REVIEW

Efficacy of Cholinesterase Inhibitors in the

Treatment of Neuropsychiatric Symptoms and
Functional Impairment in Alzheimer Disease
A Meta-analysis
Nhi-Ha Trinh, MD, MPH
Jennifer Hoblyn, MB, MRCPsych, MPH
Subhanjoy Mohanty, PhD
Kristine Yaffe, MD

LZHEIMER DISEASE (AD) IS THE

most common form of dementia, accounting for more than
50% of all dementia cases, and
the number of affected individuals will
likely quadruple over the next several
decades.1 Research in the treatment of AD
has focused on reducing cognitive decline
with cholinesterase inhibitors (ChIs), the
primary class of medications currently
available for this purpose. However, neuropsychiatric symptoms and functional
deficits also contribute greatly to the disability associated with AD. As many as
80% of patients with AD will experience neuropsychiatric symptoms such as
hallucinations, paranoia, agitation, and
affective disturbances during the course
of their illness.2,3 Functional impairment occurs in all patients with AD, first
appearing as impairment in instrumental activities of daily living (IADL) tasks,
including using the telephone and taking medications. As the disease
progresses, alterations in basic activities
of daily living (ADLs), such as feeding
and dressing, become evident.4 Both neuropsychiatric symptoms and functional
impairment contribute to an increase in
caregiver burden, poor patient quality of
life, and institutionalization.5,6
Cognitive deficits are linked to cholinergic dysfunction. More recently,
210

Context Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of
cholinesterase inhibitors are conflicting.
Objective To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD.
Data Sources We performed a literature search of trials using MEDLINE ( January
1966December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed,
and the Cochrane Controlled Trials Register. We retrieved English- and nonEnglishlanguage articles for review and collected references from bibliographies of reviews,
original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies.
Study Selection We included 29 parallel-group or crossover randomized, doubleblind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor.
Sixteen trials included neuropsychiatric and 18 included functional measures.
Data Extraction Two investigators (N.H.T. and J.H.) independently extracted study
methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured
with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease
Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with
the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales
and analyzed with the standardized mean difference method.
Data Synthesis For neuropsychiatric outcomes, 10 trials included the ADAS-noncog
and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase
inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points),
and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI,
0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no
difference in efficacy among various cholinesterase inhibitors.
Conclusions These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.
www.jama.com

JAMA. 2003;289:210-216
Author Affiliations are listed at the end of this article.
Corresponding Author and Reprints: Kristine Yaffe,
MD, Department of Psychiatry, San Francisco

JAMA, January 8, 2003Vol 289, No. 2 (Reprinted)

Veterans Affairs Medical Center, University of California, San Francisco, Box 111G, 4150 Clement St, San
Francisco, CA 94121 (e-mail: kyaffe@itsa.ucsf.edu).

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CHOLINESTERASE INHIBITORS IN ALZHEIMER DISEASE

neuropsychiatric and functional deficits have also been associated with cholinergic dysfunction, with growing interest in ChIs for treatment of these
symptoms in AD.7,8 Several clinical trials have included neuropsychiatric and
functional measures, but have had conflicting results. In addition, these trials varied in numbers of subjects (ranging from 16 to 978) and used a variety
of different measures of behavior and
function.9-11 Thus, we conducted a systematic review and meta-analysis to
quantify the efficacy of ChIs on neuropsychiatric and functional outcomes in patients with mild to moderate AD and living in the community.
METHODS
Identification of Trials

We searched MEDLINE (January 1966December 2001), Dissertation Abstracts On-line, PSYCHINFO, BIOSIS,
PubMed, and the Cochrane Controlled Trials Register using the terms
Alzheimer disease, dementia, and cholinesterase inhibitor. Based on the title
of publication and abstract, we retrieved English-language and non
English-language articles for review,
and also collected additional references from bibliographies of reviews,
original research articles, and other articles of interest. We searched for both
published and unpublished trials, contacting researchers and pharmaceutical companies.
Inclusion Criteria

Two investigators (N.H.T. and J.H.) independently reviewed all pertinent articles using predetermined inclusion criteria. A trial was included if (1) it was
randomized, double-blinded, and placebo-controlled; (2) the design of the trial
was either parallel or crossover; (3) if a
crossover trial, it had a washout period
greater than 1 week, (4) patients enrolled were outpatients diagnosed as having mild to moderate, probable AD according to National Institute of
Neurological and Communicative Disorders and StrokeAlzheimers Disease
and Related Disorders Association
(NINCDS-ADRDA) criteria,12 with a

Table 1. Trials of Cholinesterase Inhibitors Using the NPI and ADAS-noncog Scales for
Neuropsychiatric Outcomes in Patients With Alzheimer Disease

Morris et al,26 1998

Dubois et al,33 1999
Raskind et al,35 1999
Tariot et al,23 2000

408
605
264
978

Rockwood et al,24 2001

Winblad et al,41 2001

386
286

Medication,
mg/kg per d
NPI*
Metrifonate, 0.65
Metrifonate, 0.65 or 1.0
Metrifonate, 50 mg/d
Galanthamine, 8, 16,
or 24 mg/d
Galanthamine, 24 or 32 mg/d
Donepezil, 10 mg/d

Davis et al,45 1992

Farlow et al,27 1992
Knapp et al,25 1994
Wood,39 1994
Forette et al,28 1995
Becker et al,29 1996
Zemlan et al,32 1996
Becker et al,22 1998
Jann et al,38 1999
Moller et al,34 1999

215
468
653
154
130
50
309
47

ADAS-noncog
Tacrine, 40 or 80
Tacrine, 20, 40, or 80
Tacrine, 80, 120, or 160
Tacrine, 80 mg/d (mean dosage)
Tacrine, 40 or 80
Metrifonate, 2.1 mg/kg per wk
Velnacrine, 30, 75, 150, or 225
Metrifonate, 2.9 mg/kg per wk

Source

Subjects,
No.

395
181

Metrifonate, 50 mg/d
Physostigmine patch,
30 or 60 mg (5.7 mg/d)

Trial
Intention-to-Treat
Length, d
Analysis
168
168
182
150

Yes
Yes
Yes
Yes

90
365

Yes
Yes

42
84
210
84
42
84
42
180

Yes
Yes
Yes
No
Yes
No
Yes
Yes

42
168

No
No

Abbreviations: ADAS-noncog, Alzheimer Disease Assessment Scale, noncognitive; NPI, Neuropsychiatric Inventory.
*Three trials also reported the ADAS-noncog.

baseline Mini-Mental State Examination score of 10 to 26; (5) the trial involved more than 1 month of treatment
with 1 of the following ChIs: donepezil,
eptastigmine, galantamine, metrifonate, physostigmine, rivastigmine, tacrine, tacrine with lecithin, and velnacrine; (6) neuropsychiatric outcomes
were measured with the most common
neuropsychiatric scales used, the noncognitive portion of the Alzheimer Disease Assessment Scale (ADAS-noncog,
scored 0-50) or Neuropsychiatric Inventory (NPI, scored 0-120); and (7) functional outcomes were measured on a validated score separated by ADL and IADL
domains (TABLE 1). Functional measures that combined ADL and IADL domains were excluded. For each trial, the
reviewers were blinded to the authors
and journal, and independently abstracted sample size, treatment regimen, trial length, outcome measures, and
whether the trial used an intention-totreat (ITT) analysis. The reviewers discussed the abstracted data and reached
a consensus to resolve any discrepancies in the collected data.

2003 American Medical Association. All rights reserved.

Statistical Analysis

Using a random-effects model and

widely used meta-analytic methods, we
calculated effect sizes for each outcome measure to compare treatment
and placebo groups.13 For treatment and
placebo groups in each trial, we collected the mean and variance for the
change in scores from baseline, using
the ITT analysis. If data from the ITT
analysis were not available, we used the
completed subjects analysis. For trials
not providing the above data directly,
we calculated the data from given information, using widely used statistical techniques.14,15 In dose-ranging trials with multiple treatment groups, we
combined treatment groups by weighting the effects for each subgroup by its
sample size.
For the NPI and the ADAS-noncog
meta-analyses, we used the weighted
mean difference method, in which effect
size is the difference in the change of
score from baseline between the treatment and placebo groups; we present
results as points of the scale.13 If trials
reported both scales, we used the NPI

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CHOLINESTERASE INHIBITORS IN ALZHEIMER DISEASE

could be combined.13,15 If we found evidence of heterogeneity, we reanalyzed

the data to explore potential sources. We
used funnel plots and the Kendall tau to
evaluate potential publication bias.18

results because the NPI scale includes

more categories of neuropsychiatric
problems, such as anxiety, apathy, and
aggression.16 Because of diversity of
scales reported for functional measures (4 scales in ADL and 2 scales in
IADL domains), we used the standardized mean difference method to calculate effect size, defined as the difference in change of score from baseline
between the treatment and placebo
groups divided by the pooled SD of the
trial; we present results in SDs.17
We present results as overall summary estimates combining all ChIs, together with 95% confidence intervals
(CIs). For each outcome, we also conducted separate meta-analyses for each
type of ChI if 3 or more trials existed for
that agent. We tested for statistical homogeneity with the Mantel-Haenszel test
using P.10 to reject the null hypothesis that trials were homogeneous and

RESULTS
We examined a total of 3000 titles or abstracts in the literature search to identify published trials for possible inclusion. We identified 8 unpublished trials;
none met our predetermined inclusion
criteria. We reviewed 152 published trials in detail; of the 36 trials meeting inclusion criteria, 7 of these trials included overlapping data, leaving 29 trials.
Of these, 27 were parallel-group trials,
while 2 were crossover trials.19,20 Twentythree of the eligible trials required that
we calculate additional data from provided information: in 2 trials,21,22 we calculated the SD for the change in score
from initial and final score SDs; in 3 tri-

Figure 1. Behavioral Symptoms in Alzheimer Disease

A

Neuropsychiatric Inventory
Favors
Cholinesterase Inhibitor
Morris et

al,26

Favors
Placebo

1998

Dubois et al,33 1999

Raskind et al,35 1999

(6.10)

Tariot et al,23 2000

Rockwood et al,24 2001
(3.02)

Winblad et al,41 2001

Summary Effect
6

Points
B

Alzheimer Disease Assessment Scale, Noncognitive

Favors
Cholinesterase Inhibitor
Davis et al,45 1992

Favors
Placebo

(1.76)

Farlow et al,27 1992

Knapp et al,25 1994
Wood,39 1994
Forette et al,28 1995
Becker et al,29 1996
Zemlan et al,32 1996
Becker et al,22 1998
Jann et al,38 1999
(2.52)

(3.82)

Moller et al,34 1999

Summary Effect
1.5

1.0

0.5

Points

Negative scores denote improvement. Error bars indicate 95% confidence intervals.
212

JAMA, January 8, 2003Vol 289, No. 2 (Reprinted)

0.5

1.0

als,20,23,24 we calculated SDs from SEs; and

in another 3 trials,19,25,26 we calculated SDs
from CIs. For 15 trials, we calculated
pooled SDs from P values; 10 trials27-36
gave exact P values, while 5 trials37-41 required us to use estimated P values. For
14 trials23-25,27,30,33,34,36-38,40,42-44 that used
more than 1 dose compared with a single
placebo group, we combined the treatment groups by weighting the effects for
each subgroup by its sample size.
Neuropsychiatric Outcomes

Sixteen of the eligible trials included

neuropsychiatric outcomes. Six trials reported the NPI, and 10 the ADASnoncog (Table 1). Three trials reported data from both scales; for these,
we used the NPI in our analysis: 1 trial35
reported inadequate data for the ADASnoncog, and 2 trials26,33 reported both
the NPI and ADAS-noncog. Most (12
of 16) trials reported data from the ITT
analysis, with 4 trials29,34,38,39 reporting
data only from the completed subject
analysis. Initially, our goal was to combine the NPI and ADAS-noncog scales
in an overall summary estimate. Because of evidence of heterogeneity when
we combined the scales (P.01), we
calculated separate meta-analyses for
the NPI and ADAS-noncog outcomes.
For the 6 trials using the NPI, summary meta-analysis indicated that patients randomized to ChIs improved
1.72 points compared with placebo
(95% CI, 0.87-2.57 points), indicating a small but statistically significant
benefit from the use of ChIs
(FIGURE 1A). For the 10 trials using the
ADAS-noncog, summary metaanalysis indicated that patients randomized to ChIs improved 0.03 points
compared with placebo (95% CI, 0.000.05 points), indicating a trend toward benefit in neuropsychiatric dysfunction from the use of ChIs (Figure
1B). For both the ADAS-noncog and the
NPI meta-analyses, the tests of heterogeneity were not statistically significant (P =.99 for both).
Functional Outcomes

Fourteen eligible trials included ADL

measures (TABLE 2). Eight trials re2003 American Medical Association. All rights reserved.

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CHOLINESTERASE INHIBITORS IN ALZHEIMER DISEASE

ported the ITT analyses and 6 the completed subjects analyses.19,20,25,30,42,46 Two
of the included trials were crossover trials.19,20 For the fourteen trials using
ADLs, summary meta-analysis indicated that patients randomized to ChIs
improved by 0.10 SDs compared with
placebo (95% CI, 0.00-0.19), indicating a trend in benefit in ADLs from the
use of ChIs (FIGURE 2A). The test of heterogeneity was nonsignificant (P=.36).
Thirteen eligible trials included IADL
outcomes. Ten trials reported data from
the ITT analysis and 3 from the completed subjects analysis (Table 2).25,42,46
For the thirteen trials using IADLs,
summary meta-analysis indicated that
patients randomized to ChIs improved by 0.09 SDs compared with placebo (95% CI, 0.01-0.17), indicating a
small but statistically significant benefit in IADLs from the use of ChIs (Figure 2B). A test of homogeneity was not
significant (P=.47).
Additional Analyses

To determine if our meta-analyses were

sensitive to choices in methodology, we

conducted a series of sensitivity analyses. First, for the 2 trials in which both
the ADAS-noncog and NPI were used,
we recalculated both meta-analyses by
reassigning the 2 trials to the ADASnoncog meta-analysis while omitting
them from the NPI meta-analysis. There
was no change in the magnitude or statistical significance of the results of either meta-analysis. Next, we determined whether the type of ChIs had an
effect on the results using subgroup
analyses. For each outcome, if there
were 3 or more trials using the same
ChI, we calculated separate metaanalyses for each drug. We calculated
a metrifonate subanalysis for the NPI
scale, a tacrine subanalysis for the
ADAS-noncog scale, a tacrine subanalysis for the ADL scale, and a tacrine and
physostigmine subanalysis for the IADL
scale. We found similar effect sizes but
wider CIs for the subanalyses, with no
clear difference with any one ChI. Finally, when we calculated separate subanalyses comparing the results of the
ITT analyses with the completed subjects analyses for each outcome, we

found similar results. The effect size and

statistical significance were slightly
higher for the completed subject NPI
analyses (summary estimate, 1.96
points improvement; 95% CI, 1.072.84) and for the ADAS-noncog analyses (summary estimate, 0.39 points improvement; 95% CI, 0.30-0.47) but
were not different for the functional
outcomes.
For all 4 meta-analyses, funnel plots
revealed no clear asymmetry to suggest the potential for publication bias
against trials whose results showed no
benefit of treatment over placebo. Although funnel plots themselves have
low statistical power, additional formal testing using the Kendall tau
showed no statistical evidence for publication bias in the meta-analyses of
ADAS-noncog (P =.85), NPI (P=.84),
ADL (P=.70), or IADL (P =.47).
COMMENT
Based on meta-analyses of 29 trials (16
with neuropsychiatric outcomes and 18
with functional outcomes), our results support the hypothesis that ChIs

Table 2. Trials of Cholinesterase Inhibitors Reporting ADL and IADL Scales for Functional Outcomes in Patients With Alzheimer Disease
Source
Thal et al,21 1989
Eagger et al,20 1991
Molloy et al,19 1991
Davis et al,45 1992
Knapp et al,25 1994
Antuono,37 1995
Forette et al,28 1995
Rogers and Friedhoff,30 1996
Thal et al,31 1996

ADL
Scale
PSMS
PSMS
PSMS
PSMS
PSMS
PSMS
PSMS
ADLs
PSMS

IADL
Scale
IADLs

Zemlanl,32 1996
Agid et al,42 1998
Cummings et al,40 1998

PSMS
NOSGER
PSMS

IADLs
NOSGER
IADLs

309
402
480

Imbimbo et al,43 1998

Forette et al,46 1999
Imbimbo et al,44 1999
Thal et al,36 1999

SBI
NOSGER

NOSGER
IADLs
IADLs

320
114
491
475

Imbimbo et al,47 2000

van Dyck et al,48 2000

IADLs
IADLs
IADLs
IADLs

Subjects,
No.
16
89
34
215
653
449
130
161
366

IADLs

349

IADLs

176

Medication, mg/d
Physostigmine, 8, 12, or 16
Tacrine, 50-150 + 10.8 g/d lecithin
Tacrine, 50, 75,100 + 10 g/d lecithin
Tacrine, 40 or 80
Tacrine, 80, 120, or 160
Velnacrine, 150 or 225
Tacrine, 40 or 80
Donepezil, 1, 3, or 5
Extended-release physostigmine,
8, 24, or 30
Velnacrine, 30, 75, 150, or 225
Rivastigmine, 4 or 6
Metrifonate, 0.20, 0.30,
or 0.65 mg/kg/d
Eptastigmine, 30 or 45
Rivastigmine, 6-12
Eptastigmine, 45 or 60
Extended-release physostigmine,
30 or 36
Eptastigmine, 30 or 36
Extended-release physostigmine,
24 or 30

Trial
Length, d
70
91
126
42
210
168
42
84
42

Intention-to-Treat
Analysis
Yes
No
No
Yes
No
Yes
Yes
No
Yes

42
91
84

Yes
No
Yes

175
126
168
168

Yes
No
Yes
Yes

175

Yes

84

Yes

Abbreviations: ADL, activities of daily living; IADL, instrumental activities of daily living; NOSGER, Nurses Observation Scale for Geriatric Patients; PSMS, Physical Self-Maintenance
Scale; SBI, Spontaneous Behavior Interview.

2003 American Medical Association. All rights reserved.

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CHOLINESTERASE INHIBITORS IN ALZHEIMER DISEASE

have a modest beneficial role in treating neuropsychiatric symptoms and reducing functional impairment in patients with mild to moderate AD and
living in the community. For neuropsychiatric outcomes, our analysis
showed a small but statistically significant benefit of ChIs on the NPI scale
and a trend in benefit on the ADASnoncog scale. For functional outcomes, treatment with ChIs resulted in
a small but statistically significant benefit of ChIs for IADLs and a trend in

benefit for ADLs. Each of the ChIs had

similar beneficial effects.
These results are consistent with a
prior meta-analysis of 4 trials of tacrine in which there was a small but statistically significant benefit on the
ADAS-noncog.49 Our findings of a modest improvement in neuropsychiatric
scales in patients treated with ChIs are
important because neuropsychiatric
problems are common in AD and are
major contributors to loss of autonomy, morbidity, and need for nurs-

Figure 2. Functional Impairment in Alzheimer Disease

A

Activities of Daily Living Scales

Favors
Cholinesterase Inhibitor

Favors
Placebo

Thal et al,21 1989

Eagger et al,20 1991
Molloy et al,19 1991
Davis et al,45 1992
Knapp et al,25 1994
Antuono,37 1995
Forette et al,28 1995
Rogers and Friedhoff,30 1996
Thal et al,31 1996
Zemlan,32 1996
Agid et al,42 1998
Cummings et al,40 1998
Imbimbo et al,43 1998
Forette et al,46 1999
Summary Effect
2.5

2.0

1.5

1.0

0.5

0.5

SD
B

Instrumental Activities of Daily Living Scales

Favors
Cholinesterase Inhibitor
Thal et al,21 1989
Davis et

al,45

Favors
Placebo

(1.04)

1992

Knapp et al,25 1994

Forette et al,28 1995
Thal et al,31 1996
Zemlan,32 1996
Agid et al,42 1998
Cummings et al,40 1998
Forette et al,46 1999
Imbimbo et al,44 1999
Thal et al,36 1999
Imbimbo et al,47 2000
VanDyck et al,48 2000
Summary Effect
1.0

0.5

0.5

SD

Negative scores denote improvement. Error bars indicate 95% confidence intervals.
214

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1.0

ing home placement.50-53 Although neuropathological data are sparse, plausible

biological mechanisms support the role
of acetylcholine in modulating behavior in AD, and there has been increasing interest in ChIs for treatment of
neuropsychiatric symptoms.54-56 Since
the baseline ADAS-noncog scores of
these trials ranged from 3.8 to 7.7, the
improvement of less than 1 point on the
ADAS-noncog scale is very small. However, the ADAS-noncog has been criticized for its lack of sensitivity, as it does
not include some behaviors common
in AD such as aggressiveness and anxiety. The NPI, which does include these
neuropsychiatric domains, has been
thought to be more sensitive to
change.57,58 An almost 2-point improvement on the NPI is equivalent to a decrease in frequency or severity of a particular neuropsychiatric symptom, and
is notable since the baseline NPI scores
of these trials ranged from 9.2 to 13.9.59
Given the probable benefit ChIs may
have on neuropsychiatric scales, our
data suggest that for patients with mild
to moderate AD who have neuropsychiatric disturbances, ChIs should be
considered a therapeutic option. If neuropsychiatric symptoms are not improved after a trial of ChIs, then other
agents such as antipsychotics or mood
stabilizers should be considered. It is
important to note that our observed
effect size for neuropsychiatric outcomes measured with the NPI is similar to that reported in most randomized trials using other medications for
neuropsychiatric symptoms in dementia, such as valproic acid and risperidol.60,61 As with all medication, however, the decision to use ChIs needs to
be considered in light of adverse effects, cost, and feasibility.
As well as with neuropsychiatric
symptoms, the presence of functional
impairment can lead to poor healthrelated quality of life in patients with
AD.62,63 The finding of a small improvement in ADLs and IADLs in patients
treated with ChIs is of clinical importance since all patients with AD by definition have functional impairment, and
functional decline increases with dis-

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CHOLINESTERASE INHIBITORS IN ALZHEIMER DISEASE

ease progression. To interpret the results of functional outcomes in SD

units, some authors have argued that
effect sizes of 0.20 in magnitude are
clinically detectable64; thus, our results in the magnitude of 0.10 SD may
be at the lower limit of clinical detectability. Based on prior longitudinal data
of functional decline in AD, effect sizes
in the magnitude of 0.10 SD would be
similar to preventing a 2-months per
year decline in a typical patient with
AD.65 A recent study suggests that donepezil treatment for a year may have a
beneficial effect on reducing functional impairment in patients with mild
to moderate AD.66 However, because
functional impairment is closely linked
to cognitive impairment, it is unknown whether the benefit to functional impairment from ChIs is due to
reducing cognitive impairment or an independent mechanism.
Some limitations to our metaanalyses restrict the interpretation of
our results. First, not all subjects enrolled in the trials had neuropsychiatric problems, and the magnitude of the
effect of ChIs for neuropsychiatric problems might be different for patients who
all have difficult behaviors. Thus, more
randomized clinical trials of ChIs are
needed, specifically enrolling patients
with AD and neuropsychiatric problems and focusing on sensitive neuropsychiatric measures. Second, although most of our included trials
excluded patients receiving psychotropic medications, some of the trials
allowed the use of medications such as
short-acting benzodiazepines for sedation; the use of such medications may
also have altered our results. In addition, we had limited power to perform
separate meta-analyses by each ChI, and
the trials included also varied in ChI
treatment regimens and in duration of
treatment. Despite these differences,
subanalyses and tests of homogeneity
indicated that the trial results were combinable. We also were unable to evaluate individual behaviors, such as aggression or paranoia, or functional
abilities, such as the ability to cook,
bathe, or dress, as most trials did not

provide subscores. Finally, because neuropsychiatric and functional outcomes were secondary outcomes, data
were often not fully reported; however, we used widely used metaanalytic techniques to calculate the nonreported data.
Despite these limitations, we believe our results are the first attempt to
quantitatively synthesize the efficacy of
a variety of ChIs for neuropsychiatric
symptoms and functional impairment, and to suggest a modest benefit
in neuropsychiatric outcomes and functional outcomes from ChIs. The results of our meta-analyses indicate the
need for additional focused research on
neuropsychiatric and functional outcomes in patients with AD. Exploring
these issues will possibly broaden treatment for AD, an illness with growing
importance to public health.
Author Affiliations: Department of Psychiatry, Massachusetts General Hospital, Boston (Dr Trinh); Veterans Affairs Palo Alto Health Care System and Department of Psychiatry and Behavioral Sciences,
Stanford University School of Medicine, Palo Alto, Calif
(Dr Hoblyn); Center for Astrophysics, Harvard University, Boston (Dr Mohanty); and Departments of Psychiatry, Neurology, and Epidemiology, University of
California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, Calif (Dr
Yaffe).
Author Contributions: Study concept and design:
Trinh, Hoblyn, Yaffe.
Acquisition of data: Trinh, Hoblyn, Yaffe.
Analysis and interpretation of data: Trinh, Hoblyn,
Mohanty, Yaffe.
Drafting of the manuscript: Trinh, Hoblyn, Yaffe.
Critical revision of the manuscript for important intellectual content: Trinh, Hoblyn, Mohanty, Yaffe.
Statistical expertise: Trinh, Hoblyn, Mohanty, Yaffe.
Administrative, technical, or material support: Hoblyn.
Study supervision: Yaffe.
Funding/Support: Dr Yaffe was supported by Public
Health Service grant K23-AG00888 and is an American Federation for Aging Research Paul Beeson Faculty Scholar in Aging Research.
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