project
number 01KG0816) and Second-generation antipsychotics for depression, anxiety disorders and
obsessive compulsive disorder (project number: 01KG0818), amitriptyline vs placebo for major
depressive disorder. He won the ‘David Sackett Award’ of the German Network of Evidence-Based
Medicine in 2010.
Samantha Roberts is a librarian who has served for many years as the trial search coordinator of the
Cochrane Schizophrenia Group and will develop the search term.
Dr. Salanti PhD is the co-convenor of the Cochrane Collaboration’s Statistical Method Group and a
member of the Comparing Multiple Interventions Methods Group. She is specialized in meta-analytic
statistics and has experience with the method in the field of schizophrenia [29].
7.
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