Cochrane Database of Systematic Reviews (Reviews) || Haloperidol for agitation in dementia

Haloperidol for agitation in dementia (Review)

Lonergan E, Luxenberg J, Colford JM, Birks J

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

2012, Issue 5

http://www.thecochranelibrary.com

Haloperidol for agitation in dementia (Review)

Copyright © 2012 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Haloperidol vs placebo, Outcome 1 Behavioural symptoms (change from baseline) ITT. 22

Analysis 1.2. Comparison 1 Haloperidol vs placebo, Outcome 2 Agitation (change from baseline ) ITT. . . . . . 23

Analysis 1.3. Comparison 1 Haloperidol vs placebo, Outcome 3 Aggression (change from baseline ) ITT. . . . . 24

Analysis 1.4. Comparison 1 Haloperidol vs placebo, Outcome 4 CGIC (improvement ) ITT. . . . . . . . . 25

Analysis 1.5. Comparison 1 Haloperidol vs placebo, Outcome 5 Caregiver burden (change from baseline ) ITT. . . 26

Analysis 1.6. Comparison 1 Haloperidol vs placebo, Outcome 6 Activities of daily living (change from baseline ) ITT. 27

Analysis 1.7. Comparison 1 Haloperidol vs placebo, Outcome 7 dropouts by endpoint. . . . . . . . . . . 28

Analysis 1.8. Comparison 1 Haloperidol vs placebo, Outcome 8 dropouts due to adverse events. . . . . . . . 29

Analysis 1.9. Comparison 1 Haloperidol vs placebo, Outcome 9 Number suffering at least one adverse event by endpoint. 30

Analysis 1.10. Comparison 1 Haloperidol vs placebo, Outcome 10 Number suffering an adverse event (broken down by

type) by endpoint. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

33ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iHaloperidol for agitation in dementia (Review)


[Intervention Review]

Haloperidol for agitation in dementia

Edmund Lonergan1 , Jay Luxenberg2, John M Colford3, Jacqueline Birks4

1Emeryville, CA, USA. 2San Francisco, California, USA. 3Epidemiology, University of California at Berkeley, Berkeley, CA, USA.4Centre for Statistics in Medicine, University of Oxford, Oxford, UK

Contact address: Edmund Lonergan, 4 Captain Drive, Apt 215, Emeryville, CA, 94608, USA. [email protected].

Editorial group: Cochrane Dementia and Cognitive Improvement Group.

Publication status and date: Edited (no change to conclusions), published in Issue 5, 2012.

Review content assessed as up-to-date: 4 October 2010.

Citation: Lonergan E, Luxenberg J, Colford JM, Birks J. Haloperidol for agitation in dementia. Cochrane Database of Systematic

Reviews 2002, Issue 2. Art. No.: CD002852. DOI: 10.1002/14651858.CD002852.


A B S T R A C T

Background

Agitation occurs in up to 70% of demented patients. Haloperidol has been used for decades to control agitation in dementia, but its

effectiveness remains unclear. Previous meta-analyses examined only English language publications or compared haloperidol with other

drugs rather than with placebo. To study the effectiveness of haloperidol a more widely based review was performed.

Objectives

To determine whether evidence supported the use of haloperidol in agitated dementia.

Search methods

We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 2 June 2010 using the

term: haloperidol.

The search of June 2010 retrieved no studiies for inclusion and/or exclusion within the review.

The previous searches of July 2005 and January 2008 retrieved no new studies for inclusion.

Selection criteria

Randomized, placebo-controlled trials, with concealed allocation, where subjects’ dementia and agitation were assessed.

Data collection and analysis

1. Two reviewers extracted data from included trials

2. Data were pooled where possible, and analysed using appropriate statistical methods

3. Odds ratios of average differences were calculated

4. Only ’intention to treat’ data were included

5. Analysis included haloperidol treated patients, compared with placebo

1Haloperidol for agitation in dementia (Review)


mailto:[email protected]

http://www.medicine.ox.ac.uk/alois

Main results

The five included trials led to the following results:

1. There was no significant improvement in agitation among haloperidol treated patients, compared with controls.

2. Aggression decreased among patients with agitated dementia treated with haloperidol; other aspects of agitation were not affected

significantly in treated patients compared with controls.

3. Although two studies showed increased drop-outs due to adverse effects among haloperidol patients, there was no significant difference

in drop-out rates, comparing all haloperidol treated patients with controls.

4. The data were insufficient to examine response to treatment in relation to length of treatment, degree of dementia, age or sex of

patients, and cause of dementia.

Authors’ conclusions

1. Evidence suggests that haloperidol was useful in reducing aggression, but was associated with adverse effects; there was no evidence

to support the routine use of this drug for other manifestations of agitation in dementia.

2. Similar drop-out rates among haloperidol and placebo treated patients suggested that poorly controlled symptoms, or other factors,

may be important in causing treatment discontinuation.

3. Variations in degree of dementia, dosage and length of haloperidol treatment, and in ways of assessing response to treatment suggested

caution in the interpretation of reported effects of haloperidol in the management of agitation in dementia.

4. The present study confirmed that haloperidol should not be used routinely to treat patients with agitated dementia. Treatment of

agitated dementia with haloperidol should be individualized and patients should be monitored for adverse effects of therapy.

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

No evidence has been found of any significant general improvement in manifestations of agitation, other than aggression,

among demented patients treated with haloperidol, compared with controls

Agitation is common in demented patients, and often takes the form of wandering, crying out, and aggression. It is presumed to reflect

subjective distress and is associated both with risks to the patient and an increase in caregiver burden. In the present study haloperidol

treatment was associated with a lower degree of aggression than was placebo. Adverse effects occurred more frequently in haloperidol

treated patients than controls, but similar drop-out rates among treated and control patients suggested that for some patients adverse

effects may have been tolerated because of better control of behaviour. Our findings indicated that there is little evidence to support a

benefit of haloperidol on manifestations of agitation other than aggression, and that haloperidol should not be used routinely to treat

patients with agitated dementia. Treatment of agitated dementia should be individualized, with careful monitoring of benefits and

adverse effects.

B A C K G R O U N D

Agitation has been defined as “inappropriate verbal, vocal, or mo-

tor activity that is not explained by needs or confusion per se”

(Billig 1991; Cohen-Mansfield 1989a), and has been reported to

occur in up to 70% of patients with dementia. No specific link has

been found between the kind of agitation (e.g., wandering, assault,

crying out) that patients displayed and the underlying diagnosis.

Patients with Alzheimer’s dementia have been more likely to wan-

der than other demented patients, but this may be because the

motor skills of people with Alzheimer’s Disease are retained longer

than for others. Studies of the effect of medications on agitated de-

mentia, including benzodiazepines, neuroleptics, antidepressants,

beta-blocking agents, and anticonvulsants, have given varying re-

sults. The first meta-analysis of the treatment of agitated dementia



(Schneider 1990) was a 1966-1989 English language review that

examined controlled trials of the effect of several neuroleptics, in-

cluding haloperidol, and found a modest overall beneficial effect

from haloperidol, in comparison with placebo. A 1998 meta-anal-

ysis examined multiple drugs, including haloperidol, associated

with the control of agitated dementia (Lanctot 1998) and found

no significant difference in efficacy among the interventions exam-

ined, and no difference in the pooled mean dropout rates. Lanctot

1998 searched MEDLINE 1965-1995, and considered only En-

glish language studies. Most recently, an unpublished meta-analy-

sis (Stehli 2000) covering the years 1966-1999 examined the effect

of haloperidol versus placebo, or compared with other neurolep-

tics, on agitated dementia, but was limited to English language

publications and a search of the MEDLINE/Healthstar database.

Stehli 2000 concluded that, at best, haloperidol provided only a

modest improvement in the control of agitation, mostly limited

to one factor - hostility/suspiciousness. She further noted a need

to use standard outcome measures and to explore the connection

between haloperidol and amelioration of specific manifestations

of agitation (e.g. hostility, hallucinations, delusions).

Haloperidol belongs to a family of medications known as “neu-

roleptics”. These may modify dopamine receptors (D2 type), al-

though the precise mechanism of haloperidol’s influence on agi-

tation is not known. Haloperidol is among the oldest and most

widely used drugs for the control of agitated states, including those

due to dementia or psychosis, although its use has declined with the

emergence of newer antipsychotics. The drug has been distributed

internationally for decades, but there is no quantitative estimate

available of its application to agitated dementia. Haloperidol was

initially favoured because of a lower rate of adverse reactions than

for similar drugs. However, significant side effects continue to be

a problem with this medication. These include over-sedation, hy-

potension, involuntary movements (including tardive dyskinesia),

parkinsonian manifestations (rigidity, tremor), and the rare occur-

rence of high fever and vascular collapse (malignant neuroleptic

syndrome).

Haloperidol was first used in the 1960s for the control of psychotic

manifestations, including hallucinations, delusions, and agitated

behavior. Despite more than 7000 publications on the drug since

its introduction, only a handful of reports have described its use in

the control of agitated dementia. In part because of the difficulty

in carrying out studies on demented patients with agitation, and

in part because of the complex nature of symptoms of agitation,

clear guidelines for the use of haloperidol in agitated dementia

have been difficult to establish. Other factors contributing to this

difficulty include a lack of well controlled studies, the absence of a

clear definition of agitation, and a failure of some investigators to

rule out agitation due to causes other than dementia (e.g., delir-

ium, infection, drug reaction). To provide reliable guidance to

clinicians, studies of the use of haloperidol in controlling agitated

dementia should always have demonstrated that treatable causes of

agitation, especially delirium, were excluded by a medical or psy-

chiatric examination prior to entering patients into experimental

trials.

The present study updates and extends the earlier meta-analyses,

and also attempts to identify the difficulties that make interpreta-

tion of results unclear in publications on this subject. The review

is limited to the effect of haloperidol versus placebo on agitated

dementia.

O B J E C T I V E S

Primary goals:

• To determine the effect of haloperidol on agitation in

demented patients

• To measure the frequency of adverse effects among patients

treated with haloperidol

• To examine drop-out rates among patients treated with

haloperidol

• To study the effect of haloperidol on caregiver burden of

families supporting patients with agitated dementia

• To measure the effect of haloperidol on functional status of

patients with agitated dementia

Secondary goals:

To determine whether response to treatment with haloperidol is

influenced by:

1. Dose of haloperidol

2. Diagnostic classes of dementia

3. Manifestations of agitation

4. Degree of dementia

5. Sex of patients treated

6. Age of patients treated

M E T H O D S

Criteria for considering studies for this review

Types of studies

These included all relevant unconfounded, randomized, placebo-

controlled trials with concealed allocation of subjects. Trials had



to include pre- and post- treatment assessment of agitation. Be-

cause dementia is characterized by varying rates of progression, if

cross-over studies were reported only data from the first part of

the study were included. Both English and non-English language

publications were examined.

Types of participants

These were patients with dementia, unclassified or diagnosed ac-

cording to the major classifications given below, and having agi-

tation.

Diagnostic criteria for dementia: these were given in DSM IV 1994

and ICD-10 1993, and included Alzheimer’s dementia, vascular

dementia, Pick’s dementia; dementia associated with Parkinson’s

disease; dementia due to alcoholism; and unclassified dementia.

Studies prior to 1994 used criteria for dementia found in DSM

IIIR and DSM III. In the absence of these criteria, other acceptable

evidence (e.g., Mini Mental State Examination, psychiatric eval-

uation, medical evaluation, psychologic evaluation) of dementia

was used.

Diagnostic criteria for agitation: neither DSM IV nor ICD-10

provided diagnostic criteria for agitation.

A commonly accepted description of agitation was “inappropriate

verbal, vocal, or motor activity that is not explained by needs or

confusion per se.” (Billig 1991; Cohen-Mansfield 1989a; Cohen-

Mansfield 1989b), and includes wandering, crying out, abusive

vocalization, and assaultive behavior. Studies in which the Cohen-

Mansfield Agitation Inventory (CMAI) (Cohen-Mansfield 1989b;

Cohen-Mansfield 1996) was used for pre- and post- treatment

assessment of agitation and to measure response to treatment were

subjected to meta-analysis. Where the CMAI was not used, other

evidence - such as a description of the manifestations of agitation

- was accepted in reviewing the literature.

There had to be evidence that clinical investigation was under-

taken to rule out treatable causes of agitation (e.g., infection, drug

reaction, dehydration) prior to entering patients in the drug trial.

Because acute confusion (delirium) and agitated dementia may

share similar behavioural manifestations, it was important to rule

out delirium as the cause of agitation.

Types of interventions

Treatment with different doses of haloperidol, with duration of

treatment for more than one week, against placebo.

Types of outcome measures

1. Decrease in manifestations of agitation

2. Drop-outs

3. Changes in caregiver burden

4. Adverse drug reactions

Search methods for identification of studies

Electronic searches

We searched ALOIS (www.medicine.ox.ac.uk/alois) - the

Cochrane Dementia and Cognitive Improvement Group’s Special-

ized Register on 2 June 2010. The search term used was: haloperi-

dol.

ALOIS is maintained by the Trials Search Co-ordinator and con-

tains studies in the areas of dementia prevention, dementia treat-

ment and cognitive enhancement in healthy. The studies are iden-

tified from:

1. Monthly searches of a number of major healthcare

databases: Medline, Embase, Cinahl, Psycinfo and Lilacs

2. Monthly searches of a number of trial registers: ISRCTN;

UMIN (Japan’s Trial Register); the WHO portal (which covers

ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register;

the German Clinical Trials Register; the Iranian Registry of

Clinical Trials and the Netherlands National Trials Register, plus

others)

3. Quarterly search of The Cochrane Library’s Central Register

of Controlled Trials (CENTRAL)

4. Six-monthly searches of a number of grey literature sources:

ISI Web of Knowledge Conference Proceedings; Index to

Theses; Australasian Digital Theses

To view a list of all sources searched for ALOIS see About ALOIS

on the ALOIS website.

Details of the search strategies used for the retrieval of reports of

trials from the healthcare databases, CENTRAL and conference

proceedings can be viewed in the ‘methods used in reviews’ sec-

tion within the editorial information about the Dementia and

Cognitive Improvement Group.

Additional searches were performed in many of the sources listed

above to cover the timeframe from the last searches performed for

ALOIS to ensure that the search for the review was as up-to-date

and as comprehensive as possible. The search strategies used can

be seen in Appendix 1.

Searches carried out in the previous version(s) of the review can

be viewed in Appendix 2.

The latest search (June 2010) retrieved a total of 364 results. Af-

ter a first-assess and a de-duplication of these results the authors

were left with 15 references to further assess. No new studies were

identified for either inclusion or exclusion within the review.

Searching other resources

Where indicated, companies that market haloperidol and the in-

vestigators of included trials were contacted to request informa-

tion and to obtain further leads to additional trials. A hand search

for articles (up to February 2002) was done at the Library of the

University of California at San Francisco.





http://www.medicine.ox.ac.uk/alois/content/about-alois

http://www.medicine.ox.ac.uk/alois/content/about-alois

http://mrw.interscience.wiley.com/cochrane/clabout/articles/DEMENTIA/frame.html





Data collection and analysis

• Identification of studies:

1. Searching and screening of the results were performed indepen-

dently by two reviewers (ETL, JL).

2. The reviewers selected trials for relevance and against defined

inclusion criteria. Trials that did not fulfil the criteria were ex-

cluded.

3. The reviewers’ selection of trials was compared and the final

list of studies was reached by consensus between the reviewers or

adjudicated by a third reviewer(Table 1).

• Inclusion criteria:

Trials were ranked using one of the Cochrane approaches (Mulrow

1997):

Grade A: Adequate concealment (randomization; placebo-con-

trolled; concealed allocation).

Grade B: Uncertain.

Grade C: Inadequate concealment; no randomization.

Trials with inadequate concealment have been shown to overesti-

mate treatment effect (Chalmers 1983; Schulz 1994) and in this

review were excluded.

• Data extraction:

Data were sought on every patient randomized (irrespective of

compliance and of withdrawal) for each outcome measure in or-

der to conduct ’intention-to-treat’ analyses. Where such data were

unavailable, data for ’on-treatment analysis’ were extracted and

indicated as such. For continuous variables, or ordinal variables

which can be approximated to continuous variables, the main out-

comes of interest were the assessment score at the time point con-

sidered, and the change from baseline (i.e., pre-randomization or

at randomization) at this point. For some binary and ordinal out-

comes, such as the Clinical Global Impression of Change (CIBIC-

Plus), the end point itself was of clinical relevance, because all

patients had, by definition, the same initial score. The baseline

assessment score was the latest available score, no longer than one

month prior to the randomization. Studies could have included

a titration period prior to the randomization phase of the study.

Because patients were not randomized, nor was treatment alloca-

tion concealed, data from titration periods were not used to assess

safety or efficacy of haloperidol. For the same reason, data from

any open follow-on phase, after randomization, were not used to

assess safety or efficacy. Data on adverse events and drop outs were

recorded.

Where present, numeric scores such as those provided by Cohen-

Mansfield (Cohen-Mansfield 1989b; Cohen-Mansfield 1996),

were used to measure response to treatment. In addition, where

available, further measurements such as Global Clinical Scales or

other scalar assessments of agitation (e.g. MOSES) were reviewed.

Because of wide variation in the way response to treatment was

measured, it was necessary in some instances to operationalize out-

comes as simply ’improved’ versus ’not improved’, regardless of

the scale used by the authors.

• Analysis of data

The null hypothesis tested was that, for the outcomes examined,

haloperidol has no effect compared with placebo.

For continuous or ordinal variables, such as psychometric test

scores, clinical global impression scales, and the Cohen-Mansfield

Agitation Scale, there were two possible approaches. If ordinal

scale data appeared to approximate a normal distribution, or if the

analysis suggested that parametric tests were appropriate, then the

outcome measures were treated as continuous data. The second

approach (which did not exclude the first) was to concatenate into

two categories which best represented the contrasting states of in-

terest and to treat the variable as binary.

For binary outcomes the endpoint itself was of interest and the Peto

method of the typical odds ratio was used. A test for heterogeneity

of the treatment effect between the trials was made using a standard

chi-square statistic. If no heterogeneity was indicated then a fixed

effect parametric approach was taken.

Within-class efficacy of treatment was examined by subgroup, as

follows:

1. Dementia subtype (e.g., Alzheimer’s compared with Vascular

dementia).

2. Kind of agitation (e.g., crying out compared with assault com-

pared with wandering).

3. Severity of dementia as determined by the Mini-mental state

score (e.g., mild:19-16; moderate:15-10; severe:9-untestable), or

other appropriate measures.

4. Sex of patient

5. Age of patient by deciles: 60-69; 70-79; 80-89; 90 and older.

Further analyses included:

1. Examination of drop-out rates.

2. Examination of adverse drug reactions.

For the above variables data were analysed and may be found in

the Comparisons listed below. A complete list of outcomes can be

found in the table of comparisons (Table 2).

All comparisons measured haloperidol effect compared with

placebo effect. The following outcomes were examined:

01: Behavioural symptoms (change from baseline ITT)

02 Agitation (change from baseline ITT)

03 Aggression (change from baseline ITT)

04 CGIC (Clinical Global Impression of change)(improvement

ITT)

05 Caregiver burden (change from baseline ITT)

06 Activities of daily living (change from baseline ITT)

07 Drop-outs by endpoint

08 Drop-outs due to adverse events

09 Number suffering at least one adverse event by endpoint

10 Number suffering an adverse event (broken down by type) at

endpoint

R E S U L T S



Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

There were five included trials. These are summarized as follows:

1. Three studies were multicentre; two studies were from Europe;

three studies were from the United States; three studies involved

outpatients; two studies involved institutionalized patients.

2. The average age of participants ranged between 72.1 years and

81.5 years; women made up 56.3% to 66.6% of the patients stud-

ied.

3. Identification of dementia: all studies used one or more stan-

dard methods (DSM IIIR, DSM IV 1994, NINCDS-ADRDA

(McKhann 1984)) to diagnose dementia, including Alzheimer’s

dementia. Three studies were limited to Alzheimer’s dementia, and

two studies included other forms of dementia as well (e.g. due to

stroke).

4. Characterization of dementia: In four studies patients were de-

scribed as having mild to moderate dementia based on MMSE

scores ranging from a mean of 13.0 - 19.4 (Devanand 1998;

Teri 2000), or on DSM IIIR criteria (Allain 2000). In one study

(RIS-INT-24 DeDeyn) the patients had severe dementia, as mea-

sured by MMSE scores of 7.9 - 8.8.

5. Characterization of agitation and outcome measures: three stud-

ies used the CMAI scale (Cohen-Mansfield 1996) to assess agita-

tion and response to therapy; two studies used the MOSES scale

(Helms 1988); two studies used the BPRS scale (Overall 1962);

one study used the ABID inventory (Logsdon 1999).

6. Haloperidol dosage varied across the studies from 0.25 mg per

day to 6.0 mg per day. Duration of therapy varied from 3 weeks to

16 weeks. Three studies titrated the dose of haloperidol. Patients

receiving varying doses of haloperidol were titrated up to the max-

imum dose unless improvement or intolerable adverse effects ap-

peared. In Teri 2000 subjects were started at 0.5 mg per day (one

unmarked tablet) and increased by 0.5 mg per day at the next clinic

visit up to 3.0 mg per day unless they showed improvement in ag-

itation, or adverse effects appeared. If adverse effects appeared the

dosage was reduced by 0.5 mg per day. In RIS-INT-24 DeDeyn

subjects were begun on 0.25 mg per day and increased by 0.25

mg per day every four days to a total of 1.0 mg twice daily unless

improvement or adverse effects occurred. In Allain 2000 subjects

were begun on 2.0 mg per day and increased by 0.5 mg doses to

6.0 mg per day unless improvement or adverse effects occurred. In

Auchus 1997 all treated patients received haloperidol, 3.0 mg per

day, and in Devanand 1998 there were two groups of patients: one

group received 0.5 mg to 0.75 mg per day, with the other group

receiving 2.0 to 3.0 mg per day.

7. Measurement of adverse effects: in two studies (Teri 2000;

Auchus 1997) the investigators applied their own checklist to

identify adverse effects. The three other studies applied differ-

ent established side effect rating scales: the UKU Side Effect Rat-

ing Scale (Allain 2000); the Extrapyramidal Symptom Rating

Scale, (RIS-INT-24 DeDeyn); the Treatment Emergent Symp-

toms Scale (TES), theTargeting Abnormal Kinetic Effects Scale,

and the Rockland Tardive Dyskinesia scale (Devanand 1998).

8. Three studies compared the effect of haloperidol on agitated

dementia against the effect of placebo or against the effect of

another intervention (behavioural management techniques, tra-

zodone, tiapride, risperidone, fluoxetine). In one study (Devanand

1998) the effect of low dose haloperidol (0.5 to 0.75 mg per day)

was compared with standard dose haloperidol (2.0 to 3.0 mg per

day) and both doses were compared with placebo treatment.

9. Two studies measured change in caregiver burden. Teri 2000

used the Revised Memory and Behavior Problem Checklist

(RMBPC) and the Screen for Caregiver Burden (SCG); Auchus

1997 used the University of Iowa Caregive Stress Inventory (CSI).

10. All included studies described analyses based on “intention to

treat.”

11. All studies excluded patients who had other reasons for agita-

tion, including alcoholism, schizophrenia, mania, and depression,

but only Teri 2000 specifically mentioned delirium as a cause of

exclusion from study.

Outcome Measures:

• Agitation

1. The Cohen-Mansfield Agitation Inventory (CMAI) (Cohen-

Mansfield 1996) scale is widely used in nursing homes to assess ag-

itation. The scale examines 29 types of agitated behaviour, includ-

ing pacing, verbal or physical aggression, performing repetitious

mannerisms, screaming, and general restlessness. The frequency

of these behaviours is measured on a seven-point scale, ranging

from 1 (never occurs) to 7 (occurs several times an hour, and in-

cludes cluster scores for physical and verbal aggression, and total

aggression.

2. The Behavior Pathology in Alzheimer’s Disease Rating Scale

(BEHAVE-AD) (Reisberg 1989) examines 25 items and uses a

four-point scale of increasing severity to assess seven clusters of

behaviour: paranoid/delusional ideation; aggressiveness; halluci-

nations; activity symptoms; diurnal rhythm symptoms; affective

symptoms; and anxieties and phobias. An aggressiveness sub-

scale score sums three symptoms scores: verbal outbursts; physical

threats, violence or both; and other kinds of agitation (e.g., wan-

dering, thrashing about).

3. On the Brief Psychiatric Rating Scale (BPRS) (Overall 1962),

the ’hallucinatory behavior or unusual thought content’ item is

used to identify psychotic behavior with a score of at least (mod-

erate severity).

4. The Agitated Behavior Inventory for Dementia (ABID) (

Logsdon 1999) is a scale employed by caregivers of patients. It

measures 16 items (e.g., aggression, vocalization) according to fre-

quency of occurrence (0, did not occur; 3, occurred daily or more

often), and the reaction of the caregiver to the problem (0 = not

upsetting; 4 = extremely upsetting).

5. The Schedule for Affective Disorders and Schizophrenia

(SADS) (Endicott 1978) measures hallucinations, delusional be-



haviour, psychomotor activity, and a number of manifestations

linked to depression, mania, anxiety, and formal thought disorders

(e.g., incoherence, illogical thinking, flight of ideas). .

6. The Behavioral Syndromes Scale for Dementia (BSSD) mea-

sures physical aggression (e.g., hitting, verbal abuse) or psychomo-

tor agitation (e.g., restlessness, repetitive movements); a score of 4

or more is the criterion for disruptive behaviour.

7. The Multidimensional Observation Scale for Elderly Subjects

(MOSES) (Helms 1988) measures self-care functioning items, dis-

oriented behaviour, depressed/anxious mood, irritable behaviour,

and withdrawn behaviour. Aggressive behavior is measure with

the Irritable Behaviour subset of items (e.g., resisting care, verbal

abuse of staff, physical abuse with staff or others). Frequency is

measured as ’not at all’ or ’at least once a day on more than 3 days’.

• Caregiver burden

1. The Screen for Caregiver Burden (SCB) (Vitaliano 1991) pro-

vides a 25 item checklist to give two scores: objective burden (num-

ber of items checked), and subjective burden (degree of caregiver

distress). Positive scores represent worsening of caregiver burden.

Examples of objective burden include items such as “I have little

control over my spouse’s behaviour,” and “My spouse has struck

me on various occasions.” Caregiver distress is measured with the

Beck Depression Inventory.

2. The University of Iowa Caregiver Stress Inventory (CSI) mea-

sures the burden of demented patients on their families and sig-

nificant others.

3. The Revised Memory and Behavior Problem Checklist

(RMPBC) (Teri 1992), in which caregivers rate 24 problems on

two lists: frequency of problems and caregiver distress from each

problem. A five point scale is used for each list. Global scores and

sub scale scores (memory-related, depressive, and disruptive) are

derived from the two lists.

• Global change

1. The Clinical Global Impression of Change (CGIC) (Schneider

1997) is a seven point scale (1 - very much improved; 4 - no change;

7 - very much worse) which makes a global rating of all aspects

of the patient’s condition, comparing the current state with the

baseline, and using direct observation as well as information from

significant others to determine the score.

2. The Functional Assessment Staging Scale (FAST) (Reisberg

1988) measures the level of basic activities such as bathing, dress-

ing, and toileting, through 16 stages, ranging from independent

to totally dependent.

• Side effects

1. The Udvalg Kliniske Undersogelser scale (UKU) (Lingjaerd

1987) identifies a broad range of side effects, including ex-

trapyramidal symptoms (e.g., tremor, hyperkinesia, akathisia), en-

docrine symptoms (e.g., libido changes, vaginal discomfort), psy-

chic events (e.g., impaired concentration, sleepiness, nervousness),

neurologic events (e.g., dystonia, muscle rigidity), and autonomic

events (e.g., change in blood pressure), and includes subscales as

well as total scores.

2. The extrapyramidal symptom rating scale (ESRS) (Chouinard

1980) is a 55-item scale to measure the severity of parkinsonian

symptoms (e.g., hypokinesia, muscle rigidity, tremors, excess sali-

vation), dyskinetic movements (e.g., of head, limbs, tongue), and

a global estimate of tardive dyskinesia (e.g., athetoid movements

of the tongue).

3. The Treatment Emergent Symptom Scale (TES) measures sys-

temic adverse effects (e.g. temperature, changes in blood pressure).

4. The Targeting Abnormal Kinetic Effects (TAKE) scale examines

extrapyramidal signs.

5. An unstandardized measure of adverse effects by Auchus 1997

summed the total number of adverse events, including depression,

anxiety, difficulty walking and nervousness for each patient.

6. An unstandardized checklist of adverse effects was developed

by Teri 2000, and the frequency of adverse events among the dif-

ferent treatment arms was measured at week 17. Adverse events

included parkinsonian gait, dry mouth, akathisia, rigidity, dyski-

nesia, drowsiness, bradykinesia, tremor, and fatigue.

Risk of bias in included studies

Two reviewers (ETL, JL) independently estimated the quality of

the included studies. The Cochrane approach to assessing ade-

quacy of allocation concealment was used.

1. Category A (adequate concealment): allocation is determined

by: 1) a centralized randomized scheme in which subjects are en-

rolled at a registry which codes and randomizes the participants

and notifies the investigator by telephone about treatment or con-

trol group allocation; 2) a randomization controlled by a phar-

macy; 3) coded containers with identical appearing capsules which

are administered sequentially to participants; 4) an on-site or coded

computer, given that allocations were in a locked, unreadable file

that could be accessed only after inputting the characteristics of an

enrolled subject; 5) the use of sequentially numbered and sealed,

opaque envelopes; 6) combinations of the aforementioned.

2. Category B (unclear concealment): the report describes alloca-

tion of treatment by: 1) the use of a list or table to allocate assign-

ments; 2) the use of envelopes or of sealed envelopes to distribute

medications; 3) a statement in the report to the effect that the

report is randomized without further characterization.

3. Category C (inadequate): allocation of treatment by: 1) alterna-

tion of subjects to treatment or control arms of the study; 2) use of

’fixed data’ such as birth dates, record numbers, days of the week;

3) allocation that is transparent such as an open list of random

numbers or assignments. Unclear concealment methods have been

shown to increase estimates of treatment effects compared with

adequate methods of concealment.

Trials conforming to Categories A and B were accepted; trials

falling into category C were excluded from further study.



Each of the five included studies satisfied Category B criteria for

allocation concealment..

Effects of interventions

There were five included trials, all of which provided some results

for meta-analyses. One trial, Devanand 1998, was a cross-over

trial and results from the first phase only are used in the meta-

analyses. The trials used different ranges of doses of haloperidol,

and the treatment periods varied from 3 to 16 weeks. The trial

characteristics are noted in the meta-analyses so that the reader can

take these into account when evaluating the results. Meta-analyses

on the intention-to-treat population are also reported.

• Behavioral Symptoms

Four trials assessed behavioral symptoms: Auchus 1997 and RIS-

INT-24 DeDeyn, used the BEHAVE-AD scale, Devanand 1998

the BPRS scale and Teri 2000 the BSSD scale. There was no

evidence of an effect of haloperidol compared with placebo.

• Agitation:

Four trials assessed agitation: Auchus 1997, RIS-INT-24 DeDeyn

and Teri 2000 used the CMAI scale, and Devanand 1998 used the

psychomotor agitation item of the BSSD. There was no evidence

of an effect of haloperidol compared with placebo.

• Aggression:

Three trials assessed aggression: Allain 2000 used the MOSES

irritability/aggressiveness sub score, Devanand 1998 the physical

aggression item of the BSSD, and RIS-INT-24 DeDeyn the BE-

HAVE-AD aggressiveness sub score. There was a benefit associated

with haloperidol (SMD -0.31, 95% CI -0.49, -0.13 P = 0.0006).

• Clinical Global Impression of Change:

Two trials assessed CGIC: Allain 2000 and Teri 2000. There was

no evidence of an effect of haloperidol compared with placebo.

• Caregiver Burden:

Only Teri 2000 assessed caregiver burden (SCB), and there was

no evidence of an effect of haloperidol compared with placebo.

• Activities of Daily Living:

Teri 2000 assessed both the physical activities (PDL) and the in-

strumental activities (IADL) and there was no evidence of an effect

of haloperidol compared with placebo.

• Drop-outs by endpoint:

There was no evidence of an effect of haloperidol compared with

placebo.

• Drop-outs due to adverse events:

Only two trials reported drop-out numbers due to adverse effects:

Allain 2000 and Teri 2000. There was a significant difference in

favour of placebo (23/135 compared with 10/139, OR 2.52, 95%

CI 1.22, 5.21, P = 0.01).

• Number suffering at least one adverse event by endpoint:

Two trials reported the numbers of patients suffering at least one

adverse event: Allain 2000 and RIS-INT-24 DeDeyn. There was

a significant difference in favour of placebo (169/216 compared

with 152/217, OR 1.53, 95% CI 1.00, 2.35, P = 0.05).

• Number suffering at least one adverse event by endpoint,

broken down by type of event:

Three trials reported numbers suffering at least one adverse event,

broken down by type, Allain 2000, RIS-INT-24 DeDeyn and Teri

2000, but the same categories were not used in the different trials

and it was not possible to pool results. There was a significant

difference in favour of placebo for the number suffering at least one

extrapyramidal symptom (Allain 2000) (34/101 compared with

18/103, OR 2.34, 95% CI 1.25, 4.38, P = 0.008), for the number

suffering somnolence (RIS-INT-24 DeDeyn) (19/115 compared

with 4/114, OR 4.20, 95% CI 1.78, 9.91, P = 0.001) and for the

number suffering fatigue (Teri 2000) (19/34 compared with 6/36,

OR 5.39, 95% CI 2.04, 14.22, P = 0.0007).

D I S C U S S I O N

Agitation in demented patients is a complex and difficult problem

to manage, and this is reflected in the multiple ways of assessing

and treating agitated dementia found in the publications reviewed

in this report. Several questions must be addressed in considering

haloperidol for the treatment of patients with agitated dementia:

1. Does haloperidol reduce agitation among demented patients,

compared with controls?

2. Does the degree of dementia influence response to haloperidol

treatment?

3. Do other factors (age, sex, type of dementia, type of agitation)

influence response to therapy?

4. How do dose and duration of therapy affect response to haloperi-

dol in demented agitated patients?

5. Are side effects more common among haloperidol treated pa-

tients?

6. Do side effects in patients treated with haloperidol result in

increased dropout rates?

Analysis of the results failed to demonstrate that haloperidol had a

significant general effect in controlling agitation in patients, com-

pared with controls, and therefore cannot be recommended for

the routine treatment of this condition.

Three studies (Allain 2000; RIS-INT-24 DeDeyn; Devanand

1998) showed a significant improvement in one aspect of agita-

tion, aggression, in haloperidol treated patients. This finding is

similar to that of Stehli 2000. Stehli showed little overall improve-

ment in agitation with haloperidol therapy, but found that a single



aspect of agitation, hostility/suspiciousness, appeared to respond

to haloperidol. Her report was completed prior to the study by

Allain 2000 and was unable to demonstrate any effect of haloperi-

dol on aggression in demented patients. Schneider’s early meta-

analysis (Schneider 1990) showed a modest benefit of haloperi-

dol in treating agitated dementia, but in Lanctot’s meta-analysis

(Lanctot 1998) there was no demonstrated benefit of haloperidol

for patients with agitated dementia, compared with controls.

These earlier meta-analyses support our finding that the most im-

portant effect of haloperidol may be on individual manifestations

of agitation, rather than the syndrome as a whole. Studies which

examine the response of the syndrome to treatment, rather than its

components, may not be sufficiently focused to detect improve-

ment in specific aspects of agitation in treated patients. Our re-

sults and those of Stehli suggest that haloperidol should be used

to treat ONE individual manifestation of agitation, NAMELY ag-

gression, rather than be used indiscriminately for any demented

patient who has been described as agitated.

The results were insufficient to determine whether degree of de-

mentia, age or sex of patients, or dose and duration of therapy

influenced response to haloperidol. In Devanand 1998, patients

receiving 2 - 3 mg of haloperidol per day appeared to respond

better to treatment than those given 0.5 - 0.75 mg per day, but

RIS-INT-24 DeDeyn showed an improvement in overall agita-

tion in patients receiving an average dose of haloperidol of 1.2 mg

per day, while Teri 2000 found no effect of haloperidol on agitated

dementia in patients given a mean dose of 1.8 mg per day.

Haloperidol could not be shown to reduce caregiver burden or to

improve physical functioning among treated patients, compared

with controls.

Pooled analysis showed adverse effects to be more common among

haloperidol treated patients, but only three studies (Allain 2000;

RIS-INT-24 DeDeyn; Teri 2000) specified the kinds of adverse

effects, demonstrating a significant increase in adverse reactions

such as extrapyramidal symptoms, somnolence, and fatigue, com-

pared with controls. Drop-outs due to adverse effects were more

common among treated patients (Allain 2000; Teri 2000), but

pooled analysis of all five studies showed no significant difference

in drop-out rates, comparing all treated and untreated patients.

Teri 2000 suggested that similar drop-out rates among haloperidol

and control patients may represent a beneficial trade-off in which

adverse effects were tolerated because of better control of agita-

tion. None of the studies specified reasons for drop-outs among

the control patients.

A report by Pelton in 2003 (Devanand 1998), examined haloperi-

dol plasma levels in Devanand’s earlier randomized controlled

study (Devanand 1998) and found that levels of -> 1.5 mg/nl were

associated with a 20% or greater reduction in BPRS total scores (P

< 0.01) compared with patients having lower plasma levels. Higher

haloperidol plasma levels (not specified) were also associated with

increased frequency of extrapyramidal adverse effects (P < 0.01).

Pelton was unable to demonstrate any association between oral

doses of haloperidol and efficacy or side effects, although there was

a correlation between oral doses and plasma levels of haloperidol.

Because Pelton’s study was a post hoc examination of Devanand’s

clinical trial, and because no placebo group was included in the

new analysis, these results must be interpreted with caution. Nev-

ertheless, Pelton’s report represents an effort to establish the link

between patient response and haloperidol treatment on a more

scientific basis. An earlier report (Dysken 1994) found no corre-

lation between plasma/red blood cell haloperidol levels and either

adverse effects of treatment or changes in behavior of patients,

but this study involved patients who had had previous exposure

to haloperidol, whereas in Pelton’s study only one of the patients

had been treated with haloperidol at any time prior to entering

the trial.

It was difficult to compare results among the studies because of

variations in dosage, length of treatment, and ways of assessing re-

sponse to care. The dosage of haloperidol varied from 0.25 mg per

day to 6.0 mg per day. The duration of therapy was from 3 weeks

to 16 weeks. Methods of measuring effects of therapy involved

application of more than a dozen different assessment scales. It

should be stated that the present review failed to demonstrate a

beneficial effect of haloperidol on agitated dementia. This is not

the same as proving that haloperidol has no effect on this condi-

tion; further study is needed to test this assertion.

The July 2005 update of the current review revealed no new

published studies of the effect of haloperidol on agitation in de-

mented patients, compared with placebo controls, but there has

been a growing interest in comparing atypical antipsychotics with

haloperidol, most recently in a crossover study comparing the ef-

fect of haloperidol with risperidone, and reported by Suh et al (Suh

2004). This emerging area of clinical investigation may offer an

opportunity for additional systematic reviews and meta-analyses.

Limitations of the present study

The major limitation was the inapplicability of meta-analysis to the

included studies owing to heterogeneity in the degree of dementia

of the study subjects, the outcome measures used, the measures of

agitation, and in the dosage and duration of haloperidol treatment.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

1. Meta-analysis of the studies described here showed no signifi-

cant general improvement of agitated dementia among haloperi-

dol treated patients, compared with controls. Based on these re-



sults, haloperidol cannot be recommended for routine use in the

control of agitated dementia.

2. In pooled analysis, haloperidol appeared to reduce aggression

among patients, compared with controls, and may be indicated

for this feature. There is no convincing evidence in the present

study to support the use of haloperidol for other manifestations

of agitation among demented patients.

3. Although adverse events were more common among haloperi-

dol treated patients, and two studies showed increased drop-outs

due to side effects, analysis showed no difference in drop-out rates,

comparing all treated and control patients. This suggests that ad-

verse effects may be tolerated if the drug is seen as effective in other

ways.

4. Treatment of agitated dementia with haloperidol should be

individualized, used only for people displaying aggression, and

with careful attention to response to therapy and to the appearance

of drug related side effects.

Implications for research

1. Studies should be carried out employing standard methods to

evaluate agitated dementia and to assess response to treatment.

In order to make comparison among studies possible it is recom-

mended that future reports use standard doses of medication and

lengths of treatment for patients with agitated dementia. Until

better standardization is available to permit comparisons among

studies, it is unlikely that further meta-analyses of this subject will

provide the kind of information clinicians need.

2. Information is needed about the relationship between under-

lying diagnoses and behavioral manifestations as they influence

response to therapy in agitated dementia.

3. The possibility of a beneficial trade-off, in which adverse effects

are tolerated because of the effectiveness of treatment in controlling

agitation, should be the subject of formal investigation.

4. Examination of the kind of haloperidol associated symptoms

that are associated with drop-outs may lead to better tailoring of

therapy for demented patients with agitation. More information

is also needed about the reasons control patients discontinue treat-

ment.

5. The evidence suggested that future research may be more pro-

ductive if increased focus is placed on individual aspects of agi-

tated dementia (e.g., aggression, hostility/suspicion) rather than

on overall response to therapy.

6. The emergence of new studies comparing atypical antipsy-

chotics with haloperidol in the control of agitation among de-

mented patients suggests a need for further systematic reviews on

this subject.

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

1. To Peter Smith for early editorial assistance and guidance.

2. To Jacqueline Birks for editorial evaluation, statistical review,

construction of analyses, and for helpful suggestions concerning

methodology and style.

3. To Dymphna Hermans and Vittoria Lutje for invaluable assis-

tance in performing the search of electronic databases.

R E F E R E N C E S

References to studies included in this review

Allain 2000 {published data only}

Allain H, Dautzenberg PHJ, Maurer K, Schuck S,

Bonhomme D, Gerard D. Double blind study of

tiapride versus haloperidol and placebo in agitation and

aggressiveness in elderly patients with cognitive impairment.

Psychopharmacology 2000;148(4):361–6.

Auchus 1997 {published data only}

Auchus AP, Bissey-Black C. Pilot study of haloperidol,

fluoxetine, and placebo for agitation in Alzheimer’s disease.

Journal of Neuropsychiatry and Clinical Neurosciences 1997;

9:591–3.

Devanand 1998 {published data only}

Devanand DP. Haloperidol and Alzheimer’s disease [Reply].

American Journal of Psychiatry 1999;156:2019–20.

Devanand DP, Marder K, Michaels K, Sackeim HA, Bell K,

Sullivan M, Cooper T, Mayeux R. A randomized, placebo-

controlled, dose-comparison trial of haloperidol treatment

for the behavioral complications of Alzheimer’s disease.

Proceedings of the 36th Annual Meeting of the American

College of Neuropsychopharmacology; 1997 December 8-

12, Waikoloa, Hawai, USA 1997. 1997.∗ Devanand DP, Marder K, Michaels KS, Sackeim HA,

Bell K, Sullivan MA, Cooper TB, Pelton GH, Mayeux R.

A randomized, placebo-controlled dose-comparison trial

of haloperidol for psychosis and disruptive behaviors in

Alzheimer’s disease. American Journal of Psychiatry 1998;

155:1512–20.

Devanand DP, Rodriguez JF, Marder K, Bell K, Sackeim

HA, Stern Y, Mayeux R. Low dose haloperidol treatment

of behavioural complications in Alzheimer’s disease.

Proceedings of the 8th Congress of the International

Psychogeriatric Association; 1997 August 17-22, Jerusalem,

Israel 1997. 1997:83.

Pelton GH, Devangere P, Devanand MD, Bell K, Marder



K, Marston K, et al.Usefulness of plasma haloperidol levels

for monitoring clinical efficacy and side effects in Alzheimer

patients with psychosis and behavioral dyscontrol. American

Journal of Geriatric Psychiatry 2003;11:186–93.

RIS-INT-24 DeDeyn {published data only}

DeDeyn PP, Rabheru K, Rasmussen MD, Bocksberger JP,

Dautzenberg PLJ, Eriksson S, Lawlor BA. A randomized

trial of risperidone, placebo, and haloperidol for behavioral

symptoms of dementia. Neurology 1999;53:946–55.

Teri 2000 {published data only}∗ Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF,

et al.Treatment of agitation in AD. A randomized placebo-

controlled clinical trial. Neurology 2000;55(9):1271–8.

Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF,

Tractenberg RE, et al.Treatment of agitation in alzheimer’s

disease a randomized placebo controlled clinical trial.

Proceedings of the 6th International Stockholm/Springfield

Symposium on Advances in Alzheimer Therapy; 2000 April

5-8, Stockholm, Sweden 2000. 2000:153.

References to studies excluded from this review

Beuzen 1999 {published data only}

Beuzen JN, Taylor N, Wesnes K, Wood A. A comparison

of the effects of olanzapine, haloperidol, and placebo on

cognitive and psychomotor function in healthy elderly

volunteers. Journal of Psychopharmacology 1999;13:152–8.

Burgio 1992 {published data only}

Burgio LD, Reynolds CF III, Janosky JE, Perel J, Thornton

JE, Hohman MJ. A behavioral microanalysis of the effects

of haloperidol and oxazepam on psychogeriatric inpatients.


Cantillon 1996 {published data only}

Cantillon M, Brunswick R, Molina D, Bahro M. A double-

blind trial for agitation in a nursing home population with

Alzheimer’s disease. American Journal of Geriatrics 1996;4

(3):263–7.

Carlyle 1993 {published data only}

Carlyle W, Ancil RJ, Sheldon L. Aggression in the demented

patient: a double-blind study of loxapine versus haloperidol.

International Clinical Psychopharmacology 1993;8:103–8.

Chan 2001 {published data only}

Chan WC, Lam LCW, Choy CNP, Leung VPY, Li SW,

Chiu HFK. A double-blind randomised comparison of

risperidone and haloperidol in the treatment of behavioural

and psychological symptoms in Chinese dementia patients.

International Journal of Geriatric Psychiatry 2001;16(12):

1156–62.

Christensen 1998 {published data only}

Christensen DB, Benfield WR. Alprazolam as an alternative

to low-dose haloperidol in older, cognitively impaired

nursing facility patients. Journal of the American Geriatrics

Society 1998;46(5):620–5.

Coccaro 1990 {published data only}

Coccaro EF, Kramer E, Zemishlany Z, Thorne A, Rice CM,

Giorani B, et al.Pharmacologic treatment of noncognitive

behavioral disturbances in elderly demented patients.

American Journal of Psychiatry 1990;147(12):1640–5.

Cowley 1979 {published data only}

Cowley LM, Glen RS. Double-blind study of thioridazine

and haloperidol in geriatric patients with a psychosis

associated with organic brain syndrome. Journal of Clinical

Psychiatry 1979;40(10):411–9.

Devanand 1989 {published data only}

Devanand DP, Sackeim HA, Brown RP, Mayeux R. A pilot

study of haloperidol treatment of psychosis and behavioral

disturbances in Alzheimer’s disease. Archives of Neurology

1989;46:854–7.

Dysken 1994a {published data only}

Dysken MW, Johnson SB, Holden L, Vatassery G, Nygren

J, Jelinski M, et al.Haloperidol concentrations in patients

with Alzheimer’s dementia. American Journal of Geriatric

Psychiatry 1994;2(2):124–33.

Evans 1998 {unpublished data only}

Evans M. Multi-centre double blind randomized parallel

group comparison of seroquel and haloperidol in the

treatment of elderly patients presenting with dementia,

psychosis. NRR Project NO262026571.

Fuglum 1989 {published data only}

Fuglum E, Schillinger A, Andersen JB, Belstad BE,

Jensen D, Muller F, et al.Zuclopenthixol and haloperidol/

levomepromazine in the treatment of elderly patients

with symptoms of aggressiveness and agitation: a double-

blind, multi-centre study. Pharmacotherapeutica 1989;5(5):

285–91.

Fuglum 1990 {published data only}

Fuglum E, Anersen JB, Belstad BE, Jensen D, Muller F,

Muller K, et al.Zuclopenthixol or haloperidol/levopromazine

in the elderly. A controlled multicenter double-blind study

[Zuclopenthixol og haloperidol/levpromazin hos eldre.

En kontrollert multisenterundersokelse dobbelt–blind

sammenligning]. Nordisk Psykiatrisk Tidskrift 1990;44(3):

291–4.

Gaber 2001 {published data only}

Gaber S, Ronzoni S, Bruno A, Biagi A. Sertraline Versus

Small Doses of Haloperidol in the Treatment of Agitated

Behavior in Patients With Dementia. Archives of Gerontology

and Geriatrics 2001;7:159–62.

Gotestam 1981 {published data only}

Gotestam KG, Ljunghall S, Olsson B. A double-blind

comparison of the effects of haloperidol and cis(Z)-

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Scandinavia 1981;(Suppl) 294:46–53.

Harnryd 1974 {published data only}

Harnryd C, Bjerkenstedt L, Lindholm H, Ljungberg L.

A controlled clinical trial of Buronil versus haloperidol

for agitation in elderly patients [En kontrollerad klinisk

provning av Buronil och haloperidol vid forvirringstillstand

hos aldre patienter]. Nordisk Psykiatrisk Tidskrift 1974;28

(6):469–72.



Huertas 2007 {published data only}

Huertas D, Lopez-Ibor Alino JJ, Molina JD, Chamorro

L, Balanza J, Jimenez MP, et al.Antiaggressive effect of

cyproterone versus haloperidol in Alzheimer’s disease: a

randomized double-blind pilot study. Journal of Clinical

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Lemke 1995 {published data only}

Lemke MR. Effect of carbamazepine on agitation in

Alzheimer’s inpatients refractory to neuroleptics. Journal of

Clinical Psychiatry 1995;56:354–7.

Lovett 1987 {published data only}

Lovett WC, Stokes DK, Taylor LB, Young ML, Free SM,

Phelan DG. Management of behavioral symptoms in

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Petrie 1982 {published data only}

Petrie WM, Thoma AB, Berney St, Fujimori M, Guy W,

Raghed M, et al.Loxapine in psychogeriatrics: a placebo-

and standard-controlled clinical investigation. Journal of

Clinical Psychopharmacology 1982;2(2):122–6.

Rosen 1979 {published data only}

Rosen HJ. Double-blind comparison of haloperidol and

thioridazine in geriatric outpatients. Journal of Clinical

Psychiatry 1979;40(1):17–20.

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Savaskan E, Schnitzler C, Schröder C, Cajochen C, Müller-

Spahn F, Wirz-Justice A. Treatment of behavioural, cognitive

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disease: haloperidol vs. quetiapine. The International

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Smith 1974 {published data only}

Smith GR, Taylor CW, Linkous P. Haloperidol versus

thioridazine for the treatment of psychogeriatric patients: a

double-blind clinical trial. Psychosomatics 1975;15:134–8.

Steele 1986 {published data only}

Steele C, Lucas MJ, Tune L. Haloperidol versus thioridazine

in the treatment of behavioral symptoms in senile dementia

of the Alzheimer’s type: preliminary findings. Journal of

Clinical Psychiatry 1986;47(6):310–2.

Sugarman 1964 {published data only}

Sugarman AA, Williams BH, Adlerstein AM. Haloperidol

in the psychiatric disorders of old age. American Journal of

Psychiatry 1964;120:1190–2.

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Suh GH, Greenspan AJ, Choi SK. Comparative efficacy

of risperidone versus haloperidol on behavioural and

psychological symptoms of dementia. International Journal

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Lonergan 2002

Lonergan E, Luxenberg J, Colford J, Birks J. Haloperidol

for agitation in dementia. Cochrane Database of

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14651858.CD002852]∗ Indicates the major publication for the study



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 included studies [ordered by study ID]

Allain 2000

Methods Multicentre, randomized, double-blind, placebo- controlled; parallel group

3 weeks treatment

Participants Hospitalized or nursing home patients; mean age 79.6yrs; female 64%. Dementia evaluation: DSM IIIR; Mini-Mental

State Examination (MMSE). Agitation evaluation: multidimensional Observation Scale for the Elderly Subjects

(MOSES). Global status: Clinical Global Improvement Scale (CGI)

Interventions Tiapride (N=102; haloperidol (N=101); placebo (N=103).; dose, Haloperidol 1mg twice daily to 3 mg twice daily,

po; 3 wk course

Outcomes Cognition evaluation (MMSE): no significant difference between haloperidol and placebo groups. Global improve-

ment evaluation (CGI): significant improvement in haloperidol compared with placebo group. Agitation evaluation:

(MOSES irritability/aggressiveness subscores): significant decrease in agitation in haloperidol compared with placebo

group. Adverse events evaluation (UKU side effects rating scale): Significant increase in extrapyramidal symptoms in

haloperidol versus placebo group. Neurological events (dystonia, muscle rigidity, hypokinesia) were more frequent

in the haloperidol than the placebo group. Dropouts evaluation: There was no significant difference in dropouts

between the haloperidol and placebo groups, although there were more dropouts associated with adverse events in

the haloperidol group (N = 17) than in the placebo group (N = 6)

Notes Method of randomization not described. Dropouts: haloperidol group (N = 21; adverse event 17); placebo group (N

= 16; adverse event 6)

Auchus 1997

Methods Randomized, double-blind, placebo- controlled. parallel group

6 weeks treatment

Participants Outpatients; mean age 75.6 yrs; female, 66%. Alzheimer’s dementia. Dementia evaluation: NINCDS-ADRDA

criteria and Agitation evaluation: Cohen-Mansfield Agitation Inventory; Behavioral Pathology in Alzheimer’s Disease

Rating Scale; Caregiver Stress Inventory

Interventions Fluoxetine (N=6); haloperidol (N=6); placebo (N=6); dose, Haloperidol 3mg per day; 6wk course

Outcomes Cognition evaluation: no measurement of changes in cognition with treatment. Agitation evaluation (CMAI; BE-

HAVE-AD; CSI): no significant difference in any of these scales comparing haloperidol with placebo group. Adverse

events evaluation (standardized questionnaire): number of adverse symptoms significantly higher in haloperidol (N=

15.6) compared with placebo (N=7.3) group. Drop outs evaluation: 2 dropouts because of adverse events (Parkinson-

ism and sedation) in the haloperidol group; 1 dropout (Parkinsonism and akathisia) in the placebo group. Function

evaluation: no measure of function

Notes Method of randomization not described. No measure of effect of study on cognition. Power analysis indicates

inadequate sample to detect clinically relevant difference between groups (to detect 20% difference with 90% power,

need 60 subjects)



Devanand 1998

Methods Randomized, double-blind, placebo-

controlled; cross-over

6 weeks + 6 weeks

Participants Outpatients with Alzheimer’s dementia; mean age 72.1yrs; female 64.8%. Dementia evaluation : Clinical Dementia

Rating Scale; Mini-

Mental State; DSM IIIR; criteria for probable Alzheimer’s disease, National Institute of Neurological and Com-

municative Disorders; Alzheimer’s Disease and Related Disorders Association. Agitation evaluation: Schedule for

Affective Disorders and Schizophrenia (SADS); Brief Psychiatric Rating Scale (BPRS); Behavioral Syndromes Scale

for Dementia. Functional impairment: modified Blessed Functional Activities Scale

Interventions Standard dose haloperidol, 2-3mg/d (N=20); placebo (N=20); 6 wk course

Outcomes Cognition evaluation (Mini-Mental State): no difference in standard dose, low dose, or placebo groups. Agitation

evaluation (BPRS; SADS): standard dose haloperidol showed significant improvement in BPRS psychosis and psy-

chomotor agitation than placebo, but not for SADS physical aggression or for BPRS hostile-suspiciousness scores.

Low dose haloperidol group showed no significant improvement over the placebo group. Adverse drug events evalu-

ation (Treatment Emergent Symptom Scale; Targeting Abnormal Kinetic Effects Scale - extrapyramidal symptoms):

no significant difference between standard dose, low dose, and placebo groups. Authors note that four patients had

severe extrapyramidal reactions with standard dose haloperidol, despite an overall P=0.08 rating for the standard

haloperidol group compared with placebo. No difference between low dose haloperidol and placebo in so far as

adverse drug events are concerned.

Function evaluation (Blessed Functional Activities Scale): no change in function, haloperidol standard dose, vs low

dose, vs placebo group

Notes Method of randomization not given. Dropouts: low dose haloperidol group (N=1); standared dose haloperidol group

(N=1); placebo group (N=4). No information about adverse events among dropouts

RIS-INT-24 DeDeyn

Methods Multicentre, randomized, double-blind, placebo-controlled; parallel group

12 weeks treatment

Participants Institutionalized patients; age 55 or older; mean age 81.5yrs; female, 56%. Alzheimer’s disease (67%), vascular de-

mentia (26%) and mixed dementia (7%). Dementia evaluation: DSM IV, MiniMental State Examination; Functional

Assessment Staging scale. Agitation evaluation: Cohen-Mansfield Agitation Inventory; Clinical Global Impression

scale; BEHAVE-AD scale). Functional evaluation: Functional Assessment Staging

Interventions Risperidone (N=115); haloperidol (N=115); Placebo (N=114); dose, Haloperidol 0.25mg daily to 2mg twice daily;

12wk course, end point at 30% improvement in test score

Outcomes Cognition evaluation: no measure of cognitive change in either haloperidol or placebo group. Agitation evaluation

(CMAI, BEHAVE-AD): significant improvement in physical and verbal aggressiveness in haloperidol group compared

with placebo. Adverse drug reactions evaluation (Extrapyramidal Symptom Rating Scale): extrapyramidal symptoms

were significantly higher in the haloperidol group compared with placebo (22% vs 11%). Function evaluation (FAST)

: no significant difference between haloperidol and placebo groups



RIS-INT-24 DeDeyn (Continued)

Notes Method of randomization: computer generated code. Dropouts: haloperidol group (N=34); placebo group (N=40).

No breakdown of number of adverse events among dropouts (text says no significant difference - estimate is N=20

for dropouts due to adverse events in placebo and haloperidol groups

Teri 2000

Methods Multicentre randomized, double-blind, placebo-controlled

parallel group

Participants Outpatients with Alzheimer’s dementia; mean age: 74.8 (behaviour management); 75.3 (haloperidol); 73.2 (tra-

zodone); 75.8 (placebo). Female: 54% (behavioral management); 59% (haloperidol); 41% (trazodone); 67% (placebo)

. Dementia rating: criteria for probable or possible Alzheimer’s disease - National Institute of Neurological and

Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. Agitation

assessment: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Behavioral Rating Scale for

Dementia (BRSD); Cohen-Mansfield Agitation Inventory (CMAI); the Agitated Behavior Inventory for Dementia

(ABID). Functional assessment: The Physical Self-Maintenance (PSM) and Instrumental Activities of Daily Living

(IADL) scales. Cognitive Functional assessment: The Mini-Mental State Examination (MMSE). Global assessment:

the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC)

Interventions Behavioral management techniques (N=41); haloperidol (N=34), dose range 0.5mg/d - 3.0mg/d, mean dose 1.8mg/

d; trazodone (N=37); placebo (N=36); 16 week course of treatment

Outcomes Cognitive evaluation (MMSE): no difference between haloperidol and placebo. Agitation (CMAI; CERAD-BRSD;

ABID): no significant difference between haloperidol and placebo. Functional status (PSM; IADL): haloperidol

treated patients had more functional decline (P<0.05) than placebo treated patients. Overall global status (ACDS-

CGIC): no significant difference between haloperidol and placebo groups. Adverse effects: adverse effects occurred

more frequently in haloperidol treated patients than placebo treated patients. Dropout rates: there was no significant

difference in dropout rates, comparing haloperidol with placebo treated patients

Notes Method of randomization not given. Dropouts: haloperidol (N=14), placebo (N=11). No significant difference in

dropout rate between haloperidol and placebo groups

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Beuzen 1999 Double blind, placebo controlled study. Subjects were healthy elderly volunteers. Not a study of the effect of

haloperidol on agitated dementia

Burgio 1992 No placebo group. The study compared the effect of haloperidol versus oxazepam on agitated dementia

Cantillon 1996 No placebo group. The study compared the effect of haloperidol versus buspirone on agitated dementia

Carlyle 1993 No placebo group. The study compared the effect of haloperidol versus loxapine on agitated dementia



(Continued)

Chan 2001 No placebo group. The study compared the effect of haloperidol with risperidone

Christensen 1998 No placebo group. The study compared the effect of haloperidol versus alprazolam on agitated dementia

Coccaro 1990 No placebo group. The study compared the effect of haloperidol, oxazepam, and diphenhydramine on agitated

dementia

Cowley 1979 No placebo group. The study compared the effect of haloperidol with thioridazine on agitated dementia

Devanand 1989 Single blind placebo controlled pilot study of effects of haloperidol on agitated dementia

Dysken 1994a No placebo group. No randomization. Authors note response to higher doses of haloperidol (BEHAVE-AD

scores). but no correlation between plasma/rbc haloperidol levels and either response to therapy or appearance

of side effects

Evans 1998 No placebo group; randomized, double-blind, parallel group comparison of haloperidol and seroquel on agitated

dementia

Fuglum 1989 No placebo group. The study compared the effect of haloperidol/levomepromazine versus zuclopenthixol on

agitated dementia

Fuglum 1990 No placebo group. The study compared the effect of haloperidol/levomepromazine versus zuclopenthixol on

agitated dementia

Gaber 2001 No placebo control. The study compared sertraline versus haloperidol

Gotestam 1981 No placebo group. The study compared the effect of haloperidol versus cis(Z)-clopenthixol on dementia. The

effects on agitation as well as global function were estimated

Harnryd 1974 No placebo group. The study compared the effect of haloperidol versus Buronil on agitated dementia

Huertas 2007 No placebo group. The study compared haloperidol with cyproterone

Lemke 1995 Open prospective study comparing the effect of carbamazepine versus carbamazapine plus haloperidol on agitated

dementia

Lovett 1987 No placebo group. The study compared the effect of haloperidol versus trifluoperazine on agitated dementia

Petrie 1982 Although schizophrenic patients were excluded from this study it appeared that patients with other psychiatric

conditions were not. The study compared the effect of haloperidol, placebo, and loxapine on agitated patients

who were demented

Rosen 1979 No placebo group. The study compared the effect of haloperidol versus thioridazine on agitated dementia

Savaskan 2006 Open label, no placebo group. The study compared the effect of haloperidol versus quetiapine

Smith 1974 No placebo group. The study compared the effect of haloperidol versus thioridazine on agitated dementia



(Continued)

Steele 1986 No placebo group. No acceptable randomization (alternate assignment to study groups). Open study. The study

compared the effect of haloperidol versus thioridazine on agitated dementia

Sugarman 1964 Randomized, double-blind, placebo-controlled. Study contained patients with long-standing psychiatric disor-

ders

Suh 2004 No placebo group. The study compared the effect of risperidone versus haloperidol

Sultzer 1997 No placebo group. Open study. The study compared the effect of haloperidol versus trazodone on agitated

dementia

Sun 2004 No placebo group. The study compared the effect of risperidone versus haloperidol

Tariot 2006 The patient population were not diagnosed with agitation only



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

Comparison 1. Haloperidol vs placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Behavioural symptoms (change

from baseline) ITT

4 369 Std. Mean Difference (IV, Fixed, 95% CI) -0.19 [-0.40, 0.01]

1.1 Fixed dose 3mg/day,

endpoint 6 weeks


1.2 Mean dose 1.7 mg/day,

endpoint 6 weeks



endpoint 12 weeks



endpoint 16 weeks


2 Agitation (change from baseline

) ITT



endpoint 6 weeks



endpoint 6 weeks



endpoint 12 weeks



endpoint 16 weeks


3 Aggression (change from baseline

) ITT

3 489 Std. Mean Difference (IV, Fixed, 95% CI) -0.31 [-0.49, -0.13]


endpoint 3 weeks



endpoint 6 weeks



endpoint 12 weeks


4 CGIC (improvement ) ITT 2 274 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.50 [0.88, 2.55]


endpoint 3 weeks

1 204 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.70 [0.91, 3.18]


endpoint 16 weeks


5 Caregiver burden (change from

baseline ) ITT

1 70 Mean Difference (IV, Fixed, 95% CI) 0.81 [-0.89, 2.51]


endpoint 16 weeks


6 Activities of daily living (change

from baseline ) ITT

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

6.1 Physical activities of daily

living, mean dose 1.8 mg/day,

endpoint 16 weeks




6.2 Instrumental activities of

daily living, mean dose 1.8

mg/day, endpoint 16 weeks


7 dropouts by endpoint 5 573 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.00 [0.68, 1.46]


endpoint 3 weeks



endpoint 6 weeks



endpoint 6 weeks



endpoint 12 weeks



endpoint 16 weeks


8 dropouts due to adverse events 2 274 Peto Odds Ratio (Peto, Fixed, 95% CI) 2.52 [1.22, 5.21]


endpoint 3 weeks



endpoint 16 weeks


9 Number suffering at least one

adverse event by endpoint



endpoint 3 weeks



endpoint 12 weeks


10 Number suffering an adverse

event (broken down by type)

by endpoint

3 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only

10.1 Extrapyramidal symptom

(mean dose 3.5mg/day,

endpoint 3 weeks)


10.2 Endocrine symptom

(mean dose 3.5mg/day,

endpoint 3 weeks)


10.3 Somnolence (Mean dose

1.2mg/day, endpoint 12 weeks)


10.4 Drooling (mean dose 1.8

mg/day, endpoint 16 weeks)


10.5 Parkinsonian gait (mean

dose 1.8 mg/day, endpoint 16

weeks)


10.6 Dry mouth (mean dose

1.8 mg/day, endpoint 16

weeks)


10.7 Dizziness (mean dose 1.8



10.8 Akathesia (mean dose 1.8



10.9 Rigidity (mean dose 1.8





10.10 Dyskinesia (mean


weeks)


10.11 Drowsiness (mean


weeks)


10.12 Bradykinesia (mean


weeks)


10.13 Tremor (mean dose 1.8



10.14 Fatigue (mean dose 1.8



Analysis 1.1. Comparison 1 Haloperidol vs placebo, Outcome 1 Behavioural symptoms (change from

baseline) ITT.

Review: Haloperidol for agitation in dementia

Comparison: 1 Haloperidol vs placebo

Outcome: 1 Behavioural symptoms (change from baseline) ITT

Study or subgroup Haloperidol Placebo

Std.Mean

Difference Weight

Std.Mean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Fixed dose 3mg/day, endpoint 6 weeks

Auchus 1997 5 -2.6 (8.6) 5 1 (4.9) 2.7 % -0.46 [ -1.73, 0.80 ]

Subtotal (95% CI) 5 5 2.7 % -0.46 [ -1.73, 0.80 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.72 (P = 0.47)

2 Mean dose 1.7 mg/day, endpoint 6 weeks

Devanand 1998 40 -4.48 (12.95) 20 -2.95 (14.9) 14.8 % -0.11 [ -0.65, 0.43 ]

Subtotal (95% CI) 40 20 14.8 % -0.11 [ -0.65, 0.43 ]




RIS-INT-24 DeDeyn 115 -6.6 (8.3) 114 -4.2 (10.1) 63.1 % -0.26 [ -0.52, 0.00 ]

Subtotal (95% CI) 115 114 63.1 % -0.26 [ -0.52, 0.00 ]




Teri 2000 34 -5.35 (22.41) 36 -5.28 (24.36) 19.4 % 0.00 [ -0.47, 0.47 ]

-4 -2 0 2 4

Favours haloperidol Favours placebo

(Continued . . . )



(. . . Continued)


Std.Mean

Difference Weight

Std.Mean

Difference


Subtotal (95% CI) 34 36 19.4 % 0.00 [ -0.47, 0.47 ]



Total (95% CI) 194 175 100.0 % -0.19 [ -0.40, 0.01 ]

Heterogeneity: Chi2 = 1.14, df = 3 (P = 0.77); I2 =0.0%


Test for subgroup differences: Chi2 = 1.14, df = 3 (P = 0.77), I2 =0.0%

-4 -2 0 2 4


Analysis 1.2. Comparison 1 Haloperidol vs placebo, Outcome 2 Agitation (change from baseline ) ITT.



Outcome: 2 Agitation (change from baseline ) ITT


Std.Mean

Difference Weight

Std.Mean

Difference



Auchus 1997 5 -2.4 (12) 5 -1.4 (8.9) 2.8 % -0.09 [ -1.33, 1.16 ]

Subtotal (95% CI) 5 5 2.8 % -0.09 [ -1.33, 1.16 ]




Devanand 1998 40 -0.55 (2) 20 -0.25 (1.9) 14.7 % -0.15 [ -0.69, 0.39 ]

Subtotal (95% CI) 40 20 14.7 % -0.15 [ -0.69, 0.39 ]




RIS-INT-24 DeDeyn 115 -3.3 (10.6) 114 -1.6 (13.7) 63.2 % -0.14 [ -0.40, 0.12 ]

Subtotal (95% CI) 115 114 63.2 % -0.14 [ -0.40, 0.12 ]


-4 -2 0 2 4


(Continued . . . )



(. . . Continued)


Std.Mean

Difference Weight

Std.Mean

Difference




Teri 2000 34 -7.26 (22.51) 36 -5.94 (18.5) 19.3 % -0.06 [ -0.53, 0.41 ]

Subtotal (95% CI) 34 36 19.3 % -0.06 [ -0.53, 0.41 ]



Total (95% CI) 194 175 100.0 % -0.12 [ -0.33, 0.08 ]




-4 -2 0 2 4


Analysis 1.3. Comparison 1 Haloperidol vs placebo, Outcome 3 Aggression (change from baseline ) ITT.



Outcome: 3 Aggression (change from baseline ) ITT


Std.Mean

Difference Weight

Std.Mean

Difference



Allain 2000 99 -6.75 (5.46) 101 -4.71 (5.01) 41.2 % -0.39 [ -0.67, -0.11 ]

Subtotal (95% CI) 99 101 41.2 % -0.39 [ -0.67, -0.11 ]




Devanand 1998 40 -0.52 (1.9) 20 -0.25 (1.9) 11.2 % -0.14 [ -0.68, 0.40 ]

Subtotal (95% CI) 40 20 11.2 % -0.14 [ -0.68, 0.40 ]




-1 -0.5 0 0.5 1


(Continued . . . )



(. . . Continued)


Std.Mean

Difference Weight

Std.Mean

Difference


RIS-INT-24 DeDeyn 115 -1.68 (3.1) 114 -0.82 (2.8) 47.6 % -0.29 [ -0.55, -0.03 ]

Subtotal (95% CI) 115 114 47.6 % -0.29 [ -0.55, -0.03 ]



Total (95% CI) 254 235 100.0 % -0.31 [ -0.49, -0.13 ]




-1 -0.5 0 0.5 1


Analysis 1.4. Comparison 1 Haloperidol vs placebo, Outcome 4 CGIC (improvement ) ITT.



Outcome: 4 CGIC (improvement ) ITT

Study or subgroup Haloperidol PlaceboPeto

Odds Ratio WeightPeto

Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI


Allain 2000 80/101 71/103 72.1 % 1.70 [ 0.91, 3.18 ]

Subtotal (95% CI) 101 103 72.1 % 1.70 [ 0.91, 3.18 ]

Total events: 80 (Haloperidol), 71 (Placebo)




Teri 2000 11/34 11/36 27.9 % 1.09 [ 0.40, 2.96 ]

Subtotal (95% CI) 34 36 27.9 % 1.09 [ 0.40, 2.96 ]




Total (95% CI) 135 139 100.0 % 1.50 [ 0.88, 2.55 ]


0.2 0.5 1 2 5

Favours placebo Favours haloperidol

(Continued . . . )



(. . . Continued)



Odds Ratio





0.2 0.5 1 2 5

Favours placebo Favours haloperidol

Analysis 1.5. Comparison 1 Haloperidol vs placebo, Outcome 5 Caregiver burden (change from baseline )

ITT.



Outcome: 5 Caregiver burden (change from baseline ) ITT

Study or subgroup Haloperidol PlaceboMean

Difference WeightMean

Difference



Teri 2000 34 -0.44 (3.22) 36 -1.25 (4.02) 100.0 % 0.81 [ -0.89, 2.51 ]

Total (95% CI) 34 36 100.0 % 0.81 [ -0.89, 2.51 ]



Test for subgroup differences: Not applicable

-4 -2 0 2 4




Analysis 1.6. Comparison 1 Haloperidol vs placebo, Outcome 6 Activities of daily living (change from

baseline ) ITT.



Outcome: 6 Activities of daily living (change from baseline ) ITT

Study or subgroup Haloperidol PlaceboMean

Difference WeightMean

Difference


1 Physical activities of daily living, mean dose 1.8 mg/day, endpoint 16 weeks

Teri 2000 34 2.5 (4) 36 1.31 (2.47) 100.0 % 1.19 [ -0.38, 2.76 ]

Subtotal (95% CI) 34 36 100.0 % 1.19 [ -0.38, 2.76 ]



2 Instrumental activities of daily living, mean dose 1.8 mg/day, endpoint 16 weeks

Teri 2000 34 1.8 (3.2) 36 0.89 (3.2) 100.0 % 0.91 [ -0.59, 2.41 ]

Subtotal (95% CI) 34 36 100.0 % 0.91 [ -0.59, 2.41 ]




-4 -2 0 2 4




Analysis 1.7. Comparison 1 Haloperidol vs placebo, Outcome 7 dropouts by endpoint.



Outcome: 7 dropouts by endpoint



Odds Ratio



Allain 2000 21/101 16/103 29.2 % 1.42 [ 0.70, 2.89 ]

Subtotal (95% CI) 101 103 29.2 % 1.42 [ 0.70, 2.89 ]





Devanand 1998 2/40 4/20 4.7 % 0.19 [ 0.03, 1.14 ]

Subtotal (95% CI) 40 20 4.7 % 0.19 [ 0.03, 1.14 ]





Auchus 1997 2/5 1/5 2.2 % 2.36 [ 0.18, 30.67 ]

Subtotal (95% CI) 5 5 2.2 % 2.36 [ 0.18, 30.67 ]





RIS-INT-24 DeDeyn 34/115 40/114 48.3 % 0.78 [ 0.45, 1.35 ]

Subtotal (95% CI) 115 114 48.3 % 0.78 [ 0.45, 1.35 ]





Teri 2000 14/34 11/36 15.6 % 1.58 [ 0.60, 4.17 ]

Subtotal (95% CI) 34 36 15.6 % 1.58 [ 0.60, 4.17 ]




Total (95% CI) 295 278 100.0 % 1.00 [ 0.68, 1.46 ]


Heterogeneity: Chi2 = 6.29, df = 4 (P = 0.18); I2 =36%


Test for subgroup differences: Chi2 = 6.29, df = 4 (P = 0.18), I2 =36%

0.1 0.2 0.5 1 2 5 10




Analysis 1.8. Comparison 1 Haloperidol vs placebo, Outcome 8 dropouts due to adverse events.



Outcome: 8 dropouts due to adverse events



Odds Ratio



Allain 2000 17/101 6/103 70.2 % 2.99 [ 1.26, 7.10 ]

Subtotal (95% CI) 101 103 70.2 % 2.99 [ 1.26, 7.10 ]





Teri 2000 6/34 4/36 29.8 % 1.69 [ 0.45, 6.40 ]

Subtotal (95% CI) 34 36 29.8 % 1.69 [ 0.45, 6.40 ]




Total (95% CI) 135 139 100.0 % 2.52 [ 1.22, 5.21 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.9. Comparison 1 Haloperidol vs placebo, Outcome 9 Number suffering at least one adverse

event by endpoint.



Outcome: 9 Number suffering at least one adverse event by endpoint



Odds Ratio



Allain 2000 77/101 69/103 50.2 % 1.57 [ 0.86, 2.88 ]

Subtotal (95% CI) 101 103 50.2 % 1.57 [ 0.86, 2.88 ]





RIS-INT-24 DeDeyn 92/115 83/114 49.8 % 1.49 [ 0.81, 2.74 ]

Subtotal (95% CI) 115 114 49.8 % 1.49 [ 0.81, 2.74 ]




Total (95% CI) 216 217 100.0 % 1.53 [ 1.00, 2.35 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.10. Comparison 1 Haloperidol vs placebo, Outcome 10 Number suffering an adverse event

(broken down by type) by endpoint.



Outcome: 10 Number suffering an adverse event (broken down by type) by endpoint



Odds Ratio


1 Extrapyramidal symptom (mean dose 3.5mg/day, endpoint 3 weeks)

Allain 2000 34/101 18/103 100.0 % 2.34 [ 1.25, 4.38 ]

Subtotal (95% CI) 101 103 100.0 % 2.34 [ 1.25, 4.38 ]




2 Endocrine symptom (mean dose 3.5mg/day, endpoint 3 weeks)

Allain 2000 6/101 8/103 100.0 % 0.75 [ 0.25, 2.22 ]

Subtotal (95% CI) 101 103 100.0 % 0.75 [ 0.25, 2.22 ]




3 Somnolence (Mean dose 1.2mg/day, endpoint 12 weeks)

RIS-INT-24 DeDeyn 19/115 4/114 100.0 % 4.20 [ 1.78, 9.91 ]

Subtotal (95% CI) 115 114 100.0 % 4.20 [ 1.78, 9.91 ]




4 Drooling (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 2/34 0/36 100.0 % 8.08 [ 0.49, 131.94 ]

Subtotal (95% CI) 34 36 100.0 % 8.08 [ 0.49, 131.94 ]




5 Parkinsonian gait (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 7/34 3/36 100.0 % 2.68 [ 0.71, 10.14 ]

Subtotal (95% CI) 34 36 100.0 % 2.68 [ 0.71, 10.14 ]




6 Dry mouth (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 9/34 5/36 100.0 % 2.17 [ 0.68, 6.95 ]

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)



Odds Ratio


Subtotal (95% CI) 34 36 100.0 % 2.17 [ 0.68, 6.95 ]




7 Dizziness (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 2/34 3/36 100.0 % 0.69 [ 0.11, 4.23 ]

Subtotal (95% CI) 34 36 100.0 % 0.69 [ 0.11, 4.23 ]




8 Akathesia (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 4/34 4/36 100.0 % 1.07 [ 0.25, 4.60 ]

Subtotal (95% CI) 34 36 100.0 % 1.07 [ 0.25, 4.60 ]




9 Rigidity (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 11/34 5/36 100.0 % 2.81 [ 0.93, 8.50 ]

Subtotal (95% CI) 34 36 100.0 % 2.81 [ 0.93, 8.50 ]




10 Dyskinesia (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 2/34 5/36 100.0 % 0.42 [ 0.09, 1.96 ]

Subtotal (95% CI) 34 36 100.0 % 0.42 [ 0.09, 1.96 ]




11 Drowsiness (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 10/34 5/36 100.0 % 2.48 [ 0.80, 7.71 ]

Subtotal (95% CI) 34 36 100.0 % 2.48 [ 0.80, 7.71 ]




12 Bradykinesia (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 11/34 7/36 100.0 % 1.95 [ 0.67, 5.65 ]

Subtotal (95% CI) 34 36 100.0 % 1.95 [ 0.67, 5.65 ]




0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)



Odds Ratio


13 Tremor (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 9/34 5/36 100.0 % 2.17 [ 0.68, 6.95 ]

Subtotal (95% CI) 34 36 100.0 % 2.17 [ 0.68, 6.95 ]




14 Fatigue (mean dose 1.8 mg/day, endpoint 16 weeks)

Teri 2000 19/34 6/36 100.0 % 5.39 [ 2.04, 14.22 ]

Subtotal (95% CI) 34 36 100.0 % 5.39 [ 2.04, 14.22 ]




Test for subgroup differences: Chi2 = 17.36, df = 13 (P = 0.18), I2 =25%

0.01 0.1 1 10 100


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

Table 1. Baseline Characteristics

Name Country Population Mean Age % Female Intervention Diagnosis Mean MMSE

Allain 2000 France,

Holland, Ger-

many

Institutional-

ized;

Alzheimer’s

dementia; vas-

cular demet-

nia; various

dementias

79.6 64.0% Tri-

apride (N=102);

haloperidol (N=

101)

; placebo (N=

103); haloperi-

dol dose 2mg -

6mg per day, po;

3wk course

Demen-

tia: DSM IIIR

criteria for mild

or moderate de-

mentia;; Ag-

itation: MOSES

subscale

score (irritabil-

ity/aggressive-

ness)between 16

and 30; Global:

CGI;

Auchus 2000 United States Outpatients;

Alzheimer’s

dementia

75.6 66.6% Fluoxetine (N=

5);

haloperidol (N=

5); placebo (N=

5); 3 wk course;

haloperidol dose

3mg day po

Dementia:

NINCDS-

ADRDA criteria

for probable or

possible AD; Ag-

itation: CMAI

(short

15.2 (4.6)



Table 1. Baseline Characteristics (Continued)

form) score of

25 or more; BE-

HAVED-AD

DeDyn 1999 Belgium,

Canada, Den-

mark, United

Kingdom, Re-

public of Ire-

land, The

Netherlands,

Sweden,

Switzerland

Institutional-

ized;

Alzheimer’s

dementia; vas-

cular demen-

tia; various de-

mentias

81.5 56..3% Risperidone (N=

115); haloperi-

dol (N=115)

; placebo (N=

114); end point

30% re-

duction in mean

BEHAVED-AD

score from base-

line or after 12

wks; haloperidol

dose 0.25mg -

4mg per day po,

mean dose 1.

2mg per day

Dementia:

DSM IV criteria

for Alzheimer’s

dementia, vascu-

lar dementia, or

mixed dementia;

Ag-

itation: CMAI;

BEHAVED-AD

8.4

Devanand

1998

United States Outpatients;

Alzheimer’s

dementia

72.1 64.8% Haloperidol

0.5mg - 0.75mg

per day po (N=

20); haloperidol

2mg - 3mg per

day po (N=20);

placebo (N=20);

6 wk course

Dementia:

DSM IIIR crite-

ria for dementia

and the NICDS

and

ADRDA crite-

ria for probable

Alzheimer’s Dis-

ease; Agitation:

SADS-PD crite-

ria for the pres-

ence of a hallu-

cination or delu-

sion; as well as a

BPRS score of 4

(moderate sever-

ity) on the hallu-

cinatory

behaviour or

unusual thought

content item, or

a total score of

6 or more on

these two items;

the criterion for

disruptive

behaviour was 4

19.4 (11.6)



Table 1. Baseline Characteristics (Continued)

or more on the

scale for physi-

cal aggression or

psychomotor ag-

itation

on the Behavior

Syncromes Scale

for Dementia

(DSSD)

Teri 2000 United States Outpatients;

Alzheimer’s

dementia

75.3 62.8% Haloperidol 0.

5mg - 3.0 mg per

day po (N=34);

placebo (N=36);

16 wk course

Dementia:

NINCDS-

ADRDA criteria

for probable or

possible AD; Ag-

itation: Agitated

Behavior Inven-

tory for Demen-

tia

ABID), at least

two episodes per

week for

two weeks prior

to entering the

study; ADCS-

CGIC; BRSD;

CMAI; ABID

13.0 (7.5)

Table 2. Outcomes, Instruments, and Studies

Outcomes Instruments Studies

Agitation Multidimensional Observational Scale for Elderly

Subjects (MOSES), irritability, aggressiveness subscale

Allain 2000

Cohen-Mansfield Agitation Inventory (CMAI) Auchus 1997

CMAI DeDyn 1999



Table 2. Outcomes, Instruments, and Studies (Continued)

Behavioral Pathology in Alzheimer’s Disease Rating

Scale (BEHAVE-AD)

Auchus 1997

BEHAVE-AD DeDyn 1999

Brief Psychiatric Rating Scale (BPRS), hallucinatory

behavior or unusual content item

Devanand 1998

Schedule for Affective Disorders and Schizophrenia

(SADS), psychiatric disorganization item subset

Devanand 1998

Global Impression Clinical Global Impression Scale (CGI) Allain 2000

Side Effects UKU Side Effecft Rating Scale (UKU) Allain 2000

Neurologic Events Allain 2000

Number of Adverse Symptoms Auchus 1997

Extrapyramidal Symptom Rating Scale (ESRS) DeDyn 1999

Treatment Emergent Symptoms (TES) Devanand 1998

Targeting Abnormal Kinetic Effects (TAKE) Devanand 1998

Rockland Tardive Dyskenisia Scale (ROCKLAND) Devanand 1998

Cognition/Function MiniMental State Examination (MMSE) Allain 2000

MMSE Devanand 1998

Agitation Alzheimer’s Disease Cooperative Study Clinical

Global Impression of Change (ADCS-CGIC); Con-

sortium to Establish a Registry for Alzheimer’s Dis-

ease Behavioral Rating Scale for Dementia (CERAD-

BRSD); CMAI; Agitated Behavior Inventory for De-

mentia (ABID)

Teri 2000

Global Impression ADCS-CGIC Teri 2000

Side Effects Side Effects Check list Teri 2000

Cognition/Function MMSE; Physical Self-Maintenance (PMS); Instru-

mental Activities of Daily LIving (IADL)

Teri 2000



A P P E N D I C E S

Appendix 1. Update search: June 2010

Source Search strategy Hits

MEDLINE In-process and other non-

indexed citations and MEDLINE 1950-

present (Ovid SP)

1. exp Dementia/

2. Delirium/

3. Wernicke Encephalopathy/

4. Delirium, Dementia, Amnestic, Cogni-

tive Disorders/

5. dement*.mp.

6. alzheimer*.mp.

7. (lewy* adj2 bod*).mp.

8. deliri*.mp.

9. (chronic adj2 cerebrovascular).mp.

10. (“organic brain disease” or “organic

brain syndrome”).mp

11. (“normal pressure hydrocephalus” and

“shunt*”).mp.

12. “benign senescent forgetfulness”.mp.

13. (cerebr* adj2 deteriorat*).mp.

14. (cerebral* adj2 insufficient*).mp.

15. (pick* adj2 disease).mp.

16. (creutzfeldt or jcd or cjd).mp.

17. huntington*.mp.

18. binswanger*.mp.

19. korsako*.mp.

20. or/1-19

21. *Haloperidol/

22. halop*.mp.

23. Aloperid*.mp.

24. haldol*.mp.

25. (galoperidol or sigaperidol).mp.

26. (bioperidolo or brotopon or dozic or

duraperidol).mp.

27. (halosten or keselan or linton or peluces

or serenace or serenase).mp

28. or/21-27

29. 20 and 28

30. randomized controlled trial.pt.

31. controlled clinical trial.pt.

32. randomized.ab.

33. placebo.ab.

34. drug therapy.fs.

35. randomly.ab.

36. trial.ab.

37. groups.ab.

38. or/30-37

58



(Continued)

39. (animals not (humans and animals)).

sh.

40. 38 not 39

41. 29 and 40

42. 2008*.ed.

43. 2009*.ed.

44. 2010*.ed.

45. or/42-44

46. 45 and 41

EMBASE

1980-2010 week 21 (Ovid SP)

1. exp dementia/

2. Lewy body/

3. delirium/

4. Wernicke encephalopathy/

5. cognitive defect/

6. dement*.mp.

7. alzheimer*.mp.


9. deliri*.mp.




12. “supranuclear palsy”.mp.


“shunt*”).mp.






19. huntington*.mp.

20. binswanger*.mp.

21. korsako*.mp.

22. CADASIL.mp.

23. or/1-22

24. haloperidol/

25. halop*.mp.

26. aloperid*.mp.

27. haldol*.mp.



duraperidol).mp.



31. or/24-30

32. 23 and 31

33. randomized controlled trial/

34. “randomi?ed controlled trial”.mp.

35. controlled clinical trial/

123



(Continued)

36. placebo.ab.

37. randomly.ab.

38. trial.ab.

39. groups.ab.

40. or/33-39

41. 32 and 40

42. 2008*.em.

43. 2009*.em.

44. 2010*.em.

45. or/42-44

46. 41 and 45

PSYCINFO

1806-May week 4 2010 (Ovid SP)

1. exp Dementia/

2. exp Delirium/

3. exp Huntingtons Disease/

4. exp Kluver Bucy Syndrome/

5. exp Wernickes Syndrome/

6. exp Cognitive Impairment/

7. dement*.mp.

8. alzheimer*.mp.


10. deliri*.mp.




13. “supranuclear palsy”.mp.


“shunt*”).mp.






20. huntington*.mp.

21. binswanger*.mp.

22. korsako*.mp.

23. (“parkinson* disease dementia” or PDD

or “parkinson* dementia”).mp

24. or/1-23

25. exp Haloperidol/

26. halop*.mp.

27. Aloperid*.mp.

28. haldol*.mp.



duraperidol).mp.



32. or/25-31

16



(Continued)

33. 24 and 32

34. exp Clinical Trials/

35. randomi?ed.mp.

36. placebo.ab.

37. randomly.ab.

38. trial.ab.

39. groups.ab.

40. or/34-39

41. 33 and 40

42. 2008*.up.

43. 2009*.up.

44. 2010*.up.

45. or/42-44

46. 41 and 45

CINAHL (EbscoHOST) S1 (MH “Dementia+”)

S2 (MH “Delirium”) or (MH “Delir-

ium, Dementia, Amnestic, Cognitive Dis-

orders”)

S3 (MH “Wernicke’s Encephalopathy”)

S4 TX dement*

S5 TX alzheimer*

S6 TX lewy* N2 bod*

S7 TX deliri*

S8 TX chronic N2 cerebrovascular

S9 TX “organic brain disease” or “organic

brain syndrome”

S10 TX “normal pressure hydrocephalus”

and “shunt*”

S11 TX “benign senescent forgetfulness”

S12 TX cerebr* N2 deteriorat*

S13 TX cerebral* N2 insufficient*

S14 TX pick* N2 disease

S15 TX creutzfeldt or jcd or cjd

S16 TX huntington*

S17 TX binswanger*

S18 TX korsako*

S19 S1 or S2 or S3 or S4 or S5 or S6 or S7

or S8 or S9 or S10 or S11 or S12 or S13 or

S14 or S15 or S16 or S17 or S18

S20 (MH “Haloperidol”)

S21 TX halop*

S22 TX Aloperid*

S23 TX haldol*

S24 TX galoperidol OR sigaperidol

S25 TX bioperidolo OR brotopon OR

dozic OR duraperidol

S26 TX halosten OR keselan OR linton

OR peluces OR serenace OR serenase

40



(Continued)

S27 S20 or S21 or S22 or S23 or S24 or

S25 or S26

S28 S19 and S27

S29 EM 2008

S30 EM 2009

S31 EM 2010

S32 S29 or S30 or S31

S33 S28 and S32

Web of Science with Conference Proceed-

ings (1945 to present)

Topic=(haloperidol OR haldol* OR

aloperid* OR galoperidol OR sigaperidol)

AND Topic=(dement* OR alzheimer* OR

lewy) AND Topic=(random* OR trial OR

placebo OR “double-blind*”) AND Year

Published=(2008-2010)

40

LILACS (BIREME) haloperidol OR aloperid* OR galoperi-

dol OR sigaperidol OR bioperidolo OR

brotopon OR dozic OR duraperidol OR

halosten OR keselan OR linton OR peluces

OR serenace OR serenase [Words] and de-

men$ OR alzheimer$ OR lew$ OR agi-

tat$ [Words] and random$ OR trial OR

placebo [Words]

0

ALOIS (www.medicine.ox.ac.uk/alois) Advanced search: Study Aim: Treatment

Dementia AND Study Design: RCT AND

Intervention: haloperidol

41

Umin (Clinical Trial register of Japan) Keyword: haloperidol 2

CENTRAL (The Cochrane Library) #1 MeSH descriptor Dementia explode all

trees

#2 MeSH descriptor Delirium, this term

only

#3 MeSH descriptor Wernicke En-

cephalopathy, this term only

#4 MeSH descriptor Delirium, Dementia,

Amnestic, Cognitive Disorders, this term

only

#5 dement*

#6 alzheimer*

#7 “lewy* bod*”

#8 deliri*

#9 “chronic cerebrovascular”

#10 “organic brain disease” or “organic

brain syndrome”

#11 “normal pressure hydrocephalus” and

“shunt*”

24



(Continued)

#12 “benign senescent forgetfulness”

#13 “cerebr* deteriorat*”

#14 “cerebral* insufficient*”

#15 “pick* disease”

#16 creutzfeldt or jcd or cjd

#17 huntington*

#18 binswanger*

#19 korsako*

#20 (#1 OR #2 OR #3 OR #4 OR #5 OR

#6 OR #7 OR #8 OR #9 OR #10 OR #

11 OR #12 OR #13 OR #14 OR #15 OR

#16 OR #17 OR #18 OR #19)

#21 agitat* OR BPSD OR “behavioural

and psychological”

#22 (#20 OR #21)

#23 haloperidol*

#24 MeSH descriptor Haloperidol explode

all trees

#25 Aloperid*

#26 haldol*

#27 galoperidol OR sigaperidol

#28 bioperidolo OR brotopon OR dozic

OR duraperidol

#29 halosten OR keselan OR linton OR

peluces OR serenace OR serenase

#30 (#23 OR #24 OR #25 OR #26 OR #

27 OR #28 OR #29)

#31 (#30 AND #22), from 2008 to 2010

Clinicaltrials.gov Interventional Studies | dementia OR

alzheimer OR alzheimer’s OR agitation |

haloperidol OR Aloperidol OR galoperi-




OR serenace OR serenase | received from

01/01/2008 to 06/18/2010

12

ICTRP Search Portal Interventional Studies | dementia OR

alzheimer OR alzheimer’s OR agitation |

haloperidol OR Aloperidol OR galoperi-




OR serenace OR serenase | received from

01/01/2008 to 18/06/2010

8

Total 364



(Continued)

Total after de-dulication and first-assess 15

Appendix 2. Update search: January 2008

Source Search strategy Hits

CDCIG SR (now called ALOIS) Halop* OR aloperid* OR haldol OR ga-

loperidol

223

Pubmed (Halop* OR aloperid* OR haldol OR ga-

loperidol)

AND

(((Dementia OR Alzheimer$ OR (Lewy

body) OR arteriosclerosis OR (Hunting-

ton disease) OR (Kluver Bucy) OR (Pick

disease) OR delirium OR (cerebrovascu-

lar disorder$) OR (Wernicke encephalopa-

thy) OR (Korsakoff psychosis) OR ((cog-

nit$ or memory$ or mental$) AND (de-

clin$ or impair$ or los$ or deteriorat$)) OR

(cerebr$ deteriorat$) OR (cerebr$ insuffi-

cien$)

60

Embase; PsycINFO; CINAHL (Ovid SP) (Halop* OR aloperid* OR haldol OR ga-

loperidol)

AND










cien$)

72

LILACS (BIREME) Halop* OR aloperid* OR haldol OR ga-

loperidol)

AND

LILACS search strategy from “Dementia

Group Search strategy for Specialized Reg-

ister ie dementia terms)

0



(Continued)

CENTRAL (The Cochrane Library) (Halop* OR aloperid* OR haldol OR ga-

loperidol)

AND










cien$)

2

Total after de-duplication and first-assess 176

W H A T ’ S N E W

Last assessed as up-to-date: 4 October 2010.

Date Event Description

5 March 2012 Amended Additional table(s) linked to text

H I S T O R Y

Protocol first published: Issue 4, 2000

Review first published: Issue 4, 2002

Date Event Description

2 June 2010 New search has been performed An update search was performed for this review on 2

June 2010. No new studies were identified for either

inclusion or exclusion within the review

12 September 2008 New search has been performed An update search was performed in January 2008;

this search retrieved no new studies of placebo versus

haloperidol for inclusion in this update. A number of

new studies have been excluded from the review

12 September 2008 Amended Converted to new review format.



(Continued)

24 August 2005 New search has been performed A minor update was published in August 2005

27 February 2002 New citation required and conclusions have changed Substantive amendment

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

-E. Lonergan: drafting of review versions; all correspondence; selection of trials; extraction of data; entry of data; interpretation of data

analyses; updating review

-J. Luxenberg: drafting of review versions; selection of trials; extraction of data; interpretation of data analyses

-J. Colford: Statistical consultation; arbiter in selection of trials; interpretation of data analysis

-A. Ludvik: Literature searches; lay reviewer; preparation of lay reports

-This review has been peer reviewed.

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

None known

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

Internal sources

• VA Medical Center, San Francisco, USA.

• Division of Clinical Geratology, Nuffield Department of Clinical Medicine, University of Oxford, UK.

External sources

• National Health Service, Research and Development, UK.

N O T E S

17/07/03: An updated literature search revealed no new randomized controlled trials since the last review, and no new evidence to alter

the results and recommendations of our report of 2002. A new article (Pelton 2003) described plasma haloperidol levels of an earlier

RCT (Devanand 1998), finding that haloperidol plasma levels of -> 1.5 ng/ml, but not doses of haloperidol (range, 0.5 mg/d - 3.0

mg/d), correlated with improvement in agitation as measured by Brief Psychiatric Rating Scale total scores (P < 0.01), and that higher

haloperidol plasma levels were also associated with increased frequency of extrapyramidal side effects. Because the findings were derived

from a post-hoc analysis of Devanand’s 1998 study, and did not include comparison with BPRS changes among control subjects they

must be interpreted cautiously. Nevertheless, the new study represents an effort to establish a more direct link between haloperidol

therapy of demented patients with agitation, and patient response (improvement and side effects) to therapy.



I N D E X T E R M S

Medical Subject Headings (MeSH)

Aggression [drug effects]; Anti-Dyskinesia Agents [adverse effects; ∗therapeutic use]; Dementia [∗complications]; Haloperidol [adverse

effects; ∗therapeutic use]; Psychomotor Agitation [∗drug therapy; etiology]; Randomized Controlled Trials as Topic

MeSH check words

Humans



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Cochrane Database of Systematic Reviews (Reviews) || Haloperidol for agitation in dementia

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