Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue3.2001:

Galantamine, a Cholinesterase Inhibitor that
Allosterically Modulates Nicotinic Receptors: Effects
on the Course of Alzheimer’s Disease
Joseph Coyle and Paul Kershaw
Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease, there is a need for new and
more effective treatments. Galantamine is a novel treatment for Alzheimer’s disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized,
double-blind, placebo-controlled studies of up to 6 months
duration, galantamine significantly improved cognitive
function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients
who completed one of the 6-month, placebo-controlled
studies were eligible to enter a 6-month, open-extension
study of the 24-mg/day dose of galantamine. At the end of
12 months, cognitive function and activities of daily living
were preserved in those patients who had been treated
throughout the study with galantamine 24 mg/day. At 12
months, this group of patients had significantly better
cognitive functions than patients who had been treated
with a placebo for 6 months before receiving galantamine.
These studies indicate that galantamine postpones the
progression of symptoms in Alzheimer’s disease. Since
galantamine shows the greatest benefits when treatment is

started early, its long-term benefits may result from an
effect on the underlying disease process; such an effect
might be mediated by galantamine’s concomitant action
on nicotinic receptors. Biol Psychiatry 2001;49:
289 –299 © 2001 Society of Biological Psychiatry
Key Words: Galantamine, Alzheimer’s disease, nicotinic
receptors, activities of daily living, behavioral symptoms

Introduction

A

lzheimer’s disease (AD) has become a major public
health issue (Jeste et al 1999). In the United States,
AD is estimated to cost more than $100 billion annually in
direct and indirect costs (Ernst and Hay 1994; Schumock

From the Harvard Department of Psychiatry, Belmont, Massacusetts (JC) and
Janssen Research Foundation, Titusville, New Jersey (PK).
Address reprint requests to Joseph T. Coyle, M.D., Chairman, Consolidated

Department of Psychiatry, Harvard Medical School, McLean Hospital, 115
Mill Street, Belmont MA 02478.
Received May 30, 2000; revised September 28, 2000; accpted November 1, 2000.

© 2001 Society of Biological Psychiatry

1998); the aging of our population will escalate this cost.
The economic burden of AD together with the impact of
the illness on patients, family members, and other caregivers makes the search for effective long-term treatments
a high priority.
The median survival for patients with AD is approximately 8 years from the onset of symptoms (Barclay et al
1985). During this time, patients invariably exhibit functional as well as cognitive decline (Gauthier et al 1997).
The majority of patients will also develop behavioral
disturbances (Teri et al 1989). These noncognitive aspects
of the illness often cause a change in patients’ level of
care: independent living gives way to dependence on
family members or assisted living, and often to skilled care
or placement in a nursing home (Brodaty et al 1993; The
Canadian Study of Health and Aging 1994; Teri et al
1989).

Central cholinergic deficits are thought to contribute to
the development of cognitive impairment as well as some
of the behavioral symptoms associated with AD (Bartus et
al 1982; Coyle et al 1983; Cummings and Kaufer 1996).
Symptomatic pharmacotherapy for AD has therefore been
directed at enhancing cholinergic neurotransmission in the
central nervous system (CNS). To date, the most successful pharmacologic strategy has been the inhibition of
acetylcholinesterase (AChE), the enzyme responsible for
catabolizing acetylcholine (ACh) in the synaptic cleft.
Three cholinesterase inhibitors— donepezil, rivastigmine,
and tacrine—are currently available in the United States
for the treatment of AD. These treatments improve cognitive and global function in randomized controlled studies of 6 months duration (Corey-Bloom et al 1998; Knapp
et al 1994; Rogers et al 1998b; Ro¨sler et al 1999). Results
from either open-label studies or retrospective analyses
suggest that donepezil and tacrine have beneficial effects
on behavioral symptoms (Kaufer et al 1996; Mega et al
1999; Raskind et al 1997); prospective, double-blind data
are required to confirm these findings.
Since the nature of AD is progressive, treatments that
slow the decline in cognitive and daily function and delay

the development of behavioral symptoms are desirable.
0006-3223/01/$20.00
PII S0006-3223(00)01101-X

290

J. Coyle and P. Kershaw

BIOL PSYCHIATRY
2001;49:289 –299

Table 1. Potential Benefits of Enhancing Nicotinic Neurotransmission
Enhancing nicotinic neurotransmission
Increases release of acetylcholine (Newhouse et al 1997)
Upregulates nicotinic receptors
(Marks et al 1987; Rowell and Winkler 1984)
Increases presynaptic calcium (Court et al 1998)
Induces genomic expression (Court et al 1998)
Increases release of glutamate
(Albuquerque et al 1997; McGehee et al 1995)

Increases release of serotonin (Levin and Simon 1998)
Protects against b-amyloid-induced neuronal death
(Kihara et al 1998)

Potential benefits
Improves memory and learning
Increases the number of functional nicotinic
receptors
Neurotrophic effects
Neurotrophic effects
Neurotrophic effects, improves learning
and memory
Reduces emotional disturbances
Neuroprotective effects

Reproduced with permission from Maelicke, in press.

Galantamine is a novel treatment for AD, which inhibits
AChE (Bores et al 1996) and modulates nicotinic ACh
receptors (nAChRs) (Schrattenholz et al 1996). The main

focus of this review is on the results of pivotal phase III
studies to assess galantamine’s effects on the course of
AD.

Pharmacology of Galantamine
Galantamine increases the availability of ACh in the
cholinergic synapse by competitively inhibiting AChE, the
enzyme responsible for its breakdown (Bores et al 1996;
Thomsen et al 1991a). Galantamine has more than a
10-fold selectivity for AChE relative to butyrylcholinesterase (Thomsen and Kewitz 1990), which is in contrast to
nonselective agents such as tacrine and physostigmine
(Thomsen et al 1991b). The inhibition of AChE ceases
within 24 hours of discontinuing galantamine (Thomsen
and Kewitz 1990), so that anesthetic agents and muscle
relaxants, if required, can be safely administered within a
short period of stopping galantamine.
Galantamine also potentiates cholinergic neurotransmission by positively modulating the response of nAChRs
to ACh (Albuquerque et al 1997; Schrattenholz et al
1996). Galantamine is an allosteric potentiating ligand
because it acts at a site on the nAChR that is different from

the ACh-binding site (Maelicke, in press; Schrattenholz et
al 1996). Galantamine appears to enhance both pre- and
postsynaptic nAChR function by making nAChRs more
sensitive to available ACh (Albuquerque et al 1997;
Maelicke, in press; Schrattenholz et al 1996). Submicromolar concentrations of galantamine increase the frequency of opening of nicotinic receptor ion channels,
thereby potentiating submaximal ACh-activated currents.
Studies have shown that the potentiating effect of galantamine on nAChRs is maintained in cell models that are
devoid of AChE (Schrattenholz et al 1996), indicating that
the modulatory effect of galantamine on nAChRs is not
related to its AChE activity (Schrattenholz et al 1996).

There are theoretical reasons for expecting that galantamine’s effects on nAChRs might reduce the symptoms
of AD. As well as controlling the release of ACh,
presynaptic nAChRs also modulate the release of glutamate and monoamines, such as serotonin and norepinephrine (Albuquerque et al 1997; Levin and Simon 1998;
Alkondon et al 1999). These neurotransmitter systems are
also affected in AD and appear to contribute to the
cognitive and behavioral symptoms of the illness (Table
1). Thus, activating nAChRs may help to correct these
neurochemical deficits, thereby alleviating symptoms of
AD (Maelicke, in press). There are also some data to

suggest that activation of nAChRs may modify disease
progression in AD by reducing neuronal vulnerability to
the cytotoxic effects of amyloid and by reducing its
formation (Kihara et al 1998).
Enhancing nAChR function may be particularly important in the early stages of AD. Recent data suggest that in
the early phase of the illness the symptoms of AD are not
primarily caused by a loss of cholinergic function (Davis
et al 1999). It has therefore been suggested that strategies
aimed at enhancing the function of noncholinergic systems, such as the glutamatergic system, may be effective
for early cognitive decline (Davies 1999). One approach
would be to activate nAChRs because they augment the
release of glutamate (Albuquerque et al 1997; Levin and
Simon 1998).
Combining pharmacologic mechanisms has become a
popular and successful strategy for treating other CNS
disorders, including depression (Stahl 1997) and schizophrenia (Worrel et al 2000). Moreover, for Parkinson’s
disease combining two dopaminergic agents with different
mechanisms (L-dopa and a dopamine agonist) often becomes the mainstay of treatment as the disease progresses
(Olanow and Koller 1998). Allosteric modulators, by
themselves, have low intrinsic potential to activate

nAChRs. Thus, together with AChE inhibition, allosteric
modulation may produce a robust enhancement of phasic
neurotransmission at nAChRs, thereby avoiding nonselec-

Effects of Galantamine on Alzheimer’s Disease

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291

Table 2. Design of Pivotal Phase III Galantamine Studies
Study

Duration

Treatment groups

Dose escalation period
3– 4 weeks

GAL-INT-2
(Europe, Canada, Australia,
South Africa, United States)
GAL-USA-10
(United States)

3 months
flexible dose

Placebo (n 5 125)
Galantamine 24 –32 mg (n 5 261)

5 months
fixed dose

GAL-INT-1
(Europe, Canada)

6 months

fixed dose

GAL-USA-1
(United States)

6 months
fixed dose

Placebo (n 5 286)
Galantamine 8 mg/day (n 5 140)
Galantamine 16 mg/day (n 5 279)
Galantamine 24 mg/day (n 5 273)
Placebo (n 5 125)
Galantamine 24 mg/day (n 5 220)
Galantamine 32 mg/day (n 5 218)
Placebo (n 5 213)
Galantamine 24 mg/day (n 5 212)
Galantamine 32 mg/day (n 5 211)

tive overstimulation of nAChRs. An allosteric potentiating
ligand, such as galantamine, may therefore circumvent the
problem of nicotinic agonist–induced desensitization of
the nAChR and consequently the development of tolerance and loss of clinical efficacy (Maelicke, in press). This
raises the possibility that combining allosteric modulation
of nAChRs with inhibition of AChE may result in better
long-term efficacy in the treatment of AD than AChE
inhibition alone (Maelicke, in press).

Preclinical Evidence
Several lines of evidence indicate that galantamine has
cognitive-enhancing effects. In particular, Sweeney and
colleagues (Sweeney et al. 1988, 1989, 1990) have shown
that galantamine attenuates cognitive deficits in mice. In
these studies, galantamine has been shown to be highly
specific for AChE and to have a relatively long duration of
action (Sweeney et al 1988). In mice with selective
excitotoxic lesions of the nucleus basalis that produced
substantial cortical cholinergic deficits, treatment with
galantamine reversed impairments in the 24-hour retention
of passive avoidance and in the working memory component of the Morris water maze (Sweeney et al 1990).
Notably, behavioral tolerance did not occur with repeated
doses of galantamine; in fact, prior doses of galantamine
appeared to have a priming effect on later performance.
These characteristics led to the proposal that galantamine
might be an effective drug for the treatment of AD
(Sweeney et al 1988, 1990).

Methods

0 weeks
4 weeks
8 weeks
3 weeks
4 weeks
3 weeks
4 weeks

Disorders and Stroke and the Alzheimer’s Disease
and Related Disorders Association criteria (McKhann et al 1984).
• Mild to moderate dementia, which was confirmed by
a Mini-Mental State Examination (MMSE) (Folstein
et al 1975) score of 11–24 and a score of $12 on the
Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) at screening (Rosen et
al 1984). In one study (GAL-USA-10), patients had
to have an MMSE score of 10 –22 and an ADAS-cog
score of $18 at screening.
• No clinical evidence of other causes of cognitive
impairment.
• A responsible caregiver who, together with the patient (or appropriate representative), provided written
informed consent to participate in the study.
To increase the external validity of the clinical data,
patients with concomitant diseases such as hypertension,
heart failure (New York Heart Association score I–II),
non–insulin dependent diabetes mellitus, and hypothyroidism were included in these studies, provided their comorbid condition was well controlled.

Design
The design of these pivotal phase III studies are given in
Table 2. These studies were randomized, double blind, and
placebo controlled. They were multicenter studies that
were conducted in the United States, Canada, Europe,
Australia, and South Africa (Table 2). At the end of
GAL-USA-1, patients who still met the inclusion criteria
were eligible to enter a 6-month extension study using the
24-mg dose of galantamine (GAL-USA-3).

Patients
Patients who were included in galantamine studies had:
• A diagnosis of probable AD according to the National Institute of Neurologic and Communicative

Outcome Measures
Cognitive function was the main measure of efficacy, in
keeping with Food and Drug Administration guidelines

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Table 3. Effects of Galantamine on Cognitive Function in
Phase III Studies
Mean change from baseline
ADAS-cog score
Study

Treatment groups

GAL-INT-2

Placebo
Galantamine
GAL-USA-10 Placebo
Galantamine
Galantamine
Galantamine
GAL-INT-1
Placebo
Galantamine
Galantamine
GAL-USA-1 Placebo
Galantamine
Galantamine

24 –32 mg
8 mg/day
16 mg/day
24 mg/day
24 mg/day
32 mg/day
24 mg/day
32 mg/day

ITT

OC

10.6
21.1a
11.7
10.4
21.4c
21.4c
12.2
20.6c
21.3c
12.0
21.9c
21.4c

10.5
21.4a
11.8
10.1b
21.5c
21.8c
12.4
20.7c
21.7c
12.2
21.7c
21.6c

Negative change score on the Cognitive subscale of the Alzheimer’s Disease
Assessment Scale (ADAS-cog) indicates improvement, positive change score
indicates deterioration. ITT, intention-to-treat analyses; OC, observed case analyses.
a
p # .01 for galantamine-placebo difference.
b
p # .05 for galantamine-placebo difference.
c
p # .001 for galantamine-placebo difference.

Figure 1. Mean change in the Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) over 6 months
(GAL-USA-1). E, galantamine 24 mg/day; Œ, galantamine 32
mg/day; ■, placebo. ***p # .001 vs. placebo. (Reproduced with
permission from Raskind et al 2000.)

baseline score; for CIBIC-plus, efficacy was based on
CIBIC-plus scores at 6 months.

Results
(Leber 1990). This was measured by ADAS-cog, which
assesses memory, attention, language, and orientation
(Rosen et al 1984). An overall assessment of response to
treatment was measured with the Clinician’s InterviewBased Impression of Change plus Caregiver Input (CIBICplus) (Schneider et al 1997). The CIBIC-plus was scored
by a trained clinician based on separate interviews with the
patient and the caregiver. Scores ranged from 1 to 7 (1,
markedly improved relative to baseline; 7, markedly
worse). Two different scales were used to assess patients’
activities of daily living (ADL): the disability assessment
for dementia (DAD) scale (Ge´linas et al 1999) and a
23-item version of the Alzheimer’s Disease Cooperative
Study Activities of Daily Living (ADCS/ADL) inventory
(Galasko et al 1997). Behavioral symptoms were assessed
by the Neuropsychiatric Inventory (NPI) (Cummings et al
1994).

Galantamine: Effects on Cognitive Decline
In all four phase III studies, galantamine produced significant benefits on cognitive function relative to a placebo
for both OC and ITT analyses (Table 3). In the 5-month
study and both 6-month studies, the placebo groups
experienced a significant decline in cognitive function
relative to baseline (1.8 –2.4 points on ADAS-cog, p ,
.05) (Raskind et al 2000; Tariot et al 2000b; Wilcock et al,
in press). In contrast, patients in the galantamine 16-, 24-,
and 32-mg/day groups maintained a significant improvement in cognitive function relative to baseline (p , .05 for
all three groups) (Figures 1 and 2). Furthermore, a pooled
analysis of the two 6-month studies showed that galan-

Statistical Analyses
The primary statistical assessment for efficacy was observed case (OC) analysis, which includes data from
assessments made while the patient is on the study drug at
designated times. All the results that are reported in this
review are for this analysis, unless otherwise stated. Also,
intention to treat (ITT) analyses were performed using
data from patients who provided postbaseline data while
on treatment. Missing data in the ITT analyses were
handled by the last observation carried forward method.
For ADAS-cog, DAD, ADCS/ADL inventory, and NPI,
efficacy assessments were based on mean change from

Figure 2. Mean change in the Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) over 5 months
(GAL-USA-10). E, galantamine 24 mg/day; l, galantamine 16
mg/day; ■, placebo. ***p # .001 vs. placebo. (Reproduced with
permission from Tariot et al 2000b.)

Effects of Galantamine on Alzheimer’s Disease

Figure 3. Mean change in the Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) at 6 months
according to baseline disease severity (pooled data from GALINT-1 and GAL-USA-1). MMSE, Mini-Mental State Examination; h, placebo; s, galantamine 24 mg/day; ■, galantamine 32
mg/day. *p # .05 vs. baseline. (Reproduced with permission
from Lilienfeld and Parys 2000b.)

tamine maintained significant improvements in cognitive
function regardless of whether patients had mild or moderate disease (Lilienfeld and Parys, in press) (Figure 3).
The CIBIC-plus is judged by an investigator who is
blind to all other assessments and therefore is a means of
confirming the clinical relevance of any benefits observed
on cognitive function (Committee for Proprietary Medicinal Products 1997). In all of these studies, galantamine
produced a significantly better overall response to treatment than the placebo, as judged by CIBIC-plus (Raskind
et al 2000; Tariot et al 2000b; Wilcock et al, in press;
Wilkinson et al 2000).

The Long-Term Effects of Galantamine on
Cognitive Decline
Patients who completed the 6-month United States study
were eligible to enter a 6-month, open-label study (Raskind et al 2000). Approximately 80% of patients from each
of the three treatment groups (galantamine 24 mg/day,

BIOL PSYCHIATRY
2001;49:289 –299

293

Figure 5. Mean change from baseline in the Cognitive subscale
of the Alzheimer’s Disease Assessment Scale (ADAS-cog) over
12 months (GAL-USA-1,3). ■, galantamine 24 mg/galantamine
24 mg; l, placebo/galantamine 24 mg. *p # .05 vs. placebo/
galantamine 24 mg. (Reproduced with permission from Raskind
et al 2000.)

galantamine 32 mg/day, or placebo) who completed the
double-blind study entered the extension phase (n 5 353),
and 268 patients completed it. All of these patients
received a 24-mg dose of galantamine regardless of the
treatment they had received in the double-blind phase
(Figure 4). During the extension phase, investigators
remained blinded to the treatment patients had received
during the double-blind phase. This design (staggered start
design) has been put forward as a means of identifying
whether a new treatment affects the course of AD (Leber
1996).
At 12 months the group of patients who had received
the 24-mg dose of galantamine in the double-blind phase
had preserved cognitive function, as indicated by a mean
change from baseline ADAS-cog score that was not
significant on both ITT and OC analyses (Figure 5). This
stabilizing effect on cognitive function was seen for both
mild (MMSE $ 18) and moderately (MMSE , 18) severe
stages of the illness. There was a significant difference in
mean change from baseline ADAS-cog score between this
24-mg galantamine group and those patients who had

Figure 4. Design of GAL-USA-1,3.

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Table 4. Effects of Galantamine on Activities of Daily Living
in Phase III Studies
Mean change from baseline
ADL scorea
Study
GAL-INT-2
GAL-USA-10

GAL-INT-1

GAL-USA-1

Figure 6. Assessing disease modification: the randomized (staggered) start design.

received a placebo in the double-blind phase (p 5 .03 for
OC analysis, p 5 .05 for ITT analysis). Patients who had
received galantamine 32 mg/day in the double-blind phase
experienced a modest deterioration in ADAS-cog score by
12 months (1.8 points). The reduction in dose may have
resulted in a rebound effect and therefore some loss of
efficacy.
It has been proposed that if a treatment only has
symptomatic effects, placebo-treated patients who are then
placed on the active drug should approach the performance of those who were taking the active drug from the
beginning of the trial (Grundman and Thal 1998; Leber
1996) (Figure 6). At the end of 12 months, patients who
received galantamine 24 mg/day throughout the trial had
significantly better cognitive function than those who
received a placebo for the first 6 months. These results
suggest that galantamine slows the underlying disease
progress, which may reflect its concomitant action on
nAChRs (Maelicke, in press). However, further galantamine studies, designed specifically to assess diseasemodifying effects, are required to test this possibility.
Even allowing for the possible biases inherent in an
open-label study, these results are very encouraging. A
stable dose of galantamine 24 mg/day appears to postpone
the decline in cognitive function for at least 12 months.
This is a clinically important effect, particularly in a
disease in which patients typically survive 8 years from
the time of diagnosis (Barclay et al 1985). To quantify this
benefit numerically, these data can be compared with
either data from untreated patient cohorts or data extrapolated from the placebo group that participated in the

Treatment groups

ITT

OC

Placebo
Galantamine 24–32 mg/day
Placebo
Galantamine 8 mg/day
Galantamine 16 mg/day
Galantamine 24 mg/day
Placebo
Galantamine 24 mg/day
Galantamine 32 mg/day
Placebo
Galantamine 24 mg/day
Galantamine 32 mg/day

25.2
20.4b
23.8
23.2
20.7b
21.5c
25.8
22.7
22.4d
22.9
22.7
22.1

24.2
10.1c
24.0
23.1
20.5b
21.6c
25.2
22.7
21.4e
22.8
22.9
21.7

ADL, Activities of Daily Living; ITT, intention-to-treat analyses; OC, observed
case analyses.
a
For GAL-INT-2, GAL-INT-1, and GAL-USA-1 the disability assessment for
dementia scale was used. For GAL-USA-10 the Alzheimer’s Disease Cooperative
Study ADL inventory was used. For both ADL scales, a positive change score
indicates improvement.
b
p # .001 for galantamine–placebo difference.
c
p # .01 for galantamine–placebo difference.
d
p # .05 for galantamine–placebo difference.
e
p 5 .06 for galantamine–placebo difference.

double-blind phase of the study. The average annual
decline in ADAS-cog for untreated AD patients is about
eight points, but the rate of change is less for patients with
mild AD (Stern et al 1994). In this 12-month study, linear
extrapolation of the change in ADAS-cog in the placebo
group at 6 months (2.2 points) suggests that the placebo
group would have deteriorated by four to five points at 12
months. This latter estimate is similar to the annual change
in ADAS-cog scores of four to six points reported for
placebo groups from 12-month, placebo-controlled studies
in patients with mild to moderate AD (Mulnard et al 2000;
Torfs and Feldman 2000).
GALANTAMINE:

EFFECTS

ON

FUNCTIONAL

DE-

In three out of four of the pivotal phase III
studies galantamine showed significant benefits on ADL
(Table 4). In the 3-month, phase III study (Wilkinson et al
2000), galantamine produced significant benefits on ADL
as indicated by a drug–placebo difference in the mean
change from baseline DAD score of 4.3 points (p 5 .004)
(Figure 7). Moreover, in this study functional performance
was preserved in galantamine-treated patients, as indicated
by a DAD score that did not significantly differ from
baseline. This preservation of functional activity was
observed regardless of whether patients were maintained
on a dose of 32 mg/day or one of 24 mg/day. In contrast,
the decline in total DAD score for the placebo group was
statistically significant (p , .001). Analysis of the DAD
clusters showed that galantamine’s significant benefits on

CLINE.

Effects of Galantamine on Alzheimer’s Disease

Figure 7. Mean change from baseline in disability assessment
for dementia (DAD) scale score over 3 months (GAL-INT-2). Œ,
galantamine 24 –32 mg/day; ■, placebo. **p # .01 vs. placebo.

functional ability were seen for a wide range of daily
activities including both instrumental and basic ADL
(Figure 8).
The 5-month study, conducted in the United States
(Tariot et al 2000b) (Table 2), confirmed that galantamine
16- and 24-mg doses have beneficial effects on the course
of ADL. The galantamine–placebo difference in the mean
change from baseline ADCS/ADL score was 2.4 –3.5
points (p , .01 for both doses vs. placebo) (Table 4 and
Figure 9). At the end of the study functional performance
was preserved in galantamine-treated patients (16 mg/day
group), whereas the placebo group experienced a significant decline (p , .05).
The positive ADL outcome in these studies provides
consistent evidence of galantamine’s functional benefit.
For donepezil, a significant effect on ADL has been
reported in one out of four prospective, randomized,
double-blind studies (Burns et al 1999; Rogers et al 1996,
1998a, 1998b). Tacrine has failed to show significant
benefits on instrumental ADL, but favorable effects have

BIOL PSYCHIATRY
2001;49:289 –299

295

Figure 9. Mean change from baseline in Alzheimer’s Disease
Cooperative Study Activities of Daily Living (ADCS/ADL)
inventory score over 5 months (GAL-USA-10). E, galantamine
24 mg/day; l, galantamine 16 mg/day; ■, placebo. **p # .01;
***p # .001 vs. placebo. (Reproduced with permission from
Tariot et al 2000b.)

been observed on the Progressive Deterioration Scale
(Knapp et al 1994). Rivastigmine has shown favorable
effects on ADL, although specific benefits on basic ADL
have not been reported (Corey-Bloom et al 1998; Ro¨sler et
al 1999; Bentham et al 1999).
In the 6-month study conducted in the United States
(Raskind et al 2000) there were no significant differences
between galantamine and a placebo at 6 months on ADL.
However, at the end of the open-extension phase, patients
who had received galantamine 24 mg/day for 12 months
had maintained their functional ability, as indicated by a
mean DAD score that was not significantly different from
baseline (21.7 points change from baseline). Analysis of
the DAD clusters revealed that both instrumental and basic
ADL had been preserved at 12 months. In contrast,
patients who had received the placebo for the first 6
months experienced a significant decline in ADL (8.1
points, p , .001 vs. baseline). The failure of this group of
patients to achieve the same level of functional benefit as

Figure 8. Mean change from baseline in disability
assessment for dementia (DAD) scale cluster scores
at 3 months (GAL-INT-2). h, placebo; ■, galantamine. †p 5 .06; **p # .01; *p # .05 vs. placebo.

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Table 5. Proportion (%) of Patients with Adverse Events
Occurring at Least 5% More Often during Treatment with Any
Galantamine Dose than with a Placebo

Adverse event
Nausea
Vomiting
Anorexia
Diarrhea
Discontinuation due to
adverse event (%)
Any serious adverse event (%)

Figure 10. Mean change from baseline in Neuropsychiatric
Inventory (NPI) score over 5 months (GAL-USA-10). E, galantamine 24 mg/day; l, galantamine 16 mg/day; ■, placebo. *p #
.05 vs. placebo. (Reproduced with permission from Tariot et al
2000b.)

those patients who were treated continuously with galantamine 24 mg provides additional evidence that galantamine may alter the course of AD. The group of patients
who had received the 32-mg dose of galantamine in the
double-blind phase also experienced functional decline by
12 months (6.2 points, p , .001 vs. baseline).
The deterioration in day-to-day functioning contributes
to patients’ dependence on family members and other
caregivers. The early stages of AD affect instrumental
ADL, such as leisure, housework, and managing finances.
In the later stages there is a progressive loss in the ability
to undertake basic ADL, such as eating, dressing, and
personal hygiene (Gauthier et al 1997). Galantamine’s
stabilizing effects on instrumental and basic ADL for at
least 12 months would therefore be expected to be an
important benefit for patients and carers. Moreover, studies of 12 months duration indicate that the annual decrease
in DAD score in untreated patients is 11–13 points (Torfs
and Feldman 2000), confirming the clinical relevance of
maintaining ADL function at baseline levels.
GALANTAMINE: EFFECTS ON THE PROGRESSION OF

The available data suggest
that improvements in cognitive function do not necessarily
produce benefits in behavioral symptoms (Cummings
2000). The NPI scale was therefore used in the 5-month
study conducted in the United States to investigate the
effects of galantamine on behavioral symptoms (Tariot et
al 2000a). At the end of the study galantamine 16 and 24
mg/day produced significant benefits on behavioral symptoms, as indicated by a drug–placebo difference in the
mean change from baseline NPI score of 2.4 points (p ,
.05 for both doses vs. placebo) (Figure 10). Among the 10
items in the NPI scale, aberrant motor behavior, anxiety,
disinhibition, and hallucinations appeared to be the main
contributing factors to the overall significant therapeutic

BEHAVIORAL SYMPTOMS.

Placebo
(n 5 286)

Galantamine Galantamine
16 mg/day
24 mg/day
(n 5 279)
(n 5 273)

4.5
1.4
3.1
5.9
7.0

13.3
6.1
6.5
12.2
7.0

16.5
9.9
8.8
5.5
10.0

10.8

10.0

12.8

benefits of galantamine relative to the placebo (Tariot et al
2000a). At the end of the study, the NPI scores for the 16and 24-mg/day galantamine groups did not significantly
differ from baseline values (0.1-point improvement for
both doses), whereas the placebo group had experienced a
significant decline (2.3 points, p , .05 vs. baseline). These
data suggest that galantamine delays the progression of
behavioral symptoms in patients with mild to moderate
AD. Similar behavioral benefit, based on prospectively
collected data from a randomized, controlled study, has to
date only been reported for metrifonate (Morris et al
1998). An exploratory analysis of the noncognitive component of ADAS suggests that tacrine may also have
favorable effects on behavioral symptoms (Raskind et al
1997).
Behavioral symptoms cause a great deal of distress to
families and caregivers (Kaufer et al 1998) and are the
most common reason for referral to a specialist and
placement in a nursing home (Steele et al 1990). Therefore, postponing the progression of these symptoms is an
important treatment goal that would be expected to benefit
patients and their families and possibly delay nursing
home placement. Although the central cholinergic system
may, at least in part, mediate the behavioral symptoms of
AD (Cummings and Kaufer 1996), there may be differences in the psychotropic effects of different cholinergic
treatments (Cummings 2000). Further studies are required
to test this possibility.
GALANTAMINE: TOLERABILITY PROFILE. Galantamine is well tolerated. The most common adverse events
are those expected from cholinergic stimulation (Table 5).
Using a slow dose escalation of up to 8 weeks, the
discontinuation rates due to adverse events in patients who
received galantamine 16 and 24 mg were low (7% and
10%, respectively) and comparable to the discontinuation
rate in the placebo group (7%) (Tariot et al 2000b). These
data compare favorably with those from rivastigmine and
tacrine studies (Knapp et al 1994; Ro¨sler et al 1999) and

Effects of Galantamine on Alzheimer’s Disease

are comparable with data from donepezil studies (Burns et
al 1999; Rogers et al 1998b). Notably, nausea and vomiting, if they occurred, were generally associated with dose
escalation and resolved rapidly in most subjects. Since
allosteric modulators do not directly activate the nAChR
and only potentiate submaximal ACh-induced responses,
it has been suggested that they are less likely to cause
significant unwanted effects (Maelicke, in press). The
tolerability data for galantamine provide support for this
hypothesis.

Conclusions
Cholinesterase inhibition has been the traditional approach
to treating the symptoms of AD. Recently, nAChRs have
received considerable attention as potential therapeutic
targets for the treatment of AD. Activation of presynaptic
nAChRs has been shown to augment the release of a
number of neurotransmitters that are deficient in patients
with AD, including ACh, monoamines, and glutamate
(Albuquerque et al 1997; Levin and Simon 1998). Moreover, there is evidence to suggest that activation of
nAChRs may protect against b-amyloid toxicity (Kihara et
al 1998). Thus, treatments, such as galantamine, that
activate nAChRs and inhibit AChE may have long-term
efficacy superior to that of treatments that act on AChE
alone.
For new medications to be effective in the long-term
treatment of AD, they should have favorable and sustained
effects on the cognitive, functional, and behavioral symptoms of the illness. With these criteria as a measure of
treatment success, galantamine is a very promising treatment for AD. In well-designed randomized, controlled
studies of up to 6 months duration, galantamine significantly decreases the cognitive and functional symptoms of
AD and appears to postpone the emergence of behavioral
symptoms.
Historical placebo control subjects show a five- to
eight-point decline in ADAS-cog scores over 1 year. In
contrast, patients who received galantamine 24 mg/day for
12 months had maintained their baseline ADAS-cog score
and showed only a three-point decline from their peak
performance, suggesting that continuous treatment with
galantamine slows the rate of cognitive decline. Moreover,
patients treated with a placebo for 6 months who then
receive galantamine 24 mg/day do not achieve the same
level of cognitive function as those patients continuously
treated with galantamine. These two observations raise the
possibility that galantamine’s long-term benefits may be
due to an effect on the underlying disease process. This
potentially important effect, which may be due to galantamine’s concomitant activity on nAChRs, requires further
assessment in future clinical studies.

BIOL PSYCHIATRY
2001;49:289 –299

297

Aspects of this work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajardo,
Puerto Rico. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaceutica LP.

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