Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects...

Galantamine, a Cholinesterase Inhibitor thatAllosterically Modulates Nicotinic Receptors: Effectson the Course of Alzheimer’s Disease

Joseph Coyle and Paul Kershaw

Despite the proven efficacy of acetylcholinesterase inhib-itors in Alzheimer’s disease, there is a need for new andmore effective treatments. Galantamine is a novel treat-ment for Alzheimer’s disease that inhibits acetylcholines-terase and modulates nicotinic receptors. In randomized,double-blind, placebo-controlled studies of up to 6 monthsduration, galantamine significantly improved cognitivefunction. Galantamine also had beneficial effects on in-strumental and basic activities of daily living, and post-poned the progression of behavioral symptoms. Patientswho completed one of the 6-month, placebo-controlledstudies were eligible to enter a 6-month, open-extensionstudy of the 24-mg/day dose of galantamine. At the end of12 months, cognitive function and activities of daily livingwere preserved in those patients who had been treatedthroughout the study with galantamine 24 mg/day. At 12months, this group of patients had significantly bettercognitive functions than patients who had been treatedwith a placebo for 6 months before receiving galantamine.These studies indicate that galantamine postpones theprogression of symptoms in Alzheimer’s disease. Sincegalantamine shows the greatest benefits when treatment isstarted early, its long-term benefits may result from aneffect on the underlying disease process; such an effectmight be mediated by galantamine’s concomitant actionon nicotinic receptors. Biol Psychiatry 2001;49:289–299 ©2001 Society of Biological Psychiatry

Key Words: Galantamine, Alzheimer’s disease, nicotinicreceptors, activities of daily living, behavioral symptoms

Introduction

Alzheimer’s disease (AD) has become a major publichealth issue (Jeste et al 1999). In the United States,

AD is estimated to cost more than $100 billion annually indirect and indirect costs (Ernst and Hay 1994; Schumock

1998); the aging of our population will escalate this cost.The economic burden of AD together with the impact ofthe illness on patients, family members, and other care-givers makes the search for effective long-term treatmentsa high priority.

The median survival for patients with AD is approxi-mately 8 years from the onset of symptoms (Barclay et al1985). During this time, patients invariably exhibit func-tional as well as cognitive decline (Gauthier et al 1997).The majority of patients will also develop behavioraldisturbances (Teri et al 1989). These noncognitive aspectsof the illness often cause a change in patients’ level ofcare: independent living gives way to dependence onfamily members or assisted living, and often to skilled careor placement in a nursing home (Brodaty et al 1993; TheCanadian Study of Health and Aging 1994; Teri et al1989).

Central cholinergic deficits are thought to contribute tothe development of cognitive impairment as well as someof the behavioral symptoms associated with AD (Bartus etal 1982; Coyle et al 1983; Cummings and Kaufer 1996).Symptomatic pharmacotherapy for AD has therefore beendirected at enhancing cholinergic neurotransmission in thecentral nervous system (CNS). To date, the most success-ful pharmacologic strategy has been the inhibition ofacetylcholinesterase (AChE), the enzyme responsible forcatabolizing acetylcholine (ACh) in the synaptic cleft.Three cholinesterase inhibitors—donepezil, rivastigmine,and tacrine—are currently available in the United Statesfor the treatment of AD. These treatments improve cog-nitive and global function in randomized controlled stud-ies of 6 months duration (Corey-Bloom et al 1998; Knappet al 1994; Rogers et al 1998b; Ro¨sler et al 1999). Resultsfrom either open-label studies or retrospective analysessuggest that donepezil and tacrine have beneficial effectson behavioral symptoms (Kaufer et al 1996; Mega et al1999; Raskind et al 1997); prospective, double-blind dataare required to confirm these findings.

Since the nature of AD is progressive, treatments thatslow the decline in cognitive and daily function and delaythe development of behavioral symptoms are desirable.

From the Harvard Department of Psychiatry, Belmont, Massacusetts (JC) andJanssen Research Foundation, Titusville, New Jersey (PK).

Address reprint requests to Joseph T. Coyle, M.D., Chairman, ConsolidatedDepartment of Psychiatry, Harvard Medical School, McLean Hospital, 115Mill Street, Belmont MA 02478.

Received May 30, 2000; revised September 28, 2000; accpted November 1, 2000.

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00PII S0006-3223(00)01101-X

Galantamine is a novel treatment for AD, which inhibitsAChE (Bores et al 1996) and modulates nicotinic AChreceptors (nAChRs) (Schrattenholz et al 1996). The mainfocus of this review is on the results of pivotal phase IIIstudies to assess galantamine’s effects on the course ofAD.

Pharmacology of Galantamine

Galantamine increases the availability of ACh in thecholinergic synapse by competitively inhibiting AChE, theenzyme responsible for its breakdown (Bores et al 1996;Thomsen et al 1991a). Galantamine has more than a10-fold selectivity for AChE relative to butyrylcholinest-erase (Thomsen and Kewitz 1990), which is in contrast tononselective agents such as tacrine and physostigmine(Thomsen et al 1991b). The inhibition of AChE ceaseswithin 24 hours of discontinuing galantamine (Thomsenand Kewitz 1990), so that anesthetic agents and musclerelaxants, if required, can be safely administered within ashort period of stopping galantamine.

Galantamine also potentiates cholinergic neurotrans-mission by positively modulating the response of nAChRsto ACh (Albuquerque et al 1997; Schrattenholz et al1996). Galantamine is an allosteric potentiating ligandbecause it acts at a site on the nAChR that is different fromthe ACh-binding site (Maelicke, in press; Schrattenholz etal 1996). Galantamine appears to enhance both pre- andpostsynaptic nAChR function by making nAChRs moresensitive to available ACh (Albuquerque et al 1997;Maelicke, in press; Schrattenholz et al 1996). Submicro-molar concentrations of galantamine increase the fre-quency of opening of nicotinic receptor ion channels,thereby potentiating submaximal ACh-activated currents.Studies have shown that the potentiating effect of galan-tamine on nAChRs is maintained in cell models that aredevoid of AChE (Schrattenholz et al 1996), indicating thatthe modulatory effect of galantamine on nAChRs is notrelated to its AChE activity (Schrattenholz et al 1996).

There are theoretical reasons for expecting that galan-tamine’s effects on nAChRs might reduce the symptomsof AD. As well as controlling the release of ACh,presynaptic nAChRs also modulate the release of gluta-mate and monoamines, such as serotonin and norepineph-rine (Albuquerque et al 1997; Levin and Simon 1998;Alkondon et al 1999). These neurotransmitter systems arealso affected in AD and appear to contribute to thecognitive and behavioral symptoms of the illness (Table1). Thus, activating nAChRs may help to correct theseneurochemical deficits, thereby alleviating symptoms ofAD (Maelicke, in press). There are also some data tosuggest that activation of nAChRs may modify diseaseprogression in AD by reducing neuronal vulnerability tothe cytotoxic effects of amyloid and by reducing itsformation (Kihara et al 1998).

Enhancing nAChR function may be particularly impor-tant in the early stages of AD. Recent data suggest that inthe early phase of the illness the symptoms of AD are notprimarily caused by a loss of cholinergic function (Daviset al 1999). It has therefore been suggested that strategiesaimed at enhancing the function of noncholinergic sys-tems, such as the glutamatergic system, may be effectivefor early cognitive decline (Davies 1999). One approachwould be to activate nAChRs because they augment therelease of glutamate (Albuquerque et al 1997; Levin andSimon 1998).

Combining pharmacologic mechanisms has become apopular and successful strategy for treating other CNSdisorders, including depression (Stahl 1997) and schizo-phrenia (Worrel et al 2000). Moreover, for Parkinson’sdisease combining two dopaminergic agents with differentmechanisms (L-dopa and a dopamine agonist) often be-comes the mainstay of treatment as the disease progresses(Olanow and Koller 1998). Allosteric modulators, bythemselves, have low intrinsic potential to activatenAChRs. Thus, together with AChE inhibition, allostericmodulation may produce a robust enhancement of phasicneurotransmission at nAChRs, thereby avoiding nonselec-

Table 1. Potential Benefits of Enhancing Nicotinic Neurotransmission

Enhancing nicotinic neurotransmission Potential benefits

Increases release of acetylcholine (Newhouse et al 1997) Improves memory and learningUpregulates nicotinic receptors

(Marks et al 1987; Rowell and Winkler 1984)Increases the number of functional nicotinic

receptorsIncreases presynaptic calcium (Court et al 1998) Neurotrophic effectsInduces genomic expression (Court et al 1998) Neurotrophic effectsIncreases release of glutamate

(Albuquerque et al 1997; McGehee et al 1995)Neurotrophic effects, improves learning

and memoryIncreases release of serotonin (Levin and Simon 1998) Reduces emotional disturbancesProtects againstb-amyloid-induced neuronal death

(Kihara et al 1998)Neuroprotective effects

Reproduced with permission from Maelicke, in press.

290 J. Coyle and P. KershawBIOL PSYCHIATRY2001;49:289–299

tive overstimulation of nAChRs. An allosteric potentiatingligand, such as galantamine, may therefore circumvent theproblem of nicotinic agonist–induced desensitization ofthe nAChR and consequently the development of toler-ance and loss of clinical efficacy (Maelicke, in press). Thisraises the possibility that combining allosteric modulationof nAChRs with inhibition of AChE may result in betterlong-term efficacy in the treatment of AD than AChEinhibition alone (Maelicke, in press).

Preclinical Evidence

Several lines of evidence indicate that galantamine hascognitive-enhancing effects. In particular, Sweeney andcolleagues (Sweeney et al. 1988, 1989, 1990) have shownthat galantamine attenuates cognitive deficits in mice. Inthese studies, galantamine has been shown to be highlyspecific for AChE and to have a relatively long duration ofaction (Sweeney et al 1988). In mice with selectiveexcitotoxic lesions of the nucleus basalis that producedsubstantial cortical cholinergic deficits, treatment withgalantamine reversed impairments in the 24-hour retentionof passive avoidance and in the working memory compo-nent of the Morris water maze (Sweeney et al 1990).Notably, behavioral tolerance did not occur with repeateddoses of galantamine; in fact, prior doses of galantamineappeared to have a priming effect on later performance.These characteristics led to the proposal that galantaminemight be an effective drug for the treatment of AD(Sweeney et al 1988, 1990).

Methods

Patients

Patients who were included in galantamine studies had:

• A diagnosis of probable AD according to the Na-tional Institute of Neurologic and Communicative

Disorders and Stroke and the Alzheimer’s Diseaseand Related Disorders Association criteria (Mc-Khann et al 1984).

• Mild to moderate dementia, which was confirmed bya Mini-Mental State Examination (MMSE) (Folsteinet al 1975) score of 11–24 and a score of$12 on theCognitive subscale of the Alzheimer’s Disease As-sessment Scale (ADAS-cog) at screening (Rosen etal 1984). In one study (GAL-USA-10), patients hadto have an MMSE score of 10–22 and an ADAS-cogscore of$18 at screening.

• No clinical evidence of other causes of cognitiveimpairment.

• A responsible caregiver who, together with the pa-tient (or appropriate representative), provided writteninformed 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 hypothyroid-ism were included in these studies, provided their comor-bid condition was well controlled.

Design

The design of these pivotal phase III studies are given inTable 2. These studies were randomized, double blind, andplacebo controlled. They were multicenter studies thatwere conducted in the United States, Canada, Europe,Australia, and South Africa (Table 2). At the end ofGAL-USA-1, patients who still met the inclusion criteriawere eligible to enter a 6-month extension study using the24-mg dose of galantamine (GAL-USA-3).

Outcome Measures

Cognitive function was the main measure of efficacy, inkeeping with Food and Drug Administration guidelines

Table 2. Design of Pivotal Phase III Galantamine Studies

Study Duration Treatment groups Dose escalation period

GAL-INT-2 3 months Placebo (n 5 125)(Europe, Canada, Australia,

South Africa, United States)flexible dose Galantamine 24–32 mg (n 5 261) 3–4 weeks

GAL-USA-10 5 months Placebo (n 5 286)(United States) fixed dose Galantamine 8 mg/day (n 5 140) 0 weeks

Galantamine 16 mg/day (n 5 279) 4 weeksGalantamine 24 mg/day (n 5 273) 8 weeks

GAL-INT-1 6 months Placebo (n 5 125)(Europe, Canada) fixed dose Galantamine 24 mg/day (n 5 220) 3 weeks

Galantamine 32 mg/day (n 5 218) 4 weeksGAL-USA-1 6 months Placebo (n 5 213)(United States) fixed dose Galantamine 24 mg/day (n 5 212) 3 weeks

Galantamine 32 mg/day (n 5 211) 4 weeks

Effects of Galantamine on Alzheimer’s Disease 291BIOL PSYCHIATRY2001;49:289–299

(Leber 1990). This was measured by ADAS-cog, whichassesses memory, attention, language, and orientation(Rosen et al 1984). An overall assessment of response totreatment was measured with the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) (Schneider et al 1997). The CIBIC-plus was scoredby a trained clinician based on separate interviews with thepatient and the caregiver. Scores ranged from 1 to 7 (1,markedly improved relative to baseline; 7, markedlyworse). Two different scales were used to assess patients’activities of daily living (ADL): the disability assessmentfor dementia (DAD) scale (Ge´linas et al 1999) and a23-item version of the Alzheimer’s Disease CooperativeStudy Activities of Daily Living (ADCS/ADL) inventory(Galasko et al 1997). Behavioral symptoms were assessedby the Neuropsychiatric Inventory (NPI) (Cummings et al1994).

Statistical Analyses

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

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

Results

Galantamine: Effects on Cognitive Decline

In all four phase III studies, galantamine produced signif-icant benefits on cognitive function relative to a placebofor both OC and ITT analyses (Table 3). In the 5-monthstudy and both 6-month studies, the placebo groupsexperienced a significant decline in cognitive functionrelative 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 improve-ment in cognitive function relative to baseline (p , .05 forall three groups) (Figures 1 and 2). Furthermore, a pooledanalysis of the two 6-month studies showed that galan-

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

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

Table 3. Effects of Galantamine on Cognitive Function inPhase III Studies

Study Treatment groups

Mean change from baselineADAS-cog score

ITT OC

GAL-INT-2 Placebo 10.6 10.5Galantamine 24–32 mg 21.1a 21.4a

GAL-USA-10 Placebo 11.7 11.8Galantamine 8 mg/day 10.4 10.1b

Galantamine 16 mg/day 21.4c 21.5c


GAL-INT-1 Placebo 12.2 12.4Galantamine 24 mg/day 20.6c 20.7c


GAL-USA-1 Placebo 12.0 12.2Galantamine 24 mg/day 21.9c 21.7c


Negative change score on the Cognitive subscale of the Alzheimer’s DiseaseAssessment Scale (ADAS-cog) indicates improvement, positive change scoreindicates deterioration. ITT, intention-to-treat analyses; OC, observed case analy-ses.

ap # .01 for galantamine-placebo difference.bp # .05 for galantamine-placebo difference.cp # .001 for galantamine-placebo difference.


tamine maintained significant improvements in cognitivefunction regardless of whether patients had mild or mod-erate disease (Lilienfeld and Parys, in press) (Figure 3).

The CIBIC-plus is judged by an investigator who isblind to all other assessments and therefore is a means ofconfirming the clinical relevance of any benefits observedon cognitive function (Committee for Proprietary Medic-inal Products 1997). In all of these studies, galantamineproduced a significantly better overall response to treat-ment than the placebo, as judged by CIBIC-plus (Raskindet al 2000; Tariot et al 2000b; Wilcock et al, in press;Wilkinson et al 2000).

The Long-Term Effects of Galantamine onCognitive Decline

Patients who completed the 6-month United States studywere eligible to enter a 6-month, open-label study (Ras-kind et al 2000). Approximately 80% of patients from eachof the three treatment groups (galantamine 24 mg/day,

galantamine 32 mg/day, or placebo) who completed thedouble-blind study entered the extension phase (n 5 353),and 268 patients completed it. All of these patientsreceived a 24-mg dose of galantamine regardless of thetreatment they had received in the double-blind phase(Figure 4). During the extension phase, investigatorsremained blinded to the treatment patients had receivedduring the double-blind phase. This design (staggered startdesign) has been put forward as a means of identifyingwhether a new treatment affects the course of AD (Leber1996).

At 12 months the group of patients who had receivedthe 24-mg dose of galantamine in the double-blind phasehad preserved cognitive function, as indicated by a meanchange from baseline ADAS-cog score that was notsignificant on both ITT and OC analyses (Figure 5). Thisstabilizing effect on cognitive function was seen for bothmild (MMSE $ 18) and moderately (MMSE, 18) severestages of the illness. There was a significant difference inmean change from baseline ADAS-cog score between this24-mg galantamine group and those patients who had

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

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

Figure 5. Mean change from baseline in the Cognitive subscaleof the Alzheimer’s Disease Assessment Scale (ADAS-cog) over12 months (GAL-USA-1,3).■, galantamine 24 mg/galantamine24 mg; l, placebo/galantamine 24 mg. *p # .05 vs. placebo/galantamine 24 mg. (Reproduced with permission from Raskindet al 2000.)


received a placebo in the double-blind phase (p 5 .03 forOC analysis,p 5 .05 for ITT analysis). Patients who hadreceived galantamine 32 mg/day in the double-blind phaseexperienced a modest deterioration in ADAS-cog score by12 months (1.8 points). The reduction in dose may haveresulted in a rebound effect and therefore some loss ofefficacy.

It has been proposed that if a treatment only hassymptomatic effects, placebo-treated patients who are thenplaced on the active drug should approach the perfor-mance of those who were taking the active drug from thebeginning of the trial (Grundman and Thal 1998; Leber1996) (Figure 6). At the end of 12 months, patients whoreceived galantamine 24 mg/day throughout the trial hadsignificantly better cognitive function than those whoreceived a placebo for the first 6 months. These resultssuggest that galantamine slows the underlying diseaseprogress, which may reflect its concomitant action onnAChRs (Maelicke, in press). However, further galan-tamine studies, designed specifically to assess disease-modifying effects, are required to test this possibility.

Even allowing for the possible biases inherent in anopen-label study, these results are very encouraging. Astable dose of galantamine 24 mg/day appears to postponethe decline in cognitive function for at least 12 months.This is a clinically important effect, particularly in adisease in which patients typically survive 8 years fromthe time of diagnosis (Barclay et al 1985). To quantify thisbenefit numerically, these data can be compared witheither data from untreated patient cohorts or data extrap-olated from the placebo group that participated in the

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

GALANTAMINE: EFFECTS ON FUNCTIONAL DE-

CLINE. In three out of four of the pivotal phase IIIstudies galantamine showed significant benefits on ADL(Table 4). In the 3-month, phase III study (Wilkinson et al2000), galantamine produced significant benefits on ADLas indicated by a drug–placebo difference in the meanchange from baseline DAD score of 4.3 points (p 5 .004)(Figure 7). Moreover, in this study functional performancewas preserved in galantamine-treated patients, as indicatedby a DAD score that did not significantly differ frombaseline. This preservation of functional activity wasobserved regardless of whether patients were maintainedon a dose of 32 mg/day or one of 24 mg/day. In contrast,the decline in total DAD score for the placebo group wasstatistically significant (p , .001). Analysis of the DADclusters showed that galantamine’s significant benefits on

Figure 6. Assessing disease modification: the randomized (stag-gered) start design.

Table 4. Effects of Galantamine on Activities of Daily Livingin Phase III Studies

Study Treatment groups

Mean change from baselineADL scorea

ITT OC

GAL-INT-2 Placebo 25.2 24.2Galantamine 24–32 mg/day 20.4b 10.1c

GAL-USA-10 Placebo 23.8 24.0Galantamine 8 mg/day 23.2 23.1Galantamine 16 mg/day 20.7b 20.5b


GAL-INT-1 Placebo 25.8 25.2Galantamine 24 mg/day 22.7 22.7Galantamine 32 mg/day 22.4d 21.4e

GAL-USA-1 Placebo 22.9 22.8Galantamine 24 mg/day 22.7 22.9Galantamine 32 mg/day 22.1 21.7

ADL, Activities of Daily Living; ITT, intention-to-treat analyses; OC, observedcase analyses.

aFor GAL-INT-2, GAL-INT-1, and GAL-USA-1 the disability assessment fordementia scale was used. For GAL-USA-10 the Alzheimer’s Disease CooperativeStudy ADL inventory was used. For both ADL scales, a positive change scoreindicates improvement.

bp # .001 for galantamine–placebo difference.cp # .01 for galantamine–placebo difference.dp # .05 for galantamine–placebo difference.ep 5 .06 for galantamine–placebo difference.


functional ability were seen for a wide range of dailyactivities 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 galantamine16- and 24-mg doses have beneficial effects on the courseof ADL. The galantamine–placebo difference in the meanchange from baseline ADCS/ADL score was 2.4–3.5points (p , .01 for both doses vs. placebo) (Table 4 andFigure 9). At the end of the study functional performancewas preserved in galantamine-treated patients (16 mg/daygroup), whereas the placebo group experienced a signifi-cant decline (p , .05).

The positive ADL outcome in these studies providesconsistent evidence of galantamine’s functional benefit.For donepezil, a significant effect on ADL has beenreported 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 significantbenefits on instrumental ADL, but favorable effects have

been observed on the Progressive Deterioration Scale(Knapp et al 1994). Rivastigmine has shown favorableeffects on ADL, although specific benefits on basic ADLhave not been reported (Corey-Bloom et al 1998; Ro¨sler etal 1999; Bentham et al 1999).

In the 6-month study conducted in the United States(Raskind et al 2000) there were no significant differencesbetween galantamine and a placebo at 6 months on ADL.However, at the end of the open-extension phase, patientswho had received galantamine 24 mg/day for 12 monthshad maintained their functional ability, as indicated by amean DAD score that was not significantly different frombaseline (21.7 points change from baseline). Analysis ofthe DAD clusters revealed that both instrumental and basicADL had been preserved at 12 months. In contrast,patients who had received the placebo for the first 6months experienced a significant decline in ADL (8.1points,p , .001 vs. baseline). The failure of this group ofpatients to achieve the same level of functional benefit as

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

Figure 8. Mean change from baseline in disabilityassessment for dementia (DAD) scale cluster scoresat 3 months (GAL-INT-2).h, placebo;■, galan-tamine. †p 5 .06; **p # .01; *p # .05 vs. placebo.

Figure 9. Mean change from baseline in Alzheimer’s DiseaseCooperative Study Activities of Daily Living (ADCS/ADL)inventory score over 5 months (GAL-USA-10).E, galantamine24 mg/day;l, galantamine 16 mg/day;■, placebo. **p # .01;*** p # .001 vs. placebo. (Reproduced with permission fromTariot et al 2000b.)


those patients who were treated continuously with galan-tamine 24 mg provides additional evidence that galan-tamine may alter the course of AD. The group of patientswho had received the 32-mg dose of galantamine in thedouble-blind phase also experienced functional decline by12 months (6.2 points,p , .001 vs. baseline).

The deterioration in day-to-day functioning contributesto patients’ dependence on family members and othercaregivers. The early stages of AD affect instrumentalADL, such as leisure, housework, and managing finances.In the later stages there is a progressive loss in the abilityto undertake basic ADL, such as eating, dressing, andpersonal hygiene (Gauthier et al 1997). Galantamine’sstabilizing effects on instrumental and basic ADL for atleast 12 months would therefore be expected to be animportant benefit for patients and carers. Moreover, stud-ies of 12 months duration indicate that the annual decreasein DAD score in untreated patients is 11–13 points (Torfsand Feldman 2000), confirming the clinical relevance ofmaintaining ADL function at baseline levels.

GALANTAMINE: EFFECTS ON THE PROGRESSION OF

BEHAVIORAL SYMPTOMS. The available data suggestthat improvements in cognitive function do not necessarilyproduce benefits in behavioral symptoms (Cummings2000). The NPI scale was therefore used in the 5-monthstudy conducted in the United States to investigate theeffects of galantamine on behavioral symptoms (Tariot etal 2000a). At the end of the study galantamine 16 and 24mg/day produced significant benefits on behavioral symp-toms, as indicated by a drug–placebo difference in themean change from baseline NPI score of 2.4 points (p ,.05 for both doses vs. placebo) (Figure 10). Among the 10items in the NPI scale, aberrant motor behavior, anxiety,disinhibition, and hallucinations appeared to be the maincontributing factors to the overall significant therapeutic

benefits of galantamine relative to the placebo (Tariot et al2000a). At the end of the study, the NPI scores for the 16-and 24-mg/day galantamine groups did not significantlydiffer from baseline values (0.1-point improvement forboth doses), whereas the placebo group had experienced asignificant decline (2.3 points,p , .05 vs. baseline). Thesedata suggest that galantamine delays the progression ofbehavioral symptoms in patients with mild to moderateAD. Similar behavioral benefit, based on prospectivelycollected data from a randomized, controlled study, has todate only been reported for metrifonate (Morris et al1998). An exploratory analysis of the noncognitive com-ponent of ADAS suggests that tacrine may also havefavorable effects on behavioral symptoms (Raskind et al1997).

Behavioral symptoms cause a great deal of distress tofamilies and caregivers (Kaufer et al 1998) and are themost common reason for referral to a specialist andplacement in a nursing home (Steele et al 1990). There-fore, postponing the progression of these symptoms is animportant treatment goal that would be expected to benefitpatients and their families and possibly delay nursinghome placement. Although the central cholinergic systemmay, at least in part, mediate the behavioral symptoms ofAD (Cummings and Kaufer 1996), there may be differ-ences in the psychotropic effects of different cholinergictreatments (Cummings 2000). Further studies are requiredto test this possibility.

GALANTAMINE: TOLERABILITY PROFILE. Galan-tamine is well tolerated. The most common adverse eventsare those expected from cholinergic stimulation (Table 5).Using a slow dose escalation of up to 8 weeks, thediscontinuation rates due to adverse events in patients whoreceived galantamine 16 and 24 mg were low (7% and10%, respectively) and comparable to the discontinuationrate in the placebo group (7%) (Tariot et al 2000b). Thesedata compare favorably with those from rivastigmine andtacrine studies (Knapp et al 1994; Ro¨sler et al 1999) and

Figure 10. Mean change from baseline in NeuropsychiatricInventory (NPI) score over 5 months (GAL-USA-10).E, galan-tamine 24 mg/day;l, galantamine 16 mg/day;■, placebo. *p #.05 vs. placebo. (Reproduced with permission from Tariot et al2000b.)

Table 5. Proportion (%) of Patients with Adverse EventsOccurring at Least 5% More Often during Treatment with AnyGalantamine Dose than with a Placebo

Adverse eventPlacebo

(n 5 286)

Galantamine16 mg/day(n 5 279)

Galantamine24 mg/day(n 5 273)

Nausea 4.5 13.3 16.5Vomiting 1.4 6.1 9.9Anorexia 3.1 6.5 8.8Diarrhea 5.9 12.2 5.5Discontinuation due to

adverse event (%)7.0 7.0 10.0

Any serious adverse event (%) 10.8 10.0 12.8


are comparable with data from donepezil studies (Burns etal 1999; Rogers et al 1998b). Notably, nausea and vomit-ing, if they occurred, were generally associated with doseescalation and resolved rapidly in most subjects. Sinceallosteric modulators do not directly activate the nAChRand only potentiate submaximal ACh-induced responses,it has been suggested that they are less likely to causesignificant unwanted effects (Maelicke, in press). Thetolerability data for galantamine provide support for thishypothesis.

Conclusions

Cholinesterase inhibition has been the traditional approachto treating the symptoms of AD. Recently, nAChRs havereceived considerable attention as potential therapeutictargets for the treatment of AD. Activation of presynapticnAChRs has been shown to augment the release of anumber of neurotransmitters that are deficient in patientswith AD, including ACh, monoamines, and glutamate(Albuquerque et al 1997; Levin and Simon 1998). More-over, there is evidence to suggest that activation ofnAChRs may protect againstb-amyloid toxicity (Kihara etal 1998). Thus, treatments, such as galantamine, thatactivate nAChRs and inhibit AChE may have long-termefficacy superior to that of treatments that act on AChEalone.

For new medications to be effective in the long-termtreatment of AD, they should have favorable and sustainedeffects on the cognitive, functional, and behavioral symp-toms of the illness. With these criteria as a measure oftreatment success, galantamine is a very promising treat-ment for AD. In well-designed randomized, controlledstudies of up to 6 months duration, galantamine signifi-cantly decreases the cognitive and functional symptoms ofAD and appears to postpone the emergence of behavioralsymptoms.

Historical placebo control subjects show a five- toeight-point decline in ADAS-cog scores over 1 year. Incontrast, patients who received galantamine 24 mg/day for12 months had maintained their baseline ADAS-cog scoreand showed only a three-point decline from their peakperformance, suggesting that continuous treatment withgalantamine slows the rate of cognitive decline. Moreover,patients treated with a placebo for 6 months who thenreceive galantamine 24 mg/day do not achieve the samelevel of cognitive function as those patients continuouslytreated with galantamine. These two observations raise thepossibility that galantamine’s long-term benefits may bedue to an effect on the underlying disease process. Thispotentially important effect, which may be due to galan-tamine’s concomitant activity on nAChRs, requires furtherassessment in future clinical studies.

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

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