1. Treatments for Cognitive and Functional
a. Cholinesterase Inhibitors
The efficacy of tacrine in mild to moderate Alzheimer's disease
has been extensively studied, although its effects on patients with
more severe or very mild Alzheimer's disease or with other
forms of dementia have not been assessed. At least five double-blind
placebo-controlled trials with parallel-group comparisons including
a total of more than 2,000 patients have been reported (131–135).
Overall, these clinical trials consistently demonstrated differences
between tacrine and placebo. Approximately 30%–40% of
patients taking tacrine who completed the trials showed modest improvements
in cognitive and functional measures over study periods ranging
from 6 to 30 weeks, compared to up to 10% of those taking
placebo. Modest improvement in these studies corresponded to maintaining
or improving function by an amount typically lost over 6 months
in untreated groups of similar patients with Alzheimer's
disease. Response appeared to be related to dose, at least in the
largest clinical trial (133), in which patients who
could tolerate 120–160 mg/day were more likely
to respond. However, only approximately 60% of the patients
were able to complete the tacrine trials even at moderate doses;
30% of the subjects were dropped from these trials prior
to completion because of elevation in hepatic transaminases, and
another 10% had to leave because of other adverse effects,
mainly cholinergic effects (e.g., nausea and vomiting). The benefits
and adverse effects of administration beyond 30 weeks are unknown.
The efficacy of donepezil has been evaluated in more than 15
randomized, double-blind, placebo-controlled trials (136–146).
Trial sizes have varied from fewer than 20 subjects to 818 subjects
(138), and many trials have been multicentered. Most
trials have been 12–24 weeks in duration, although at least
two have lasted 1 year (137, 139), and
one lasted more than 2 years (136). Studies have generally
been conducted with community-dwelling patients, although one trial
included nursing home residents with moderate to severe dementia
(145). The majority of studies have enrolled patients
with mild to moderate Alzheimer's disease (MMSE scores
in the 10–26 range), although at least two have focused
on patients with moderate to severe dementia (MMSE scores in the
5–17 range) (107, 142), and one
focused exclusively on patients with early Alzheimer's
disease with MMSE scores in the 21–26 range (146, 480).
Published studies consistently have found a benefit of donepezil
over placebo in both cognitive and functional measures, including
measures of clinicians' impressions of improvement. The
size of the effect of donepezil has likewise been consistent across
most studies, with improvement over placebo of about 1 point on
the MMSE and 3 points on the ADAS-cog. On cessation of donepezil,
improvement was lost over a 3–6-week period in all studies
that examined this outcome. In one study in which donepezil treatment
was interrupted for 6 weeks and then reinstated at the original
dose, patients' cognition and function did not return to
the level achieved prior to donepezil discontinuation (166).
Most studies comparing 5 mg/day dosing with 10 mg/day
found greater benefit with the higher dosage (138, 140),
although this result has not been found in some studies comparing
these dosages (141). Donepezil is administered once
The question of whether donepezil treatment delays nursing
home placement is an important one and has been addressed in two
studies. One study found a delay in nursing home placement in patients
treated with open-label donepezil for up to 240 weeks (481).
However, these findings have been contested on methodological grounds
(482). The AD2000 trial conducted in the United Kingdom followed
565 community-dwelling patients randomly assigned to receive donepezil
or placebo for more than 2 years (136). Although donepezil-treated
patients had better cognitive and activities of daily living scores
than the placebo group, there was no difference in the primary endpoint
of time to institutionalization. However, the trial was underpowered,
had a high dropout rate, and may have been influenced by treatment
The efficacy of rivastigmine has been evaluated in at least eight
randomized, placebo-controlled, double-blind studies of patients
with Alzheimer's disease (147–152).
The sizes of the studies have varied from 50 subjects (148)
to as many as 725 subjects (149). The duration of most
trials was 26 weeks or shorter, although one trial lasted 12 months
(150). All trials thus far have been conducted with
community-dwelling patients with mild to moderate dementia severity
These studies consistently have found a benefit of rivastigmine
over placebo on both cognitive and functional measures, including
measures of clinicians' impressions of improvement. The
size of the effect of rivastigmine has likewise been consistent
across most studies, with improvement over placebo of about 1 point
on the MMSE and 3 points on the ADAS-cog, a magnitude of effect
similar to that of donepezil. The dosage range found to have maximum
efficacy is 6–12 mg/day in divided doses.
The efficacy of galantamine has been evaluated in at least eight
randomized, placebo-controlled, double-blind studies (153–159).
The numbers of subjects have ranged from under 100 to 978 (157).
Duration of most trials was one-half year or shorter. All trials
thus far have been conducted with community-dwelling patients with
mild to moderate Alzheimer's disease (480).
These studies consistently have found a benefit of galantamine
over placebo in both cognitive and functional measures, including
measures of clinicians' impressions of improvement. The
size of the effect of galantamine has likewise been consistent across
most studies, with improvement over placebo of about 1 point on
the MMSE and 3 points on the ADAS-cog, a magnitude of effect similar
to that of donepezil. The dosage range found to have maximum efficacy
is 16–24 mg/day in divided doses. An extended
release, once-daily dosing form of galantamine has recently been
A number of randomized, double-blind, placebo-controlled trials
have been conducted in patients with vascular dementia or mixed
Alzheimer's disease and vascular dementia. In two 24-week
trials conducted with patients with probable or possible vascular
dementia (616 subjects and 603 subjects, respectively), donepezil
(5 mg/day and 10 mg/day) was compared to placebo
(484, 485). Improvements in measures of
cognition and function were found in patients given either dose
of donepezil, although in one of the trials (484) one
of the two primary outcome measures did not demonstrate benefit
of donepezil, compared with placebo. The effect size was comparable
to that found in Alzheimer's disease trials. Two 6-month
trials of galantamine (592 and 786 subjects, respectively) in patients
with vascular dementia or mixed Alzheimer's disease and
vascular dementia had similar findings (358, 486).
Of concern, in one unpublished trial of donepezil for vascular
dementia, there was a significantly higher rate of death in the
subjects taking donepezil than in the placebo group (167),
raising a significant safety concern that requires further study.
3. Dementia with Lewy bodies
One 20-week, randomized, double-blind, placebo-controlled
study with 120 subjects examined the effects on cognition of 6–12
mg/day of rivastigmine in patients with Lewy body dementia
(168). The results showed overall cognitive benefits
with rivastigmine, compared with placebo, although differences were
not statistically significant for all measures. A small 4-week,
placebo-controlled, double-blind, double-crossover, randomized trial
of donepezil also demonstrated cognitive benefits in subjects with
Lewy body dementia (169).
4. Parkinson's disease dementia
In a 24-week, randomized, double-blind, placebo-controlled
study with 541 subjects, the effects on cognition and function of
3–12 mg/day of rivastigmine were examined in patients
with mild to moderate Parkinson's disease dementia (170).
Improved cognition and function were found in the rivastigmine group,
compared with the placebo group, and rivastigmine was tolerated
by this patient population. In a 48-week open-label active treatment
(3–12 mg/day of rivastigmine) extension study
that included 334 subjects who completed the above-mentioned 24-week
study, cognitive and functional benefits appeared to continue over
time (171). Patients treated with placebo in the initial
study who were then treated with rivastigmine in the open-label
study had improvements in cognitive and functional scores similar to
those of the patients who received rivastigmine in the initial study.
5. Mild cognitive impairment
Two randomized, double-blind, placebo-controlled studies have
investigated donepezil for the treatment of mild cognitive impairment,
neither of which demonstrated benefit in the primary study outcomes.
In one study of 270 subjects, there was no benefit of donepezil
on most (but not all) cognitive tests studied, including the primary
efficacy measures (172). The second study included
769 subjects with mild cognitive impairment and used a primary endpoint
of progression from mild cognitive impairment to meeting the criteria for
the diagnosis of possible or probable Alzheimer's disease over
a 3-year period (173). Although fewer donepezil-treated
subjects had progressed to Alzheimer's disease in the first
year of the study, compared to placebo-treated subjects, there was
no difference between the groups by the end of 3 years. Donepezil-treated
subjects did better than the placebo group on a number of cognitive
tests, but this modest difference did not persist beyond 18 months.
There have been two randomized, placebo-controlled, clinical
trials of galantamine in subjects with mild cognitive impairment.
Each study was of 2 years' duration and included approximately
1,000 patients. Overall, there were no statistically significant
benefits for galantamine compared to placebo, either in increasing
the time to the onset of dementia or improving cognitive function,
activities of daily living, or global assessment ratings. Of concern
in these two trials together, 13 subjects who were taking galantamine
died, compared to one subject who received placebo. This finding
was statistically significant and represents a precaution in the
use of galantamine in this patient population. It is noteworthy that
the rates of death in these two trials were much lower in both the
placebo and the galantamine groups than would have been expected
based on previously conducted clinical trials in patients with actual
dementia. As in trials of cholinesterase inhibitors for Alzheimer's
disease subjects, there were substantial dropouts due to adverse
events in the trials for subjects with mild cognitive impairment.
Memantine, a noncompetitive NMDA antagonist, has been studied
extensively in recent years for the treatment of Alzheimer's
disease and vascular dementia. Trials have ranged from 6 weeks to
6 months in duration and have primarily included outpatients, although
one study included nursing home residents (180). Studies
have enrolled patients with moderate to severe dementia (MMSE scores
ranging from 3 to 15) as well as mild to moderate dementia (MMSE
scores ranging from 10 to 24).
Among randomized placebo-controlled trials that have included
patients with mild to moderate Alzheimer's disease, two
unpublished trials did not find benefit of memantine over placebo
(487), whereas one trial demonstrated cognitive and
functional improvement with memantine, compared to placebo (177).
A meta-analysis of these three trials showed a statistically significant
but very small advantage to memantine over placebo (108).
Nonetheless, the FDA has not approved the use of memantine for treatment
of mild Alzheimer's disease.
Among studies of patients with moderate to severe Alzheimer's
disease, two published trials (with 252 and 404 subjects, respectively)
(174, 175) found cognitive and functional
improvement with memantine, compared with placebo. In one of those
studies, which included only patients who were already taking stable dosages
of donepezil, random assignment to treatment with memantine led
to improvement in cognition and function, compared to random assignment
to the placebo group (175). One unpublished study did
not show any benefit of memantine over placebo (487).
In a trial that included 166 subjects with severe dementia due to
Alzheimer's disease or vascular dementia, cognitive and
functional improvement was greater with memantine than with placebo
In summary, there is evidence supporting the use of memantine
for moderate to severe Alzheimer's disease, and memantine
is approved by the FDA for this use. Data are not yet available
to argue for or against the use of memantine beyond 6 months (108, 176).
There have been two large 6-month clinical trials (with 579
and 321 subjects, respectively) of memantine to treat patients with
mild to moderate vascular dementia (178, 179).
In both trials, cognition and behavior improved, but there was no
demonstrated functional improvement and no improvement on clinical
global ratings of change (Clinician's Interview-Based Impression
of Change Plus). No studies of memantine have been conducted with
patients with severe vascular dementia alone. Nonetheless, in one
randomized placebo-controlled trial that included 166 patients with severe
dementia, of which 51% had vascular dementia and 49% had
Alzheimer's disease, there was improvement in cognitive
and functional outcome measures for both the Alzheimer's
disease and vascular dementia subjects (180).
There has been considerable interest in vitamin E (-tocopherol)
as a treatment for Alzheimer's disease and other dementias
because of its antioxidant properties and efficacy in Parkinson's
disease. Vitamin E has been shown to slow nerve cell damage and
delay death in animal models and cell cultures (including damage
associated with amyloid deposition) and thus may be relevant to
the development and progression of Alzheimer's disease
One large clinical trial of vitamin E for treatment of Alzheimer's
disease has been conducted (183). This placebo-controlled,
double-blind, multicenter trial included 341 subjects with moderate
Alzheimer's disease (CDR of 2) who were randomly assigned
to receive 1,000 IU b.i.d. of vitamin E alone, 5 mg b.i.d. of selegiline
alone, both agents, or placebo. Vitamin E alone, selegiline alone,
and the combination each delayed reaching the study endpoints (defined
as a poor outcome, namely death, institutionalization, or significant
functional decline). The benefit observed was equivalent to a delay
of approximately 5–7 months in reaching the composite endpoint.
It is noteworthy that no evidence was found for improvement in function
or cognition, compared to baseline. Despite the evidence for a better
functional outcome in the treatment groups, compared to the placebo group,
all groups showed similar rates of cognitive decline during the
2-year study period. There are no studies of the effects of vitamin
E in subjects with Alzheimer's disease with mild or severe
impairment or in subjects with other dementias. There are also no
data concerning the effect of vitamin E in combination with medications
other than selegiline.
In one clinical trial, the effects of donepezil, vitamin E, and
placebo were compared in patients with mild cognitive impairment
(173). These patients were followed for 3 years. Overall,
no differences were found between vitamin E (2,000 IU/day) and
placebo on measures of cognition, level of function, or progression
Although vitamin E has been widely used clinically and in numerous
clinical trials for a variety of indications and has been considered
to have low toxicity, more recent evidence suggests that vitamin
E may be associated with a small but significantly increased risk
for morbidity and possibly even mortality. At high doses, it may
worsen blood coagulation defects in patients with vitamin K deficiency
(184). Of greater concern is evidence linking vitamin
E usage in clinical trials to increased mortality in a dose-dependent fashion.
A meta-analysis of 11 clinical trials of vitamin E in a mixed population
that included some individuals with significant cardiac disease
found a very small but statistically significant increase in mortality
in trials using doses greater than 400 IU/day and a dose-dependent
increase in mortality with doses above 150 IU/day (181).
In addition, a carefully conducted large, randomized clinical trial
of vitamin E (400 IU/day) for the prevention of heart disease
or cancer in patients with diabetes mellitus and/or vascular
disease had an unanticipated finding that vitamin E was associated
with an increased risk of heart failure (182).
A number of medications marketed for other indications have
been proposed for the treatment of dementia on the basis of epidemiological
data or pilot studies. Aspirin and other NSAIDs have been proposed
because of epidemiological data suggesting that they protect against
the development of dementia (185–189) and
because of hypotheses regarding the involvement of inflammatory
mechanisms in the pathogenesis of Alzheimer's disease (491).
In a single small treatment trial for patients with Alzheimer's
disease, patients receiving 100–150 mg/day of
indomethacin experienced less decline over 6 months than did a matched
control group (186). However, a number of larger studies
with other NSAIDs (rofecoxib, naproxen, and diclofenac) did not
show benefit over placebo in slowing the cognitive decline in Alzheimer's disease
(190–192). Moreover, several studies have
suggested cardiac toxicity, especially with more selective cyclooxygenase-2
inhibitors. Finally, use of aspirin and NSAIDs can be associated with
other significant adverse events such as gastrointestinal bleeding
and impairment of renal function. Thus, NSAIDs are not recommended
for the treatment of Alzheimer's disease.
Hormone replacement therapy is known to affect cognitive function
(492) and was shown to be beneficial in the treatment
of dementia in at least two case series (493, 494).
It was also associated with later onset and/or decreased risk
of cognitive decline in at least two observational studies of postmenopausal
women (495, 496). In contrast, in the
prospective Women's Health Initiative Memory Study (WHIMS),
increased rates of conversion to Alzheimer's disease were
found in women age 65 years or older who were randomly assigned
to receive an estrogen/progestin combination compared with
those who received placebo (193). Results of a number
of other prospective trials also showed no benefit of estrogen over
placebo in the treatment of cognitive symptoms of Alzheimer's
disease (194, 195). Therefore, hormone
replacement therapy is not recommended for use in the treatment
of cognitive symptoms of Alzheimer's disease.
There is also interest in the hormone melatonin and in botanical
agents such as ginkgo biloba, which are available without a prescription.
There are no data supporting the use of most of these agents in
Alzheimer's disease. Numerous clinical trials of ginkgo
biloba have been conducted. Most of these have been small trials
with considerable methodological problems (497). In
one randomized placebo-controlled trial that included 309 subjects,
1-year efficacy of ginkgo was found in subjects with Alzheimer's
disease or vascular dementia, but there were significant methodological
problems with the trial, including a very high dropout rate (498).
In a large, 26-week, randomized, double-blind, placebo-controlled
trial that included 513 subjects with mild to moderate Alzheimer's
disease (MMSE score of 10–24), the effects of 120 mg/day
of ginkgo, 240 mg/day of ginkgo, and placebo were compared
(196). There was no advantage to ginkgo over placebo
for cognitive function, but these results are qualified by the fact
that there was very little cognitive decline in the placebo group
as well. At this point, the preponderance of the evidence does not
support the routine use of ginkgo for the treatment of dementia
The chelating agent desferrioxamine has also been studied
as a possible treatment for Alzheimer's disease on the
basis of hypotheses regarding heavy metals in the pathogenesis of
the disease. In one small single-blind trial, there was some evidence
of a decrease in cognitive decline over 2 years (499).
One study of another chelating agent failed to confirm this finding
(500). Because chelating agents are quite toxic and
support for them is so weak, they are not recommended for the treatment of
dementia. Newer agents that chelate copper and zinc are in clinical
development as potential Alzheimer's disease therapies
because they may lower beta-amyloid burden (501).
As reviewed in a Cochrane meta-analysis that included negative
trials, the irreversible MAO-B inhibitor selegiline has been studied
in a large number of randomized controlled clinical trials, with
mixed results (199). One large trial comparing selegiline
with vitamin E and placebo demonstrated some benefit of selegiline
over placebo (183), but numerous other trials have
not shown clinically meaningful benefit. Although use of selegiline
at dosages of 5–10 mg/day is generally safe and
well tolerated, few clinicians actually use this medication in clinical
practice for the treatment of cognitive decline in dementia. Selegiline
use is considered contraindicated in combination with meperidine, SSRIs,
or tricyclic antidepressants. Use of the selegiline patch for treatment
of dementia has not been studied.
A mixture of ergoloid mesylates is currently marketed under
the trade name Hydergine for the treatment of nonspecific cognitive
impairment. It has been available for at least 40 years and has
been studied in at least 150 clinical trials, seven of which were
double-blind, placebo-controlled, randomized trials with a parallel-group
design involving a total of 297 patients with diagnoses consistent
with Alzheimer's disease. Studies have been conducted in
patients with vascular dementia as well. Although a number of trials
have produced weakly positive results, these have generally been
on isolated cognitive measures or on measures of psychiatric symptoms,
and the overall evidence suggests little or no effect (200).
Side effects are usually mild and affect the gastrointestinal system.
Dosages used in the studies ranged from 3 to 9 mg/day.
2. Treatments for Psychosis and Agitation
Because treatments for psychosis and behavioral disturbances
overlap to a considerable extent, and because investigations often
include subjects with both groups of symptoms, they are grouped
together in this discussion.
First-generation antipsychotic medications (also known as "conventional" or "typical" antipsychotic
agents) have been extensively studied in the treatment of psychosis
and agitation in individuals with dementia. For example, a 1990 review
(210) identified seven double-blind, placebo-controlled,
randomized, parallel-group clinical trials including 252 patients studied
over periods of 3–8 weeks (203–209).
Despite some methodological flaws, notably small numbers of subjects
and a lack of diagnostic specificity, these studies, when taken
together, constitute reasonable evidence for a modest improvement
in target symptoms in some patients treated with first-generation
antipsychotic medications. A meta-analysis of these seven trials
(210), using clinician assessment of improvement in
a variety of behavioral symptoms as the primary outcome, showed
improvement in 59% of the subjects taking antipsychotics
and 41% of those taking placebo. The studies used a wide
variety of dosages (ranging from 66 to 267 mg/day in chlorpromazine
equivalents), and efficacy for behavioral symptoms was not correlated
with standardized dose. Adverse effects were common, but specific
rates are not available. Dropout rates were also high, whether associated
with side effects or poor efficacy.
In a more recent meta-analysis of studies of first-generation
antipsychotics in patients with dementia, clinically significant
improvement was found in 64% of patients treated with active
medication versus 38% of patients treated with placebo,
translating to an effect size of 26% (211).
No differences in efficacy were seen among the different agents
used. Significant side effects were found in 25% more of
the patients who received active treatment, compared with those
who received placebo. This meta-analysis did not include a number
of more recent studies (212–216); however,
the data from these newer studies generally conformed to the results
of the meta-analyses (210, 211). In another
review of antipsychotics used in dementia (217), which
also included several trials of second-generation antipsychotic
agents, mean improvement rates were 61% with antipsychotics
and 35% with placebo, yielding a treatment effect of 26%.
The modest treatment effects estimated by these meta-analyses and
reviews are generally consistent with results from placebo-controlled
trials of second-generation antipsychotics.
Second-generation antipsychotic agents have also been studied
in well-controlled trials in patients with dementia. Three placebo-controlled
trials of risperidone have been conducted among nursing home residents
with severe dementia complicated by agitation and/or psychosis
(212, 218). In the first trial, a fixed-dose
study that included 625 patients, the response rates of 45% and
50% for 1 mg/day and 2 mg/day, respectively,
were significantly different than placebo (33%) (the 0.5-mg/day
dose was not more effective than placebo). Parkinsonism was seen
in 21% of patients who received 2 mg/day, and
it was concluded that 1 mg/day represented the most effective
dose. In the second trial, a flexible-dose study that included 344
patients, response rates were 47%, 63%, and 54%,
respectively, for placebo, haloperidol (mean dosage 1.2 mg/day),
and risperidone (mean dosage 1.1 mg/day); these response
rates did not differ statistically. Secondary outcomes related to
aggression decreased in the two active treatment groups, compared
with the placebo group, but cognitive and functional outcomes were
not different across treatment groups. In the third trial, the effects of
flexibly dosed risperidone were compared to those of placebo in
337 nursing home patients with severe dementia who required treatment
for aggression; a significant difference in response rates of 37% for
placebo and 63% for risperidone (mean dosage 1 mg/day)
was found (219).
Three clinical trials have been conducted to study the effects
of oral olanzapine for the treatment of persisting agitation and/or
psychosis in patients with severe dementia. The first trial, reported
only as an abstract, compared flexibly dosed olanzapine (mean dosage
of about 2.3 mg/day) with placebo in 238 patients, and
no difference in efficacy or tolerability was found. This negative
result may in part be explained by the mean dosage's being
too low (502). In the second trial, in which participants
consisted of 206 nursing home residents, response rates of 66%,
57%, and 43% were found with fixed dosages of
5, 10, and 15 mg/day of olanzapine, respectively, versus
36% for placebo (the response rates with 5 mg/day
and 10 mg/day were significantly different from those with
placebo) (220). Some patients from this trial received
follow-up open-label, flexible-dose treatment for 18 weeks; the
results were consistent with the findings of the original report
(221). The third trial included 652 residents of nursing
homes or continuing care hospitals who met the operational criteria for
psychosis (222). Patients were assigned to treatment
with olanzapine at doses of 1, 2.5, 5, or 7.5 mg/day or
placebo; no drug-placebo differences were seen in measures of psychosis
or other behavioral features.
Meehan et al. (223) studied acute treatment of
agitation with intramuscular olanzapine in a group of 272 inpatients
or nursing home residents with Alzheimer's disease and/or
vascular dementia. Olanzapine at doses of 2.5 and 5.0 mg was found
to be superior to placebo in treating agitation at 2 hours; the
response rates were 62%, 66.7%, and 37.3%,
respectively. The response rate for those treated with intramuscular
lorazepam was 72.1%; all response rates for participants
who received active treatment were different from those for participants who
received placebo group but not from each other. Adverse events were
not significantly different between groups.
Evidence for the use of quetiapine is limited to findings from
three open-label trials that suggested possible benefits for agitation
(503–505). A 10-week, multicenter, placebo-controlled
trial of flexibly dosed quetiapine versus haloperidol was conducted in
a group of elderly nursing home patients with operationally defined
psychosis, criteria for which were implemented before the development
of the recently proposed clinical criteria for the psychosis of
Alzheimer's disease (201). Results from the
subgroup of 284 patients with Alzheimer's disease were
analyzed separately. In these subjects, the mean daily dosage of
haloperidol was 2 mg/day at endpoint, whereas that of quetiapine
was about 120 mg/day. Neither of the treatment groups differed
with respect to reduction in measures of psychosis, the primary
outcome of the trial. One secondary measure of agitation showed
improvement with both haloperidol and quetiapine treatment but not
placebo. These studies led to a second placebo-controlled trial of
100 mg/day of quetiapine, achieved by day 4, or 200 mg/day,
achieved by day 8, in which the participants were 333 nursing home
residents with dementia (227). A dose of quetiapine at 200 mg/day
was superior to placebo on numerous outcomes, with less benefit
seen at 100 mg/day. A more critical review of the data
will be possible once the trial results are published. A placebo-controlled
trial of quetiapine in a group of 93 subjects with Alzheimer's
disease and agitation failed to show any benefit over placebo for
the medication (506).
Three placebo-controlled studies of aripiprazole have been
published or presented in abstract form. In all three studies, the
primary outcomes were not reached, but significance on individual
outcomes was shown. In a placebo-controlled trial that included
208 outpatients who met the clinical criteria for psychosis of Alzheimer's
disease (201), there was no difference between flexibly
dosed aripiprazole (mean dosage of 10 mg/day) and placebo
on the primary outcome variable of psychosis, although post hoc
analyses showed benefits at some time points (224).
The second study, with findings presented in abstract form, was
a placebo-controlled study of fixed-dose aripiprazole conducted
with 587 nursing home residents with dementia and psychotic features
(507). A significant effect was found only for the
10-mg/day dose on the primary outcome, a measure of psychosis,
with 50% of patients who received placebo and approximately 68% who
received 10 mg/day of aripiprazole considered to have responded
clinically. The third study, with findings presented in abstract
form, was a placebo-controlled flexible-dose study conducted with
256 nursing home residents with dementia and psychotic features
(508). The results showed no drug-placebo difference
in the primary outcome with a mean aripiprazole dosage of 8.6 mg/day.
A fuller appreciation of these studies will be possible once the
results are published.
Clozapine has been found to be useful in controlling psychotic
symptoms in patients with Parkinson's disease (233)
and dementia with Lewy bodies (234) and may also be
useful for patients with Alzheimer's disease who are sensitive
to the extrapyramidal effects of first-generation antipsychotic
agents (509). Currently no specific data are available
on the use of ziprasidone in the treatment of elderly patients.
A recent meta-analysis that included the randomized controlled
trials described in preceding paragraphs showed that benefits tended
to be greater for symptoms of agitation than for psychosis (225).
These data also demonstrate a significant placebo response, a finding
that underscores the importance of nonpharmacological interventions
for relief of these signs and symptoms. The nonspecific aspects
of clinical trial participation (e.g., increased attention from
staff), as well as the frequent clinical evaluations that occur
during a clinical trial, may contribute to the improvement seen
in patients in the placebo arm of a trial. Finally, much of the
data discussed earlier are from studies that have not been published
yet, so they will need to be reevaluated.
The available studies comparing antipsychotics to one another
are of limited power but suggest no clinically significant differences
in efficacy (40, 210, 212, 215, 225).
The first direct comparison of second-generation antipsychotics
with placebo in patients with Alzheimer's dementia has
been undertaken as part of the NIMH-funded CATIE-AD (228).
In this trial 421 outpatients with Alzheimer's disease and
psychosis and/or aggression were randomly assigned to treatment
with olanzapine, quetiapine, risperidone, or placebo with dosages
adjusted as needed and followed for as long as 36 weeks. There were
no differences among treatments in the main outcome, time to all-cause
discontinuation, with initial treatments maintained for about 8
weeks. Time to discontinuation due to lack of efficacy, however,
favored olanzapine and risperidone, both of which were maintained for
about 24 weeks, whereas quetiapine and placebo were maintained for
approximately 9 weeks. Time to discontinuation due to adverse events
or intolerability favored placebo, with discontinuation in 24% of
patients who received olanzapine, 16% of patients who received
quetiapine, 18% of patients who received risperidone, and
5% of patients who received placebo. Although there were
no differences in improvement as rated with the Clinical Global
Impression of Change (olanzapine 32%, quetiapine 26%,
risperidone 29%, placebo 21%), some symptom ratings
favored the drugs over the first 12 weeks. Adverse effects offset
advantages in efficacy of second-generation antipsychotic drugs
for treatment of psychosis, aggression, or agitation in patients
with Alzheimer's disease.
It is important to note that there are limited data on the
efficacy of antipsychotic medications for patients with dementia
beyond 8–12 weeks of follow-up, although these medications
are often used for much longer periods of time in clinical practice.
Extensive clinical experience has suggested that they are sometimes
helpful for longer periods of time. Several studies of the effects
of withdrawal of treatment have suggested that a substantial proportion
of patients can be withdrawn from treatment successfully after a
period of time (40, 229).
2. Side effects and toxicity
Antipsychotic agents are associated with a risk of serious complications
that must be considered in weighing the risks and benefits of antipsychotic
Tardive dyskinesia, whose incidence
increases with increasing dose and duration of treatment and which
occurs more commonly in women, is also more common in individuals
with dementia and in elderly patients in general. The risk may be
as high as 30% for elderly patients with significant exposure
to first-generation antipsychotic agents (510–512).
This risk may be considerably lower with the use of second-generation
antipsychotics. For example, Jeste et al. (513) reported
a cumulative incidence of tardive dyskinesia of 2.6% in
330 patients with dementia treated openly with risperidone (mean
dosage of about 1 mg/day) for a median of 273 days. This
figure is much lower than that reported for older people treated
with first-generation antipsychotics (511) and is consistent
with data reported in a recent prospective longitudinal study of
risperidone and haloperidol in older subjects with mixed psychiatric
disorders (514). There are, however, no placebo-controlled
studies addressing this issue and no studies employing withdrawal
maneuvers. Clozapine is the agent least associated with tardive dyskinesia,
although the rare occurrence of clozapine-induced tardive dyskinesia
has been reported (515).
Neuroleptic malignant syndrome is
a rare but potentially lethal adverse effect of antipsychotic medications.
It occurs less frequently with second-generation antipsychotic agents
than with first-generation agents, but it has been reported with
both types (516–520). The core features of
this syndrome are muscle rigidity (leading to elevated serum creatinine
phosphokinase levels), fever, leukocytosis, tremor, delirium, autonomic
instability, and diaphoresis. Older age and dementia may increase
the risk of neuroleptic malignant syndrome.
Clozapine is associated with risk of agranulocytosis (about
1%), which is more common in elderly patients than in younger
patients (509), and regular monitoring of blood counts
is required. Other antipsychotics may rarely be associated with
this adverse event, but its incidence is so infrequent that routine monitoring
of blood counts for this syndrome is not required for patients who
take other antipsychotics.
Metabolic abnormalities caused by second-generation antipsychotic
medications are not well studied in individuals with dementia but
may be more common with use of these agents in older individuals
(258). These metabolic abnormalities include hyperlipidemia, weight
gain, and diabetes mellitus (228).
There is also evidence of an increased risk of cerebrovascular
adverse events with at least three of the second-generation
antipsychotics (aripiprazole, olanzapine, and risperidone) when
used in the treatment of patients with dementia. In October 2002, Health
Canada issued a letter to health care professionals stating that
risperidone use may be associated with cerebrovascular events in
elderly patients with dementia (521). In April 2003,
the FDA issued a similar warning regarding risk of cerebrovascular
events with risperidone in patients with dementia and noted that
risperidone had not yet been shown to be safe or effective in treating
dementia-related psychosis (522). Pooled data from
four placebo-controlled trials suggested a rate of "cerebrovascular
events" (variably defined) of 4% in patients treated
with risperidone, compared with about 2% in those treated
with placebo. The available data suggest that the risk is greater
among those with pre-existing risk factors for cerebrovascular disease.
In January 2004, Eli Lilly and Company issued a warning to
prescribers that there was an increased incidence of cerebrovascular
adverse events in patients with dementia who were treated with olanzapine
(1.3%) versus placebo (0.4%), as well as increased
mortality (3.5% vs. 1.5%) (523).
In February 2005, Bristol-Myers Squibb issued a warning to prescribers
that there was an increased risk of cerebrovascular adverse events
in patients with dementia who were treated with aripiprazole (1.3% vs.
0.6% in those given placebo).
At present no warning has been issued regarding quetiapine
and increased risk of cerebrovascular events. Schneider et al. (225, 524)
reported an event rate of 0.8% for quetiapine and 1.9% for
placebo among placebo-controlled studies of quetiapine in the dementia
population. They also noted that the 95% confidence intervals
(CIs) for the relative risks for risperidone, olanzapine, and aripiprazole
all indicated increased risk for such events, whereas the CI for
quetiapine could not distinguish among increased risk, decreased
risk, or no risk. It is possible that patients with existing cerebrovascular
disease or other risk factors might be most susceptible to these events.
However, this possibility has yet to be definitively addressed with
studies designed to assess side effects or efficacy as a function
of baseline medical condition.
Finally, a recent meta-analysis of randomized controlled clinical
trials of second-generation antipsychotics in patients with dementia
performed by Schneider et al. (525) compared mortality in
the treatment and placebo groups during the clinical trial period.
In total, the meta-analysis included 15 trials, three of aripiprazole,
five of olanzapine, three of quetiapine, and five of risperidone.
The subjects were nursing home residents in 11 of the trials and
outpatients in the remaining four trials; a total of 3,353 subjects
received medication and 1,757 received placebo. When data from all
the trials were pooled, the odds ratio for death in subjects who
received second-generation antipsychotics was 1.54, compared to
the placebo group, with a 95% CI of 1.06–2.23.
Although for no individual medication or individual trial was the
odds ratio of death in the medication group statistically different
from that for the placebo group, for all medications and for 12
of the 15 trials the odds ratio favored placebo over the medication.
This finding has been underscored by the "black box" warning
applied by the FDA on April 11, 2005, to all of the second-generation
antipsychotics, stating that analysis of 17 placebo-controlled trials
of aripiprazole, olanzapine, quetiapine, or risperidone in patients
with dementia showed a death rate of about 4.5% in those
receiving active treatment versus about 2.6% in those receiving
placebo. Causes of death were varied, with the most common being
cardiovascular (heart failure, sudden death) or infectious (pneumonia) in
There is also evidence that first-generation antipsychotics are
similarly associated with increased mortality among patients who
take them and that this increased mortality may exceed that found
with second-generation antipsychotics. In a large retrospective
review of 22,890 patients over age 65 years in Pennsylvania who
received either first- or second-generation antipsychotic agents
between 1994 and 2003, Wang et al. (230) found a 1.37
relative risk (CI, 1.27–1.49) of death among users of first-generation
agents versus users of second-generation agents. The risk was highest
with higher doses and closer to the initiation of treatment. The
increased risk was independent of the presence of dementia and of
residence (nursing home versus community). The magnitude of this difference
was such that the authors concluded that for every 100 patients
treated with first-generation antipsychotics instead of second-generation
agents, there would be seven additional deaths. At this time, there
is no FDA "black box" warning on first-generation
Clinicians facing the challenge of treating patients with significant
psychosis or behavioral disturbances must weigh the risk of not
treating these complications of dementia against the risks of active
treatment described in this section. Clinicians must take into account
the evidence supporting the efficacy of the agent in question, the
morbidity and risk associated with the target symptoms, the patient's
general medical condition, and the evidence of risk and benefit
of any alternative treatment being considered.
b. Mild to moderate side effects
In addition to their association with the serious side effects
described in Section V.B.2.a.2.a,
antipsychotic medications are associated with numerous more common
but milder side effects.
First-generation antipsychotic agents have a broad range of
common side effects that vary with medication potency, although
any side effect can be seen with any agent. Reviews regarding first-generation
agents have cited side effects including akathisia, parkinsonism,
sedation, peripheral and central anticholinergic effects, postural
hypotension, cardiac conduction defects, and falls (211).
Most of these data come from short-term controlled trials; evidence
regarding long-term safety is generally lacking. Data available
from other studies in the elderly population, however, indicate
that caution is warranted. For instance, rates of tardive dyskinesia
are five- to sixfold greater in older than in younger populations
after long-term treatment with first-generation agents (511).
For practical purposes, side effects often guide selection of these
agents when used in patients with dementia. High-potency agents
(e.g., haloperidol, fluphenazine) are most strongly associated with
akathisia (which can worsen the target symptoms) and parkinsonian
symptoms. Low-potency agents (e.g., thioridazine, chlorpromazine)
are associated with sedation (which can lead to worsening cognition
or falls), central anticholinergic effects (e.g., confusion, delirium),
postural hypotension (which can also lead to falls), and a variety
of peripheral anticholinergic effects (e.g., dry mouth, constipation,
bladder dysfunction, tachycardia). When individuals with dementia
have co-occurring extrapyramidal disorders (as in dementia with
Lewy bodies), extraordinary sensitivity to first-generation antipsychotic agents
may be seen (526).
Risperidone treatment of patients with dementia is associated
with a low to moderate risk of dose-related parkinsonism. In the
large trial by Katz et al. (218), the rates of parkinsonism
were 21%, 13%, and 7% among patients
who received 2 mg/day of risperidone, 1 mg/day
of risperidone, and placebo, respectively. In the trial of De Deyn
et al. (212), the incidence of parkinsonism was 15% for
subjects who received risperidone at a mean endpoint dosage of 1.1 mg/day
and 11% for subjects who received placebo. Brodaty et al.
(219) found an incidence of parkinsonism of 23% among
subjects who received risperidone (mean dosage of 0.95 mg/day)
and 16% among subjects who received placebo. These results
are similar to those from a smaller study by Chan et al. (215)
in which risperidone and haloperidol were compared and are also
consistent with the results of a large meta-analysis of randomized
controlled trials of risperidone, which found an overall odds ratio
for extrapyramidal signs and symptoms of 1.80 (CI, 1.35–2.42)
for risperidone versus placebo (225). These studies
also showed a greater risk of sedation. In the trial of De Deyn
et al. (212), sedation affected 12% of patients
taking risperidone but only 4.4% of those who received
placebo, a finding also confirmed by the meta-analysis (odds ratio,
2.43; CI, 1.78–3.32). In the meta-analysis, a higher rate
of peripheral edema was found in patients treated with risperidone,
compared to those who received placebo (225). Risperidone
may also cause an abnormal gait in some patients (225).
For olanzapine, side effect information is primarily available
from the one randomized controlled trial that demonstrated clear
clinical efficacy (220); in one other clinical trial,
the doses used were not sufficient to help or harm or to provide
meaningful information about side effects (502), and
in the other trial specific characteristics were not described for
the side effects that occurred (222). In the one trial
with side effect information, sedation (at rates of 25%–36%)
and abnormal gait (at rates of 14%–20%) were
observed at all dosages used (5–15 mg/day). Results
of the meta-analysis of randomized controlled trials of olanzapine
showed substantially increased risk with the medication, compared
to placebo, of sedation (odds ratio, 4.00; CI, 2.27–7.04)
and urinary tract infections or incontinence (odds ratio, 6.69;
CI, 1.27–35.10) (225). Gait abnormalities
also developed in more subjects taking olanzapine than in those
who received placebo (225).
In the one trial comparing quetiapine to haloperidol, tolerability
of quetiapine was superior, with comparable effects on a simple
measure of agitation (527). Several measures of parkinsonism
showed worsening with haloperidol but no difference between quetiapine
and placebo (527). Sedation was seen in 4.1% of
patients who received placebo versus 25.3% and 36.2% of
those who received quetiapine and haloperidol, respectively. In
the subsequent trial in which the most efficacious dosage of quetiapine
was 200 mg/day, sedation occurred in 17.6% of
patients taking 200 mg/day, compared with 11.3% of
those taking 100 mg/day and 6.5% of those who
received placebo (227). A recent meta-analysis of randomized controlled
trials of quetiapine similarly found an odds ratio for sedation
of 3.90 (CI, 1.41–10.78) for quetiapine versus placebo
Aripiprazole treatment of patients with dementia is commonly
associated with sedation, occurring in 5%–15% of those
treated versus 1% of those receiving placebo. In the one published
randomized controlled trial, 8% of aripiprazole-treated
subjects but only 1% of placebo-treated subjects experienced
sedation (224). This finding was confirmed in a recent
meta-analysis that focused on adverse events (225).
Regarding ziprasidone in the treatment of patients with dementia,
there are insufficient data to make assertions regarding safety
Most short-term side effects can be minimized by using the
lowest effective dose. This principle is particularly important
in order to minimize sedation and akathisia, both of which can actually
worsen target symptoms (528). It may also be helpful
to select an agent with the side effect profile most suited to a
given patient. Anticholinergic agents may be effective in the treatment
of parkinsonian side effects, but the high risk of associated cognitive
decline, delirium, and other anticholinergic effects suggests that
they should be used only with extreme caution for elderly patients both
with and without dementia.
The use of benzodiazepines in the treatment of behavioral symptoms
in dementia has been studied in at least eight randomized clinical
trials. In six studies including a total of 873 subjects, benzodiazepines
were compared to antipsychotics administered orally (238–243).
In two studies, benzodiazepines were compared to placebo (529, 530).
Most of these studies were limited by the presence of poorly specified
diagnoses, a mixture of target symptoms, limited outcome measures,
and, in most cases, high doses of long-acting agents. Nonetheless,
they demonstrated that benzodiazepines perform better than placebo
but not as well as antipsychotics in reducing behavior problems.
These results are supported by a more recent randomized controlled
trial of comparing intramuscular lorazepam with intramuscular olanzapine,
which showed equal efficacy of lorazepam and olanzapine at 2 hours
but inferior efficacy of lorazepam at 24 hours (223).
There are no data concerning the efficacy of benzodiazepines after
8 weeks or whether one benzodiazepine is more effective than another.
Use of carbamazepine has support from several case series
(248), a small open trial (249), a double-blind
nonrandomized trial (250a), and two double-blind randomized
trials (250b, 250c) that showed modest
benefit for agitation at low doses, with low side-effect rates over
a short treatment period. One of these trials was followed by an
open-label extension that further supported efficacy, safety, and
tolerability (251). One small randomized crossover
trial showed nonsignificant decreases in behavioral measures (252).
Although several favorable case reports and open trials have
been reported for the anticonvulsant valproate (531–533),
four placebo-controlled trials have not demonstrated efficacy. In
a 6-week, randomized, placebo-controlled trial that included 172
nursing home residents with Alzheimer's disease and secondary
mania, subjects treated with divalproex sodium had no more improvement
in symptoms of mania than did subjects treated with placebo (253).
In another randomized placebo-controlled study conducted with 42
patients with Alzheimer's disease and behavioral disturbances,
valproic acid (dosage of 480 mg/day) was not more effective
than placebo in reducing overall agitation, although in secondary
analyses certain individual symptoms were improved (254).
However, because these results were derived from an analysis of
secondary outcomes, they are not sufficient to define practice.
In another 6-week, randomized, placebo-controlled trial that included
56 nursing home residents with dementia and behavioral disturbance,
results were suggestive of benefit with divalproex sodium; 68% of
the treatment group had improvement in agitation, compared with
52% of the control group (256). The largest
study, which prospectively addressed agitation as the primary outcome
in 153 nursing home residents with Alzheimer's disease,
found no difference between divalproex sodium (mean dosage of 800
mg/day) and placebo in either the primary outcome (agitation)
or secondary outcome measures (255).
There are no controlled trials of newer anticonvulsants such
as lamotrigine, gabapentin, and topiramate. The few case reports
and case series that suggest benefit with gabapentin (e.g., reference 534)
do not provide sufficient evidence to recommend their use.
A number of other agents have been proposed for the treatment
of agitation in patients with dementia (reviewed in references 210, 535, 536).
Efficacy data for these agents generally come from case reports
or small open trials, often of mixed populations.
For example, data on trazodone are primarily from case reports,
case series (260, 261), and a few small
trials (262) in which decreased irritability, anxiety,
restlessness, and affective disturbance was reported in a total
of 13 patients. In a small double-blind, randomized clinical trial
that was not placebo controlled, improvement in agitation with trazodone was
comparable to that seen with haloperidol (263). However,
in the largest and only placebo-controlled trial, which included
37 patients receiving trazodone, no benefit of trazodone, compared
to placebo, was found (214). A small randomized, placebo-controlled,
double-blind study of trazodone in patients with frontotemporal
dementia showed benefit over placebo (264).
Preliminary data suggest that SSRIs may be useful in the treatment
of agitation (262, 270). These preliminary
reports are supported by two case series and a small controlled
trial showing benefit of a variety of SSRIs for reduction of agitation
in patients with frontotemporal dementia (537–539),
although one trial of paroxetine in patients with frontotemporal
dementia did not demonstrate improvement in symptoms but did show
worsening of cognition (540). A rigorous placebo-controlled
trial examined the short-term benefit of citalopram versus perphenazine
in inpatients with agitation or psychotic features (271).
Double-blind treatment lasted no more than 3 weeks. Although both
perphenazine and citalopram, compared to placebo, produced clinical
improvement on general measures of behavior, improvement in agitation
and aggression specifically was seen only with citalopram. Patients
taking citalopram had few side effects.
The effects of buspirone for treatment of agitation or anxiety
in elderly patients with dementia have been reported in a number
of case reports (265–267) and assessed in
two open trials (268, 269). These limited
data are insufficient to establish efficacy.
A 6-week, randomized, double-blind, placebo-controlled trial
of propranolol that included 31 subjects with Alzheimer's
disease and behavioral disturbance who resided in nursing homes
showed benefit of the medication, compared with placebo, for certain
symptoms, although it was noted that use of beta-blockers was contraindicated
for many subjects who would otherwise have been eligible for the
study (277). The mean dose was 106 mg/day.
The benefits noted in the 6-week trial were lost to a great extent
over the ensuing 6 months of open-label treatment.