Cochrane Database of Systematic Reviews (Reviews) || Anticholinergic medication for non-clozapine...

Anticholinergic medication for non-clozapine neuroleptic-

induced hypersalivation in people with schizophrenia (Review)

Essali A, Rihawi A, Altujjar M, Alhafez B, Tarboush A, Alhaj Hasan N

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

2013, Issue 12

http://www.thecochranelibrary.com

Anticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia (Review)

Copyright © 2013 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

12DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

18INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAnticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia (Review)


[Intervention Review]

Anticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia

Adib Essali1, Anas Rihawi2 , Mohammad Altujjar3, Bishr Alhafez4, Amjad Tarboush4 , Nahla Alhaj Hasan4

1Psychiatry Centre, Modern Psychiatry Hospital, Damascus, Syrian Arab Republic. 2Internal Medicine, St.Elizabeth’s Medical Center,

Brighton, Massachusetts, USA. 3Faculty of Medicine, Aleppo University, Aleppo, Syrian Arab Republic. 4 Faculty of Medicine, Damascus

University, Damascus, Syrian Arab Republic

Contact address: Adib Essali, Psychiatry Centre, Modern Psychiatry Hospital, 27 Al Zahrawi Street, Rawda, Damascus, Syrian Arab

Republic. [email protected]. [email protected].

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: New, published in Issue 12, 2013.

Review content assessed as up-to-date: 7 December 2012.

Citation: Essali A, Rihawi A, Altujjar M, Alhafez B, Tarboush A, Alhaj Hasan N. Anticholinergic medication for non-clozapine

neuroleptic-induced hypersalivation in people with schizophrenia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.:

CD009546. DOI: 10.1002/14651858.CD009546.pub2.


A B S T R A C T

Background

Treatment of schizophrenia depends heavily on neuroleptic drugs. Hypersalivation is a common side effect when people with schizophre-

nia are treated with neuroleptic drugs. Hypersalivation can be an embarrassing and stigmatising problem, can affect quality of life and

can result in discontinuation of neuroleptic treatment. It can also be difficult to treat.

Objectives

To summarise the best available evidence of the effects of anticholinergic drugs in the treatment of non-clozapine neuroleptic-induced

hypersalivation in people with schizophrenia. Clozapine-induced hypersalivation has been addressed in another Cochrane review.

Search methods

We searched the Cochrane Schizophrenia Group Trials Register (15 November 2012) and inspected references of all identified studies

for further relevant studies. We were to contact the first author of each included study for information regarding unpublished trials.

Selection criteria

All randomised controlled trials comparing an anticholinergic drug with placebo, no treatment, another anticholinergic drug or any

other intervention.

Data collection and analysis

We inspected the results of the search to identify relevant studies. We were to extract data onto standard, simple forms. Disagreements

were resolved through discussion. The risk of bias was to be assessed using the Cochrane risk assessment tool. For binary outcomes, we

were to calculate a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). For continuous outcomes, we were

to estimate the mean difference between groups.

1Anticholinergic medication for non-clozapine neuroleptic-induced hypersalivation in people with schizophrenia (Review)


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Main results

The search resulted in four potential studies; after inspection, all were excluded. Three studies were excluded because they involved

people with clozapine-induced hypersalivation - a topic covered in another Cochrane review. The fourth study was excluded because it

involved people with schizophrenia, mood disorders or other mental disorders who were suffering from clozapine- and non-clozapine

induced hypersalivation and were treated with Chinese medicines with unknown anticholinergic properties. People in the control

group received an anticholinergic drug (artane) or an antihistamine (phenergan). It was not possible to separate clozapine- from non-

clozapine-treated people in the intervention group, or to separate artane-treated people from phenergan-treated people in the control

group.

Authors’ conclusions

We have been unable to locate any studies addressing the question raised in this review. Accordingly, this empty review points out

an important clinical problem that needs to be investigated via well-designed and well-conducted randomised trials. Clinicians and

patients are likely to continue with their current dependence on clinical judgement and personal experience. Policy makers have no

trial-based evidence upon which to base guidelines for the treatment of hypersalivation induced by neuroleptics other than clozapine.

They are likely to continue to rely on opinion and habit when making recommendations. Funders of studies may wish to make this

important subgroup of people a priority in future research.

P L A I N L A N G U A G E S U M M A R Y

Anticholinergic medication for excessive salivation caused by use of antipsychotics other than clozapine

The first line of treatment of schizophrenia is usually antipsychotic drugs. These drugs help in the treatment of the ‘positive symptoms’

of schizophrenia, such as hearing voices, seeing things and having strange beliefs. However, these drugs often have serious side effects,

such as weight gain, muscle stiffness, tiredness, apathy and lack of drive. Dribbling or drooling (hypersalivation) is another common

side effect, which frequently occurs at night when asleep. This can be an embarrassing and stigmatising problem that can affect quality

of life and cause people to stop their medication, which may result in relapse and going back into hospital. Dribbling and drooling can

be difficult to treat; however, anticholinergic drugs can decrease production of saliva and dribbling. This review assessed the evidence

for the benefit or harm of anticholinergic drugs used in treating hypersalivation caused by antipsychotic or neuroleptic medication.

The review excluded the antipsychotic clozapine, as its role in causing hypersalivation has been the subject of another Cochrane review.

The search was carried out 15 November 2012 and resulted in identification of four potential studies, but none could be included.

Three of these were excluded because they involved clozapine-related hypersalivation. The fourth study was excluded because it involved

people with mood or other mental disorders and Chinese medicines. Dribbling or hypersalivation is an important problem that needs

to be investigated via well-designed research and randomised trials. Until such time, psychiatrists and patients are likely to continue

their treatment of hypersalivation on the basis of daily clinical judgement and personal experience rather than hard evidence. Treatment

of hypersalivation caused by antipsychotics or neuroleptics other than clozapine does not seem to have received adequate research

attention to help guide practice. The review authors conclude that using anticholinergics to treat dribbling or hypersalivation caused

by antipsychotic drugs other than clozapine cannot be justified without further study.

This plain language summary has been written by Benjamin Gray, Service User and Service User Expert: Rethink Mental Illness. Email:

[email protected]

B A C K G R O U N D

Description of the condition

Schizophrenia is a serious, disabling, enduring and relapsing men-

tal illness, the onset of which frequently occurs relatively early in



http://mailto:[email protected]

life. It can cause a person to experience problems with the abil-

ity to think, feel and perceive things clearly (Carpenter 1994).

The worldwide lifetime prevalence of the disorder is about 1%

(Almeida-Filho 1997).

Treatment of schizophrenia depends heavily on neuroleptic drugs,

which usually are classified into first-generation ’typical’ and sec-

ond-generation ’atypical’ drugs (Miyamoto 2005). Hypersaliva-

tion (or sialorrhoea or drooling) is a significant adverse effect of

both typical and atypical neuroleptic drugs. It is most commonly

seen in people with schizophrenia treated with clozapine, among

whom it affects approximately 31% of patients, usually develop-

ing early in the course of treatment, and is more prominent at

night (Safferman 1991). Clozapine has been confirmed as a po-

tent cause of hypersalivation in a systematic overview of Cochrane

reviews on anticholinergic effects of antipsychotic drugs (Ozbilen

2009). In the short term (up to 12 weeks), only zotepine was more

potent than clozapine in inducing hypersalivation. However, the

second-generation ’atypical’ drugs tend to cause this problem less

frequently than the first-generation ’typical’ drugs, with the excep-

tion of perphenazine (Table 1).

Description of the intervention

Hypersalivation seems paradoxical because antipsychotic drugs

tend to cause a dry mouth as a result of anticholinergic adverse

effects (Hori 2006). However, several studies suggest that differ-

ent receptors located on the salivary glands, including adrenergic

and muscarinic receptors, can alter salivary flow (Mandel 1975;

Ukai 1989; Zorn 1994; Corrigan 1995). Muscarinic and adrener-

gic receptors have been targeted by pharmacological intervention

of neuroleptic-induced hypersalivation. This review will focus on

muscarinic anticholinergic antagonists such as pirenzepine (Fritz

1995), benzhexol (trihexyphenidyl) (Spivak 1997), benztropine

(Reinstein 1999), atropine (Antonello 1999), hyoscine hydrobro-

mide and ipratropium bromide (Calderon 2000).

How the intervention might work

Anticholinergic medication for neuroleptic-induced hypersaliva-

tion may work by blocking muscarinic receptors. The combina-

tion of an antimuscarinic agent (benztropine) and an adrener-

gic alpha1 receptor antagonist (terazosin) may be more successful

in controlling hypersalivation than either drug alone (Reinstein

1999).

Why it is important to do this review

Hypersalivation is a common effect when people with schizophre-

nia are treated with neuroleptic drugs (Table 1, Hori 2006). Hyper-

salivation can be an embarrassing and stigmatising problem, can

affect quality of life and can result in discontinuation of neurolep-

tic treatment. It can also be difficult to treat. Another Cochrane

review has focused on the treatment of clozapine-induced hyper-

salivation (Syed 2008). This review is important because it aims

to evaluate the quality of evidence for the benefit and harm of

anticholinergic drugs used in treating hypersalivation induced by

neuroleptics other than clozapine.

O B J E C T I V E S

To summarise the best available evidence of the effects of anti-

cholinergic drugs in the treatment of non-clozapine neuroleptic-

induced hypersalivation in people with schizophrenia. Clozapine-

induced hypersalivation has been addressed in another Cochrane

review.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All relevant randomised controlled trials. If a trial was described

as ’double blind’ but implied randomisation, we were to include

such trials in a sensitivity analysis (see Sensitivity analysis). If in-

clusion of such trials did not result in a substantive difference, they

would have remained in the analyses. If their inclusion did result

in statistically significant differences, we were not to add the data

from these lower-quality studies to the results of the better trials

but rather would present such data within a subcategory. We were

to exclude quasi-randomised studies, such as those allocating by

alternate days of the week. When people were given additional

treatments with an anticholinergic medication, we would have in-

cluded data only if the adjunct treatment was evenly distributed

between groups and if it was only the anticholinergic medication

that had been randomly assigned.

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 with non-

clozapine neuroleptic-induced hypersalivation, however identified

(including recipient, carer and clinician).

We are interested in making sure that information is as relevant

to the current care of people with schizophrenia as possible, so we

proposed that if possible, we would clearly highlight the current

clinical state (acute, early post-acute, partial remission, remission),



as well as the stage (prodromal, first episode, early illness, persis-

tent), and would ascertain whether the studies primarily focused

on people with particular problems (e.g. negative symptoms, treat-

ment-resistant illnesses).

Types of interventions

1. Anticholinergic drugs

Any anticholinergic drug at any dose and by any route of ad-

ministration. Such drugs include pirenzepine, benzhexol (tri-

hexyphenidyl), benztropine, atropine, hyoscine hydrobromide

and ipratropium bromide. We proposed to compare the effects of

these with the following.

2. Placebo

This includes placebo or no treatment.

3. Any another anticholinergic drug

4. Any other intervention

Types of outcome measures

All outcomes were to be divided into short-term (within three

months), medium-term (3 to 12 months) and long-term (longer

than one year).

Primary outcomes

1. Measurement of salivation

1.1 Cured

1.2 Clinically important improvement in hypersalivation

2. Adverse effects

general and specific

2.1 Clinically important general adverse effects

Secondary outcomes

1. Measurement of salivation

1.1 Average endpoint hypersalivation score

1.2 Average change in hypersalivation scores

2. Quality of life (recipient of care or informal carers or

professional carers)

2.1 Clinically important change in quality of life

2.2 Average endpoint quality of life score

2.3 Average change in quality of life scores

2.4 Clinically important change in specific aspects of quality of

life

2.5 Average endpoint specific aspects of quality of life

2.6 Average change in specific aspects of quality of life

3. Adverse effects

general and specific

3.1 Average endpoint general adverse effect score

3.2 Average change in general adverse effect scores

3.3 Clinically important specific adverse effects

3.4 Average endpoint specific adverse effects

3.5 Average change in specific adverse effects

3.6 Sudden and unexpected death

4. Global state

4.1 Relapse

4.2 Clinically important change in global state (as defined by in-

dividual studies)

4.3 Average endpoint global state score

4.4 Average change in global state scores

4.5 Use of other medications

5. Service outcomes

5.1 Hospitalisation

5.2 Time to hospitalisation

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

negative symptoms of schizophrenia)

6.1 Clinically important change in general mental state

6.2 Average endpoint general mental state score

6.3 Average change in general mental state scores

6.4 Clinically important change in specific symptoms (positive

symptoms of schizophrenia, negative symptoms of schizophrenia,

depression, mania)

6.5 Average endpoint specific symptom score

6.6 Average change in specific symptom scores

7. General functioning

7.1 Clinically important change in general functioning

7.2 Average endpoint general functioning score

7.3 Average change in general functioning scores

7.4 Clinically important change in specific aspects of functioning,

such as social or life skills



7.5 Average endpoint specific aspects of functioning, such as social

or life skills

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

or life skills

8. Behaviour

8.1 Clinically important change in general behaviour

8.2 Average endpoint general behaviour score

8.3 Average change in general behaviour scores

8.4 Clinically important change in specific aspects of behaviour

8.5 Average endpoint specific aspects of behaviour

8.6 Average change in specific aspects of behaviour

9. Satisfaction with treatment

9.1 Leaving the studies early

9.2 Recipient of care satisfied with treatment

9.3 Recipient of care average satisfaction score

9.4 Recipient of care average change in satisfaction scores

9.5 Carer satisfaction with treatment

9.6 Carer average satisfaction score

9.7 Carer average change in satisfaction scores

10. Economic outcomes

10.1 Direct costs

10.2 Indirect costs

11. Summary of findings table

We were to use the GRADE approach to interpret findings

(Schünemann 2008) and to use the GRADE profiler (GRADE

PRO) to import data from RevMan 5.1 (Review Manager) to cre-

ate ’Summary 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 outcomes that we will rate as important to patient- care and

decision making. We were to select the following main outcomes

for inclusion in a ’Summary of findings’ table.

1. Measurement of salivation (binary)

2. Quality of life

3. Adverse effects

4. Satisfaction with treatment

5. Economic outcome

Search methods for identification of studies

Electronic searches

1. Cochrane Schizophrenia Group Trials Register

(November 2012)

We searched the register using the phrase:

[((*hypersaliv* or *drool* or * saliva* or *ptyalism* or *sialism*

or *sailorr* in title abstract or index terms of REFERENCE or

outcomes of STUDY) or (*hypersaliv* in Helath care conditions

of STUDY)) AND (*anticholinergic* OR *atropine* OR *ben-

zatropine* OR *benzhexol* OR *hyoscine hydrobromide* OR

*ipratropium bromide* OR *muscarinic* OR *pirenzepine* OR

*trihexyphenidyl* in interventions of STUDY)]

This register is compiled by systematic searches of major databases,

handsearches and searches of conference proceedings (see group

module).

Searching other resources

1. Reference searching

We were to inspect references of all included studies for further

relevant studies.

2. Personal contact

We were to contact the first author of each included study for

information regarding unpublished trials.

Data collection and analysis

Selection of studies

Review authors AR, MFA, BA and AT independently inspected

citations from the searches to identify relevant abstracts. AE and

NAH were to independently re-inspect a random 20% sample

to ensure reliability, but this was not needed as the number of

studies was low. Full reports of abstracts meeting review criteria

or of references/abstracts about which review authors disagreed

were to be obtained and inspected by AR, MFA, BA and AT.

Again, AE and NAH were to re-inspect a random 20% of reports

to ensure reliable selection. Where it was not possible to resolve

disagreement by discussion, we contacted the authors of the study

for clarification.

Data extraction and management

1. Extraction

Review authors AR, MFA, BA and AT were to extract data from all

included studies. In addition, to ensure reliability, AE and NAH

were to independently extract data from a random sample of these



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studies, constituting 50% of the total. Again, any disagreement

would have been discussed and decisions documented, and, if nec-

essary, we were to contact the authors of studies for clarification.

With remaining problems, AE and NAH would have helped to

clarify issues, and we would have documented these final deci-

sions. We were to extract data presented only in graphs and figures

whenever possible, but we were to include the data only if two

review authors independently achieved the same result. We would

have attempted to contact authors through an open-ended request

to obtain missing information or for clarification whenever nec-

essary. If studies were multi-centre, where possible, we were to ex-

tract data relevant to each component centre separately.

2. Management

2.1 Forms

We extracted data onto standard, simple forms.

2.2 Scale-derived data

We were to include continuous data from rating scales only if:

a. the psychometric properties of the measuring instrument had

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

b. the measuring instrument had not been written or modified by

one of the trialists for that particular trial.

Ideally the measuring instrument should be a self-report or

should be completed by an independent rater or relative (not the

therapist). We realise that this often is not reported clearly; in

’Description of studies’, we will note whether or not this is the

case.

2.3 Endpoint versus change data

Both endpoint and change data provide advantages. 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 to

perform in unstable and difficult to measure conditions such as

schizophrenia. We have decided to use primarily endpoint data

and to use change data only if the former are not available. We

were to combine endpoint and change data in the analysis, as we

were to use mean differences (MDs) rather than standardised mean

differences (SMDs) throughout (Higgins 2011).

2.4 Skewed data

Continuous data on clinical and social outcomes often are not

normally distributed. To avoid the pitfall of applying parametric

tests to non-parametric data, we aimed to apply the following

standards to all data before inclusion: (a) standard deviations (SDs)

and means are reported in the paper or are obtainable from the

authors; (b) 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)); and (c) if a scale started from a

positive value (such as the Positive and Negative Syndrome Scale

(PANSS), 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.

Endpoint scores on scales often have finite start and end points,

and these rules can be applied. We were to enter skewed endpoint

data from studies of fewer than 200 participants as other data

within the data and analyses section rather than into a statistical

analysis. Skewed endpoint data pose less of a problem when means

are used if the sample size is large and if we synthesise such data.

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 or not data are skewed. We were to enter skewed

change data into analyses.

2.5 Common measure

To facilitate comparison between trials, we intended 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, efforts were to be made to convert outcome mea-

sures to dichotomous data. This can be done by identifying cut-off

points on rating scales and dividing participants accordingly into

’clinically improved’ and ’not clinically improved’. It is generally

assumed that if a 50% reduction is seen in a scale-derived score

such as the Brief Psychiatric Rating Scale (BPRS; Overall 1962)

or the PANSS (Kay 1986), this could be considered a clinically

significant response (Leucht 2005, Leucht 2005a). If data based

on these thresholds were not available, we were to use the primary

cut-off presented by the original authors.

2.7 Direction of graphs

Where possible, we were to enter data in such a way that the area

to the left of the line of no effect indicates a favourable outcome

for anticholinergic medication. Where keeping to this makes it

impossible to avoid outcome titles with clumsy double-negatives

(e.g. ’Not improved’), we were to report data in such a way that

the area to the left of the line indicates an unfavourable outcome.

We were to note this in the relevant graphs.



Assessment of risk of bias in included studies

Again AR, MFA, BA and AT worked independently to assess risk

of bias by using criteria described in the Cochrane Handbook for

Systematic Reviews of Interventions (Higgins 2011) to assess trial

quality. This set of criteria is based on evidence of associations

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.

If the raters disagreed, we were to make the final rating by con-

sensus, with the involvement of AE and NAH. Where inadequate

details of randomisation and other characteristics of trials were

provided, we contacted the authors of the studies to obtain further

information. We were to report non-concurrence in quality assess-

ment, but if disputes arose regarding to which category a trial was

to be allocated, we were to resolve them by discussion.

We were to note the level of risk of bias in both the text of the

review and ’Summary of findings’ table.

Measures of treatment effect

1. Binary data

For binary outcomes, we were to 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 RR by

clinicians (Deeks 2000).

2. Continuous data

For continuous outcomes, we were to estimate the MD between

groups. We preferred not to calculate effect size measures (SMD).

However, if scales of very considerable similarity were used, we

would have presumed a small difference in measurement, and we

would have calculated effect size and transformed the effect back

to the units of one or more of the specific instruments.

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 can pose problems. First, authors often fail to ac-

count for intraclass correlation in clustered studies, leading to a

’unit of analysis’ error (Divine 1992) whereby P values are spuri-

ously low, CIs unduly narrow and statistical significance overesti-

mated. This causes type I errors (Bland 1997; Gulliford 1999).

If clustering was not accounted for in primary studies, we would

have presented data in a table, with an (*) symbol to indicate the

presence of a probable unit of analysis error. In subsequent versions

of this review, we will seek to contact the first authors of such

studies to obtain intraclass correlation coefficients (ICCs) for their

clustered data and to adjust for these by using accepted methods

(Gulliford 1999).

If clustering had been incorporated into the analysis of primary

studies, we would have presented these data as if from a non-cluster

randomised study with adjustment for the clustering effect.

We have sought statistical advice and have been advised that the

binary data as presented in a report should be divided by a ’design

effect’. This is calculated by using the mean number of participants

per cluster (m) and the ICC [Design effect = 1 + (m 1) * ICC]

(Donner 2002). If the ICC was not reported, we were to assume

that it was 0.1 (Ukoumunne 1999).

If cluster studies had been appropriately analysed by taking into

account ICCs and relevant data documented in the report, syn-

thesis with other studies would have been possible through the

generic inverse variance 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, psychologi-

cal) of the treatment in the first phase is carried over to the second

phase. As a consequence, on entry to the second phase, 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 were to use only

data from the first phase of cross-over studies.

3. Studies with multiple treatment groups

Where a study involved more than two treatment arms, if relevant,

we were to present the additional treatment arms in comparisons.

If data were binary, we were to simply add and combine them

within the two-by-two table. If data were continuous, we were to

combine data in accordance with the formula in Section 7.7.3.8

(Combining groups) of the Cochrane Handbook for Systematic Re-

views of Interventions. Where the additional treatment arms were

not relevant, we were not to reproduce the 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 chose that for any particular outcome, should

more than 50% of data be unaccounted for, we would not have

reproduced these data or used them within analyses, except for the

outcome of leaving the study early. If, however, more than 50%



of those in one arm of a study were lost, but the total loss was

less than 50%, we would have marked such data with an (*) to

indicate that such a result may well be prone to bias.

2. Binary

In the case where attrition for a binary outcome was between 0%

and 50% and where these data were not clearly described, we

were to present the data on a ’once-randomised-always-analyse’

basis (an intention-to-treat analysis). All of those leaving the study

early would have been assumed to have the same rates of negative

outcome as those who completed the study. We were to undertake

a sensitivity analysis to test how prone the primary outcomes were

to change when ’completer’ data only were compared with the

intention-to-treat analysis using the above assumptions.

3. Continuous

3.1 Attrition

In cases where attrition for a continuous outcome was between

0% and 50% and completer-only data were reported, we were to

reproduce these data.

3.2 Standard deviations

If SDs were not reported, we were to try first to obtain the miss-

ing values from the authors. If these data were not available and

measures of variance for continuous data were missing, but an ex-

act standard error (SE) and CIs were available for group means,

and either P or t values were available for differences in mean,

we were to calculate them according to the rules described in the

Cochrane Handbook for Systematic Reviews of Interventions (Higgins

2011): When only the SE is reported, SDs are calculated by the

formula SD = SE * square root (n). Chapters 7.7.3 and 16.1.3

of the Cochrane Handbook for Systematic Reviews of Interventions

(Higgins 2011) present detailed formulas for estimating SDs from

P values, t or F values, CIs, ranges or other statistics. If these for-

mula did not apply, we were to calculate the SDs according to a

validated imputation method based on the SDs of the other in-

cluded studies (Furukawa 2006). Although some of these impu-

tation strategies can introduce error, the alternative would be to

exclude a given study’s outcome and thus to lose information. We

nevertheless were to examine the validity of the imputations in a

sensitivity analysis while excluding imputed values.

3.3 Last observation carried forward

We anticipated that in some studies, the method of last observation

carried forward (LOCF) would have been employed within the

study report. As with all methods of imputation used to deal with

missing data, LOCF introduces uncertainty about the reliability of

the results (Leucht 2007). Therefore, where LOCF data had been

used in the trial, if less than 50% of the data had been assumed,

we would have reproduced these data and indicated that they are

the product of LOCF assumptions.

Assessment of heterogeneity

1. Clinical heterogeneity

We were to consider all included studies initially, without seeing

comparison data, to judge clinical heterogeneity. We were simply

to inspect all studies for clearly outlying people or situations that

we had not predicted would arise. When such situations or par-

ticipant groups were noted, they were to be fully discussed.

2. Methodological heterogeneity

We were to consider all included studies initially, without seeing

comparison data, to judge methodological heterogeneity. We were

simply to inspect all studies for clearly outlying methods that we

had not predicted would arise. When such methodological outliers

were noted, they were to be fully discussed.

3. Statistical heterogeneity

3.1 Visual inspection

We were to visually inspect graphs to investigate the possibility of

statistical heterogeneity.

3.2 Employing the I2 statistic

We were to investigate heterogeneity between studies by consid-

ering the I2 method alongside the Chi2 P value. The I2 statistic

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 the magnitude and direction of effects and

the strength of the evidence for heterogeneity (e.g. P value from

Chi2 test, or CI for I2). We will interpret an I2 estimate greater

than or equal to around 50% accompanied by a statistically signifi-

cant Chi2 statistic as evidence of substantial levels of heterogeneity

(Section 9.5.2 Higgins 2011). When substantial levels of hetero-

geneity were found in the primary outcome, we were to 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 (Higgins 2011). We were to try to locate

protocols of included randomised trials. If the protocol was avail-

able, we would have compared the outcomes in the protocol with

those in the published report. If the protocol was not available, we

would have compared outcomes listed in the methods section of

the trial report with actual reported results.

2. Funnel plot

Publication biases arise when the dissemination of research find-

ings is influenced by the nature and direction of results (Egger

1997). These again are described in Section 10 of the Cochrane

Handbook for Systematic Reviews of Interventions (Higgins 2011).

We are aware that funnel plots may be useful in investigating pub-

lication biases but are of limited power for detecting small study

effects. We were not to use funnel plots for outcomes where 10 or

fewer studies were included, or where all studies were of similar

size. In other cases, where funnel plots were possible, we were to

seek statistical advice in their interpretation.

Data synthesis

We understood that there was no closed argument regarding pref-

erence for use of fixed-effect or random-effects models. The ran-

dom-effects method incorporates an assumption that 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 no statis-

tically significant heterogeneity is noted. However, the random-

effects model provides a disadvantage. It puts added weight onto

small studies, which often are the most biased ones. Depending

on the direction of effect, these studies can inflate or deflate the

effect size. We intended to use a fixed-effect model for all analyses.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses

only primary outcomes

1.1 Intervention

We anticipated subgroup analyses to investigate the use of anti-

cholinergic drugs in combination with other drugs for hypersali-

vation.

1.2 Clinical state, stage or problem

We proposed to undertake this review and provide an overview

of the effects of anticholinergic medication among people with

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

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

similar problems.

2. Investigation of heterogeneity

If inconsistency was high, we were to report it. First, we would

have investigated whether data had been entered correctly. Sec-

ond, if data were correct, we would have visually inspected the

graph and removed outlying studies to see whether heterogeneity

could be restored. For this review, we had decided that should this

occur with data contributing to the summary finding of no more

than around 10% of the total weighting, we would have presented

the data. If not, we would not have pooled data but would have

discussed the relevant issues in the text. We knew of no support-

ing research for this 10% cut-off but were investigating the use of

prediction intervals as an alternative to this unsatisfactory state.

When unanticipated clinical or methodological heterogeneity was

obvious, we simply would have stated hypotheses regarding this

for future reviews or future versions of this review. We did not

anticipate undertaking analyses related to these.

Sensitivity analysis

1. Implication of randomisation

We aimed to include trials in a sensitivity analysis if they were de-

scribed in some way as to imply randomisation. For primary out-

comes, we were to include these studies; if no substantive differ-

ence was noted when the implied randomised studies would have

been added to those with better descriptions of randomisation, we

were to use all data from these studies.

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 were to compare the

findings of primary outcomes when we use our assumption with

completer data only. If a substantial difference was noted, we were

to report results and discuss them but continue to employ our

assumption.

Where assumptions have to be made regarding missing SD data

(see Dealing with missing data), we were to compare the findings

of primary outcomes when we use our assumption with completer

data only. We were to undertake a sensitivity analysis to test how

prone results were to change when ’completer’ data only are com-

pared with imputed data using the above assumption. If a sub-

stantial difference was noted, we were to report results and discuss

them but continue to employ our assumption.



3. Risk of bias

We were to analyse the effects of excluding trials that had been

judged to be at high risk of bias across one or more of the domains

of randomisation (implied as randomised with no further details

available), allocation concealment, blinding and outcome report-

ing for the meta-analysis of the primary outcome. If the exclusion

of trials at high risk of bias did not substantially alter the direc-

tion of effect or the precision of effect estimates, we would have

included data from these trials in the analysis.

4. Imputed values

We were to undertake a sensitivity analysis to assess the effects of

including data from trials where we used imputed values for ICC

in calculating the design effect in cluster-randomised trials.

If substantial differences were noted in the direction or precision

of effect estimates in any of the sensitivity analyses listed above, we

would have not pooled data from the excluded trials with those of

other trials contributing to the outcome but would have presented

them separately.

5. Fixed-effect and random-effects models

We were to synthesise all data using a fixed-effect model; however,

we were also to synthesise data for the primary outcome using a

random-effects model to evaluate whether the greater weight as-

signed to larger trials with greater event rates altered the signifi-

cance of the results compared with more evenly distributed weight

in the random-effects model.

R E S U L T S

Description of studies

Results of the search

The search yielded only four references, all of which were ran-

domised controlled studies. See also Figure 1.



Figure 1. Study flow diagram.



Included studies

No included studies are provided in this review.

Excluded studies

Three studies (Reinstein 1999; Bai 2001; ISRCTN47146067

2010) were excluded because they involved people with clozapine-

induced hypersalivation - a topic covered in another Cochrane

review (Syed 2008). The fourth study (Hui 2002) was excluded

because it investigated people with schizophrenia, mood disor-

ders or other mental disorders who were suffering from clozapine-

and non-clozapine-induced hypersalivation and were treated with

Chinese medicines with unknown anticholinergic properties. Peo-

ple in the control group received an anticholinergic drug (artane)

or an antihistamine (phenergan). It was not possible to separate

clozapine- from non-clozapine-treated people in the intervention

group or to separate artane-treated people from phenergan-treated

people in the control group. We have sought this information but

have not yet received an answer.

Risk of bias in included studies


Allocation


Blinding


Incomplete outcome data


Selective reporting


Other potential sources of bias


Effects of interventions


D I S C U S S I O N

Treatment of schizophrenia depends heavily on neuroleptic drugs.

Hypersalivation is a common side effect when people with

schizophrenia are treated with neuroleptic drugs. Hypersalivation

can be an embarrassing and stigmatising problem, can affect qual-

ity of life and can result in discontinuation of neuroleptic treat-

ment. It can also be difficult to treat. The aim of this review was

to evaluate the quality of evidence for the benefit and harm of

anticholinergic drugs used in treating hypersalivation induced by

neuroleptics other than clozapine.

We have been unable to locate any studies addressing the ques-

tion raised in this review. Accordingly, this may be considered an

“empty review”, pointing at an important clinical problem that

needs to be investigated (Yaffe 2012). Well-designed and well-con-

ducted RCTs in the treatment of hypersalivation induced by neu-

roleptics other than clozapine are needed. Such trials are feasible

as demonstrated by the excluded studies described in this review.

Summary of main results

The main result is that no randomised controlled trials have in-

vestigated the effects of anticholinergic drugs for non-clozapine

neuroleptic-induced hypersalivation.

Overall completeness and applicability ofevidence

No included studies are provided in this review. The evidence is

not complete, and no randomised controlled trials could guide

treatment decisions in this area.

Quality of the evidence


Potential biases in the review process

No included studies are provided in this review. We might have

missed some studies, but this is unlikely because we searched the

Schizophrenia Group Trial Register, which is compiled by system-

atic searches of major databases, handsearches and searches of con-

ference proceedings



Agreements and disagreements with otherstudies or reviews

We were unable to locate any studies, and we are not aware of

another systematic review that has addressed the effects of anti-

cholinergic medication for non-clozapine neuroleptic-induced hy-

persalivation.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

1. For clinicians

Treatment of hypersalivation induced by neuroleptics other than

clozapine does not seem to have received adequate research atten-

tion, and no RCT-based evidence is available to help guide prac-

tice. Clinicians are likely to continue with their current practices

of using clinical judgement.

2. For people with schizophrenia

Patients suffering from hypersalivation induced by neuroleptics

other than clozapine and their relatives are justified to be disap-

pointed in the medical/research fraternity.

3. For policy makers

Policy makers have no RCT-based evidence upon which to base

guidelines for the treatment of hypersalivation induced by neu-

roleptics other than clozapine. They are likely to continue to rely

on opinion and habit when making recommendations.

Implications for research

The treatment of hypersalivation induced by neuroleptics other

than clozapine cannot be justified without well-designed, well-

conducted and well-reported randomised studies. At present, no

convincing evidence supports any intervention for hypersalivation

induced by neuroleptics other than clozapine. Clinically mean-

ingful randomised studies are needed to help guide clinicians in

the management of people suffering from hypersalivation induced

by neuroleptics other than clozapine. Available publications prove

that such studies are possible.

Funders of studies may wish to make this important subgroup of

people a priority in future research.

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

The Cochrane Schizophrenia Group Editorial Base in Notting-

ham produces and maintains standard text for use in the Methods

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

appears here and have adapted it as required.

We would like to acknowledge the contribution of Maher Sharaf,

who helped develop the protocol and assisted in writing the review.

R E F E R E N C E S

References to studies excluded from this review

Bai 2001 {published data only}

Bai YM, Lin CC, Chen JY, Liu WC. Therapeutic effect

of pirenzepine for clozapine-induced hypersalivation: a

randomized, double-blind, placebo-controlled, cross-over

study. Journal of Clinical Psychopharmacology 2001;21(6):

608–11. [MEDLINE: 11763010]

Hui 2002 {published data only (unpublished sought but not used)}

Flaws B. The Chinese medical treatment of hypersalivation

as an adverse reaction to anti-pyschotic medication. Blue

Poppy Press 2003. [: http://bluepoppy.com/cfwebstore/

index.cfm/feature/898/the–chinese–medical–treatment–

of–hypersalivation–as–an–adverse–reaction–to–anti–

pyschotic–medication.cfm]∗ Hui L, Xingxing P. Treatment of neuroleptic salivation by

Chinese Luijunazi Wan: a clinical observation of 56 cases.

China Academic Journal 2002;8:19–29.

ISRCTN47146067 2010 {published data only}

ISRCTN47146067. Reducing excess salivation in clozapine

treatment: hyoscine for the treatment of clozapine induced

nocturnal sialorrhoea, 2010. http://www.controlled-

trials.com.

Reinstein 1999 {published data only}

Reinstein MJ, Sirotovskaya LA, Chasanov MA, Jones

LE, Mohan S. Comparative efficacy and tolerability

of benzatropine and terazosin in the treatment of

hypersalivation secondary to clozapine. Clinical Drug

Investigation 1999;17(2):97–102.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Bai 2001 Allocation: randomised.

Participants: people with clozapine-induced hypersalivation.

Hui 2002 Allocation: randomised.

Participants: people with schizophrenia, mood disorders or other mental disorders and patients with

clozapine-induced and non clozapine-induced hypersalivation

Interventions.

1. Radix Codonopsis Pilosulae (Dang Shen), Rhizoma Atractylodis Macrocephalae (Bai Zhu),

Sclerotium Poriae Cocos (Fu Ling), Pericarpium Citri Reticulatae (Chen Pi), lime processed Rhizoma

Pinelliae Ternatae (Ban Xia) and Radix Glycyrrhizae (Gan Cao).

2. Artane or phenergan.

ISRCTN47146067 2010 Allocation: randomised.


Reinstein 1999 Allocation: randomised.




D A T A A N D A N A L Y S E S

This review has no analyses.

A D D I T I O N A L T A B L E S

Table 1. Prevalence of Increased Salivation, Short-term Results (by 12 Weeks or Less) (adopted from Ozbilen 2009)

Compound n RCTs % (95% CI)

Placebo 403 10 7.7 (5 to 11)

Clozapine 559 16 32.7 (29 to 37)

Zotepine 53 1 41.5 (29 to 55)

Zuclopenthixol hydrochloride 66 2 24.2 (16 to 36)

Haloperidol 1115 12 18.4 (16 to 21)

Thioridazine 66 2 15.2 (8 to 26)

Chlorpromazine 499 12 14.2 (11 to 18)

Trifluoperazine 44 6 13.6 (6 to 27)

Molindone 42 2 9.5 (4 to 22)

Bromperidol depot 27 1 3.7 (1 to 18)

Olanzapine 1857 5 8.2 (7 to 10)

Fluphenazine hydrochloride 110 2 8.2 (4 to 15)

Amisulpride 115 1 7.8 (4 to 14)

Sulpiride 154 6 7.1 (4 to 12)

Risperidone depot 317 2 5.7 (4 to 9)

Perphenazine 74 3 5.4 (2 to 13)

Risperidone 325 3 3.7 (2 to 6)



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

Adib Essali - developed protocol and wrote review.

Nahla Alhaj Hasan - developed protocol and wrote review.

Anas Rihawi - developed protocol and wrote review.

Bishr Alhafez - developed protocol and wrote review.

Amjad Tarboush - developed protocol and wrote review.

Mohammad Fakhri Al-tujjar - help with selection of trials and data extraction.

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

None.

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

Internal sources

• Association for Evidence-Based Medicine, Syrian Arab Republic.

Training

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

None

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antipsychotic Agents [∗adverse effects]; Cholinergic Antagonists [∗therapeutic use]; Schizophrenia [∗drug therapy]; Sialorrhea [chem-

ically induced; ∗drug therapy]

MeSH check words

Humans



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