haloperidol discontinuation for schizophrenia (protocol)

Haloperidol discontinuation for schizophrenia (Protocol)

Essali A, Turkmani K, Aboudamaah S, AbouDamaah A, Dia’a Aldeen MR, Marwa ME,

AlMounayer N

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane

Library 2014, Issue 12

http://www.thecochranelibrary.com

Haloperidol discontinuation for schizophrenia (Protocol)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iHaloperidol discontinuation for schizophrenia (Protocol)


[Intervention Protocol]

Haloperidol discontinuation for schizophrenia

Adib Essali1, Khaled Turkmani2 , Shaimaa Aboudamaah2 , Alaa AbouDamaah3 , Mohammad Reyad Dia’a Aldeen2, Mohamad Essam

Marwa2 , Nawar AlMounayer2

1Manaaki Centre, Waikato District Health Board, Thames, New Zealand. 2Faculty of Medicine, Damascus University, Damascus,

Syrian Arab Republic. 3Damascus Health Unit, Damascus University, Damascus, Syrian Arab Republic

Contact address: Adib Essali, Manaaki Centre, Waikato District Health Board, crn Rolleston and Mary Streets, Thames, 3575, New

Zealand. [email protected]. [email protected].

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: New, published in Issue 12, 2014.

Citation: Essali A, Turkmani K, Aboudamaah S, AbouDamaah A, Dia’a Aldeen MR, Marwa ME, AlMounayer N. Haloperi-

dol discontinuation for schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD011408. DOI:

10.1002/14651858.CD011408.


A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:

To review the effects of haloperidol discontinuation in people with schizophrenia who are stable on haloperidol.

B A C K G R O U N D

Description of the condition

Schizophrenia is often a chronic and disabling psychiatric disor-

der. It afflicts approximately one percent of the population world-

wide with little gender differences (Berger 2003). The median

incidence of schizophrenia was 15.2/100,000 persons (McGrath

2008). The typical manifestations of schizophrenia are ’positive’

symptoms such as fixed, false beliefs (delusions) and perceptions

without cause (hallucinations); ’negative’ symptoms such as apa-

thy and lack of drive, disorganisation of behaviour and thought;

and catatonic symptoms such as mannerisms and bizarre postur-

ing (Carpenter 1994). The degree of suffering and disability is

considerable, with 80% to 90% not working (Marvaha 2004), and

up to 10% dying by suicide (Tsuang 1978).

Description of the intervention

Haloperidol is one of the most frequently used antipsychotic com-

pounds (Lohse 2009). It is a first-generation (’typical’, ’conven-

tional’) antipsychotic drug with very high antidopaminergic ac-

tivity. Its mean elimination half-life has been reported to range

from 15 to 37 hours and its bioavailability is 60% to 70% (Kudo

1999). Haloperidol is highly effective in treating schizophrenia,

but the downside is that it is associated with severe extrapyrami-

dal side effects. The most predominant among these extrapyra-

midal side effects are dystonia, parkinsonian-like syndrome, and

tardive dyskinesia. Other side effects include anticholinergic ef-

fects (e.g. constipation, dry mouth, blurred vision, and urinary

hesitancy), sexual dysfunction, elevations in serum prolactin, se-

dation and there could even be shown a relationship with sudden

death. Therefore, clinicians and people with schizophrenia often

face a trade-off between protection against psychotic episodes and

adverse effects.

Haloperidol is effective in treating the acute phases of schizophre-

nia (Irving 2006). However, it remains unclear how long haloperi-

1Haloperidol discontinuation for schizophrenia (Protocol)


mailto:[email protected]

mailto:[email protected]

dol treatment should continue after the acute phase of the illness

subsides. The intervention studied in this review is the discon-

tinuation of haloperidol in people with schizophrenia who have

already responded to haloperidol treatment.

How the intervention might work

Haloperidol is one of the butyrophenone family of antipsy-

chotic (neuroleptic) drugs (López-Munoz 2009). It is thought that

haloperidol prevents the occurrence of delusions and hallucina-

tions by blocking the dopamine D2 receptors in the meso-cortico-

limbic system. A similar antidopaminergic activity in the dorsolat-

eral striatum may contribute to the adverse extrapyramidal effects

that are associated with haloperidol treatment (Xiberas 2001).

Why it is important to do this review

Although schizophrenia is generally thought to be a lifelong disor-

der requiring long-term pharmacological treatment (Essali 1993),

the course of schizophrenia varies, and may follow one of four

patterns (Shepherd 1989):

1. 13% may have a single episode with no subsequent

impairment;

2. 30% may have several episodes with no or minimal

impairment;

3. 10% may suffer impairment following the first episode with

occasional exacerbation of symptoms and no return to normality;

4. 47% show impairment increasing after each exacerbation.

Presently, it is impossible to predict the course of schizophrenia.

Medication cessation studies may help identify the characteristics

of those patients who will have a single episode and not require

maintenance drug treatment, those who will follow a relapsing

course and may benefit from intermittent treatment, and those

who require inde nite maintenance drug treatment. In this re-

view, we aim to investigate the quantitative effects of stopping

haloperidol for people stable on this drug by reviewing available

trial-based evidence.

O B J E C T I V E S

To review the effects of haloperidol discontinuation in people with

schizophrenia who are stable on haloperidol.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All relevant randomised controlled trials (RCTs).

If a trial is described as ’double blind’ but implies randomisa-

tion, we will include such trials in a sensitivity analysis (Sensitivity

analysis). If their inclusion does not result in a substantive differ-

ence, 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.

We will exclude quasi-randomised studies, such as those allocating

by alternate days of the week. Where people are given additional

treatments, we will only include data if the adjunct treatment is

evenly distributed between groups and it is only the haloperidol

that is randomised.

Types of participants

Adults, however defined, with schizophrenia or related disorders,

including schizophreniform disorder, schizoaffective disorder and

delusional disorder, again, by any means of diagnosis, who are on

stable doses of haloperidol (oral or injection).

We are interested in making sure that information is as relevant

to the current care of people with schizophrenia as possible so

propose to clearly highlight the current clinical state (acute, early

post-acute, partial remission, remission) as well as the stage (pro-

dromal, first episode, early illness, persistent) and as to whether

the studies primarily focused on people with particular problems

(for example, negative symptoms, treatment-resistant illnesses).

Types of interventions

1. Discontinuation of haloperidol treatment, however this is

done in the trials, e.g. gradually, abruptly or under cover of

placebo

2. Continuation of haloperidol treatment at any dose or mode

of administration (oral or by injection)

Types of outcome measures

We will divide all outcomes into short-term (up to three months),

medium-term (over three and up to six months) and long-term

(over six months).

Primary outcomes

1. Global state

1.1 Global state improvement

1.2 Relapse - as defined by each study



Secondary outcomes

1. Death - suicide and natural causes

2. Global state

2.1 Average endpoint global state score

2.2 Average change in global state scores

3. Service outcomes

3.1 Hospitalisation

3.2 Inability to be discharged from hospital

4. Mental state (with particular reference to the positive and

negative symptoms of schizophrenia)

4.1 Clinically important change in general mental state

4.2 Average endpoint general mental state score

4.3 Average change in general mental state scores

4.4 Clinically important change in specific symptoms (positive

symptoms of schizophrenia, negative symptoms of schizophrenia,

depression, mania)

4.5 Average endpoint specific symptom score

4.6 Average change in specific symptom scores

5. General functioning

5.1 Clinically important change in general functioning including

working ability

5.2 Average endpoint general functioning score

5.3 Average change in general functioning scores

5.4 Clinically important change in specific aspects of functioning,

such as social or life skills

5.5 Average endpoint specific aspects of functioning, such as social

or life skills

5.6 Average change in specific aspects of functioning, such as social

or life skills

6. Behaviour

6.1 Clinically important change in general behaviour

6.2 Average endpoint general behaviour score

6.3 Average change in general behaviour scores

6.4 Clinically important change in specific aspects of behaviour

6.5 Average endpoint specific aspects of behaviour

6.6 Average change in specific aspects of behaviour

7. Adverse effects - general and specific (Important adverse

effects included movement disorders, weight gain, fits and

blood reactions leading to therapy discontinuation)

7.1 Clinically important general adverse effects

7.2 Average endpoint general adverse effect score

7.3 Average change in general adverse effect scores

7.4 Clinically important specific adverse effects

7.5 Average endpoint specific adverse effects

7.6 Average change in specific adverse effects

8. Satisfaction with treatment (including subjective well-

being and family burden)

8.1 Leaving the studies early

8.2 Recipient of care not satisfied with treatment

8.3 Recipient of care average satisfaction score

8.4 Recipient of care average change in satisfaction scores

8.5 Carer not satisfied with treatment

8.6 Carer average satisfaction score

8.7 Carer average change in satisfaction scores

9. Quality of life

9.1 Clinically important change in quality of life

9.2 Average endpoint quality of life score

9.3 Average change in quality of life scores

9.4 Clinically important change in specific aspects of quality of

life

9.5 Average endpoint specific aspects of quality of life

9.6 Average change in specific aspects of quality of life

10. Economic outcomes

10.1 Direct costs

10.2 Indirect costs

11. Cognitive functioning

11.1 Clinically important change in cognitive functioning

11.2 Average endpoint cognitive functioning score

11.3 Average change in cognitive functioning scores

11.4 Clinically important change in specific aspects of cognitive

functioning

11.5 Average endpoint specific aspects of cognitive functioning

11.6 Average change in specific aspects of cognitive functioning

12. Summary of findings table

We will use the Grading of Recommendations Assessment, De-

velopment and Evaluation (GRADE) approach to interpret find-

ings (Schünemann 2011). We will use the software GRADEpro

(GRADEpro) to import data from the Cochrane Collaboration



http://tech.cochrane.org/gradepro

statistical software, Review Manager (RevMan), 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 rate 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. Global state

1.1 Global state improvement (any time frame).

1.2 Relapse as defined by each study (any time frame).

2 . Mental state

2.1 Clinically important change in general mental state (any time

frame).

3. General functioning

3.1 Clinically important change in general functioning including

working ability (any time frame).

4. General behaviour

4.1 Clinically important change in general behaviour (any time

frame).

5. Quality of life

5.1 Clinically important change in quality of life (any time frame).

Search methods for identification of studies

Electronic searches

1. Cochrane Schizophrenia Group Specialised Register

The Trials Search Co-ordinator of the Cochrane Schizophrenia

Group will search the Group’s Specialised Reg-

ister (http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/

SCHIZ/frame.html) using the following search terms:

• (haloperi* or R-1625 or haldol* or alased* or aloperidi* or

bioperido* or buterid* or ceree* or dozic* or duraperido* or

fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or

zafri*) in Title or Abstract of REFERENCE or (haloperi* or R-

1625 or haldol* or alased* or aloperidi* or bioperido* or

buterid* or ceree* or dozic* or duraperido* or fortuna* or serena*

or serenel* or seviu* or sigaperid* or sylad* or zafri*) in

Intervention of STUDY

The Cochrane Schizophrenia Group’ss Specialised Register 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.

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.

Data collection and analysis

Selection of studies

All seven review authors will independently scrutinise the abstracts

of retrieved studies. Where disputes arise, we will acquire the full

reports for more detailed scrutiny. All seven authors will inspect

the full reports of the abstracts meeting the review criteria will be

inspected by all seven review authors in order to ensure reliable

selection. Where it is not possible to resolve disagreement by dis-

cussion, one author (AE) will act as the final arbiter and we will

attempt to contact the authors of the study for clarification.

Data extraction and management

1. Extraction

Four authors (KT, SAD, AAD, MRDA) will extract data from

all included studies. In addition, to ensure reliability, two authors

(MEM, NAM) will independently extract data from all included

studies. We will discuss any disagreement will be discussed, deci-

sions documented and, if necessary, we will contact the authors

of studies for clarification. With any remaining problems, one au-

thor (AE) will help clarify issues and we will document these final

decisions.

We will extract data presented only in graphs and figures wherever

possible, but they will only be included if two authors indepen-

dently reach the same result. We will attempt to contact authors



http://tech.cochrane.org/revman

http://onlinelibrary.wiley.com/o/cochrane/clabout/articles/SCHIZ/frame.html









through an open-ended request in order to obtain missing infor-

mation or for clarification whenever necessary. For Multicentre

studies, where possible, we will extract data relevant to each com-

ponent 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:

1. the psychometric properties of the measuring instrument

have been described in a peer-reviewed journal (Marshall 2000);

and

2. 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 a self-report or

completed by an independent rater or relative (not the therapist).

We realise that this is not often reported clearly, and we will include

the relevant information in the ’Description of studies’ section in

the full review.

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.

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 will use mean differ-

ences (MDs) rather than standardised mean differences (SMDs)

throughout (Higgins 2011).

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 following stan-

dards to all data before inclusion:

1. standard deviations (SDs) and means are reported in the

paper or obtainable from the authors;

2. when a scale starts from the finite number zero, the SD,

when multiplied by two, is less than the mean (as otherwise the

mean is unlikely to be an appropriate measure of the centre of

the distribution (Altman 1996);

3. if a scale started from a positive value (such as the Positive

and Negative Syndrome Scale) , which can have values from 30

to 210) (Kay 1986), 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.

Endpoint scores on scales often have a finite start and end point

and these rules can be applied. Skewed data pose less of a problem

when looking at means if the sample size is large (> 200) and

we will enter these into the syntheses. We will present skewed

endpoint data from studies of less than 200 participants as ’other

data’ within the data and analyses section rather than enter such

data into statistical analyses.

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 analyses.

2.5. Common measure

To facilitate comparison between trials, we intend to convert vari-

ables that can be reported in different metrics, such as days in hos-

pital (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 every effort to convert outcome

measures to dichotomous data. This can be achieved by identi-

fying cut-off points on rating scales and dividing participants ac-

cordingly 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 or the Posi-

tive and Negative Syndrome Scale (Kay 1986; Overall 1962), this

could be considered as a clinically significant response (Leucht

2005a; Leucht 2005b). If data based 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 haloperidol discontinuation. Where keeping to this makes it

impossible to avoid outcome titles with clumsy double-negatives

(e.g. ’Not improved’), we will report data where the left of the

line indicates an unfavourable outcome. We will note this in the

relevant graphs.

Assessment of risk of bias in included studies

Review authors (KT, SAD, AAD, MRDA, MEM and NAM) will

work independently to assess risk of bias using criteria described

in the Cochrane Handbook for Systemic reviews of Interventions



(Higgins 2011). This set of criteria is based on evidence of as-

sociations between overestimate of effect and high risk of bias of

the article such as sequence generation, allocation concealment,

blinding, incomplete outcome data and selective reporting.

We will resolve any disagreement by consensus, with the involve-

ment of an arbiter (AE). Where inadequate details of randomisa-

tion and other characteristics of trials are provided, we will contact

authors of the studies in order to obtain further information. We

will report non-concurrence in quality assessment, but if disputes

arise as to which category 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 a ’Summary of findings’ table.

Measures of treatment effect

1. Binary data

For binary outcomes, we will calculate standard estimation of the

risk ratios (RRs) and their 95% confidence intervals (CIs). It has

been shown that RR is more intuitive than odds ratios (ORs)

(Boissel 1999), and that ORs tend to be interpreted as RRs by

clinicians (Deeks 2000). The number needed to treat (NNT) or

number needed to harm (NNH) statistics with their CIs are intu-

itively attractive to clinicians, but they are problematic in terms of

accurate calculation in meta-analyses and their subsequent inter-

pretation (Hutton 2009). For binary data presented in the ’Sum-

mary of findings’ tables, where possible, we will calculate illustra-

tive comparative risks.

2. Continuous data

For continuous outcomes, we will estimate MDs between groups.

We prefer not to calculate effect size measures (SMDs). 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. If SMDs are used, this will only

be calculated for endpoint data.

Unit of analysis issues

1. Cluster trials and cross-over trials

We do not anticipate that drug discontinuation studies would use

cluster randomisation or cross-over designs, and in the unlikely

event that we do encounter such designs, we will use methods de-

scribed in the Cochrane Handbook for Systemic reviews of Interven-

tions to avoid ’Unit of analysis’ issues in data synthesis (Higgins

2011).

2. 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, these will be simply added and combined within

a two-by-two table. If data are continuous, we will combine data

following the guidance in the Cochrane Handbook for Systemic re-

views of Interventions (Higgins 2011). Where the additional treat-

ment arms are not relevant, we will not use these data.

Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow-up, data must lose credibility (Xia

2009). We choose that, for any particular outcome, should more

than 50% of data be unaccounted for, we will not reproduce these

data or use them within analyses (except for the outcome ’leaving

the study early’). 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 mark

such data with an asterisk (*) to indicate that such a result may

well be prone to bias.

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, the rate of those who stay in the study - in

that particular arm of the trial - will be used 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 (SDs)

If SDs 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 (SE) and CIs 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

Systemic reviews of Interventions (Higgins 2011):

• when only the SE is reported, SDs are calculated by the

formula: SD = SE * square root (n).

The Cochrane Handbook for Systemic reviews of Interventions

presents detailed formula for estimating SDs from P values, t or

F values, CIs, ranges or other statistics (Higgins 2011). If these

formula do not apply, we will calculate the SDs according to a

validated imputation method which is 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 validity of the imputations in a

sensitivity analysis excluding imputed values.

3.3. Last observation carried forward (LOCF)

We anticipate that in some studies the method of last observation

carried forward (LOCF) will be employed within the study report.

As with all methods of imputation to deal with missing data,

LOCF introduces uncertainty about the reliability of the results

(Leucht 2007). Therefore, where LOCF data have been used in

the trial, if less than 50% of the data have been assumed, we will

present and use these data and indicate that they are the product

of LOCF assumptions.

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 discuss these in detail.

3. Statistical heterogeneity

3.1. Visual inspection

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

I2 depends on both the magnitude and direction of effects as well

as the strength of evidence for heterogeneity (e.g. P value from Chi2 test, or CIs for I2). We will interpret I2 estimates greater than

or equal to around 50% accompanied by a statistically significant

Chi2 statistic as evidence of substantial levels of heterogeneity (

Higgins 2011). 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 find-

ings is influenced by the nature and direction of results. These are

described in greater detail in the Cochrane Handbook for Systemic

reviews of Interventions (Higgins 2011). We will try to locate pro-

tocols of included randomised trials. If the protocol is available, we

will compare outcomes in the protocol to those 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 actual

reported results.

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 detail in the Cochrane Handbook

for Systemic reviews of Interventions (Higgins 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

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 choose a fixed-effect model for all analyses. The reader is,

however, able to choose to inspect the data using the random-

effects model.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses

Clinical state, stage or problem

We propose to undertake this review and provide an overview

of the effects of haloperidol discontinuation for people with

schizophrenia in general. In addition, we will try to report data

on subgroups of people in the same clinical state, stage and with

similar problems.

2. Investigation of heterogeneity

If inconsistency is high, we will report this in the full review.

First, we will investigate whether data has been entered correctly.

Second, if data is correct, we will visually inspect the graph and

we will remove studies outside of the company of the rest to see if

homogeneity is restored.

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 described

in some way as to imply randomisation. For the primary outcomes,

we will include these studies and if there is no substantive difference

when the implied randomised studies are added to those with

better description of randomisation, then we will employ all data

from these studies.

2. Assumptions for lost binary data

Where assumptions have to be made regarding people lost to fol-

low-up (Dealing with missing data), we will compare the findings

of the primary outcomes when we use our assumptions 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 data

(Dealing with missing data), we will compare the findings of the

primary outcomes when we use our assumptions and when we

use data only from people who complete the study to that point.

We will undertake a sensitivity analysis to test 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

meta-analysis of the primary outcome. If the exclusion of trials at

high risk of bias does not substantially alter the direction of effect

or the precision of the effect estimates, we will include data from

these trials in the analysis.

4. Imputed values

We will undertake a sensitivity analysis to assess the effects of in-

cluding data from trials where we used imputed values. If sub-

stantial differences are noted in the direction or precision of effect

estimates in any of the sensitivity analyses listed above, we will not

pool data from the excluded trials with the other trials contribut-

ing to the outcome, but will present them separately.

5. Fixed-effect and random-effects model

We will synthesise all data using a fixed-effect model. However, we

will also synthesise data for the primary outcome using a random-

effects model to evaluate whether this alters the significance of the

results.

A C K N O W L E D G E M E N T S

We are grateful to the Association for Evidence-based Medicine

(http://www.a4ebm.org/) for the training courses on conducting

systematic reviews and for the ongoing support.

The Cochrane Schizophrenia Group Editorial Base in Notting-

ham produces and maintains standard text for use in the Methods

section of their reviews. We have used this text as the basis of what

appears here and adapted it as required.

The search term was developed by the Trials Search Co-ordinator

of the Cochrane Schizophrenia Group, Farhad, and the contact

author of this protocol.



http://www.a4ebm.org/



We would like to thank Farooq Naeem and Shuo Xiang for peer

reviewing this protocol.

R E F E R E N C E S

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C O N T R I B U T I O N S O F A U T H O R S

All authors contributed to writing this protocol and approved the final version.

D E C L A R A T I O N S O F I N T E R E S T

All authors have no known conflict of interest.

S O U R C E S O F S U P P O R T

Internal sources

• Association for Evidence-based Medicine, Damascus, Syrian Arab Republic.

Training on writing Cochrane reviews, and ongoing support

• Manaaki Centre, Waikato District Health Board, Thames, New Zealand.

• Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic.

• Damascus Health Unit, Damascus University, Damascus, Syrian Arab Republic.

External sources

• No sources of support supplied



haloperidol discontinuation for schizophrenia (protocol)

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