The Management of Alzheimer’s Disease and Related Dementias

The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer’s Disease and Related Dementias

Steven G. Potkin, MD

ABC: The Key Symptom Domains of AD and Their Assessment Instruments

Activities of daily living– PDS – ADFACS– ADCS/ADL

Behavior– NPI– BEHAVE-AD

Cognition– ADAS-Cog– MMSE

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

Mild4 Moderate4 Severe4

Number of patients1 Diagnosed2 Treated with AChE inhibitor3

1Mattson Jack; 2MMI MDAD, 2001; 3On CHeI—midpoint of last year’s treatment by severity rates and rates reported in Reminyl uptake 2001; 4Decision Resources.

Nu

mb

er o

f P

atie

nts

Disease Stages

Potential to Increase Diagnosis and Treatment Across Disease Stages

Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360

Pro

bab

ilit

y o

f In

stit

uti

on

aliz

atio

n

0.0

0.2

0.4

0.6

0.8

1.0

Mild(MMSE: 21–30)

Moderate(MMSE: 11–20)

Severe(MMSE: 0–10)

Severity of AD

0.017

0.345

0.867

Increased Probability of Institutionalization by Disease Severity

Inab

ility

to

hand

le m

oney

Inab

ility

to te

ll tim

e

Tim

e do

ing

hobb

ies

Dre

sses

pro

perly

Forg

etfu

lnes

sTi

me

rear

rang

ing

obje

cts

Con

duct

ing

fam

ilyfin

ance

s

Abi

lity

to u

se p

hone

Con

fusi

onEa

ting

man

ners

Mild AD(GDS 3)

Moderate AD(GDS 4)

Severe AD(GDS 5 or 6)

80

70

60

50

40

30

20

Adapted from Grossberg, 1999.

Mo

re i

mp

airm

ent

Mea

n P

DS

Sco

reEffects of Disease Severity on Impairment of ADL in Patients With AD

Improvement

Deterioration

Baseline 4 8 12 16 20

1

0

–1

–2

–3

–4

–5–6A

DC

S/A

DL

Sco

res

Mea

n(±

SE

M)

Ch

ang

e fr

om

Bas

elin

e

Time (Weeks)

AD Cooperative Study Activities of Daily Living Inventory; OC analysisTariot et al, 2000.

Placebo (n = 234)

Galantamine 8 mg/day (n=106)

Galantamine 16 mg/day (n=211)

Galantamine 24 mg/day (n=212)

Effects of Galantamine on ADL: ADCS/ADL Scores Mean Change from Baseline

*

Mohs et al, 2001; Feldman et al, 2001; Winblad et al, 2001.

*P<.05 vs placebo**P<.01 vs placeboOC analysis

0

10

20

30

Ch

ang

e fr

om

Bas

elin

e (%

)

Donepezil

Placebo

Clinicaldecline

Assessmentscale PDS ADFACS DAD

n=181 n =196n = 97 n=126n=95 n=121

MMSE=17.1

MMSE=19.35

MMSE=12.05

**

Effect of Donepezil on ADL at Endpoint: Change in Assessment Scale Score from Baseline

Corey-Bloom et al, 1998.

2

1

0

–1

–2

–3

–4

–5

–6

–7

Mea

n C

han

ge

fro

m B

asel

ine

0 12 18 26

Improvement

Decline

6–12 mg (n=231)

1–4 mg (n=233)

Placebo (n=235)

*

*P<.05 vs placebo; **P<.001 vs placebo

Weeks

**

Effects of Rivastigmine on ADL: Progressive Deterioration Scale (PDS)

Improvement in ADL: Rivastigmine Treatment vs Placebo (PDS)

Potkin et al, 2002.

ItemMild

(GDS ≤3)Moderate (GDS=4)

Severe(GDS ≥5)

Ability to handle money

Ability to tell time

Time spent on hobbies

Participating in family finanaces

Ability to dress properly

Reduced forgetfulness

Time rearranging objects

Ability to use the phone

Comfort in different settings

Proper eating manners

Agitation

Diurnalrhythm

IrritabilityWandering

Aggression

HallucinationsMoodchange

Socially unacceptable behavior

DelusionsSexually inappropriate behavior

Accusatorybehavior

Suicidalideation

Paranoia

Depression

Months before/after Diagnosis

Anxiety

Socialwithdrawal

100

80

60

40

20

0–40 –30 –20 –10 0 10 20 30

Fre

qu

ency

(%

of

Pat

ien

ts)

Jost and Grossberg, 1996.

Peak Frequency of Behavioral Symptoms as AD Progresses

N=69; CDR=clinical dementia rating scale; most common psychotic symptoms: agitation, wandering, irritability, withdrawal, physical assaultFarber NB, et al. Arch Gen Psychiatry. 2000(Dec):57(12):1165-1173

Pat

ien

ts A

ffec

ted

(%

)

0

20

40

60

80

CDR 0.5 CDR 1 CDR 2 CDR 3

Psychotic Symptom Frequency Increases With Disease Severity

NPI=neuropsychiatric inventory; Tariot et al, 2000.N=978

Effect of Galantamine on Behavioral Symptoms: NPI Total Scores

–3

–2

–1

0

1

2

3

4

Mea

n (

± S

EM

) C

han

ge

in N

PI

Sco

re f

rom

Bas

elin

e

Baseline 1 2 3 4 5

Placebo

Galantamine 8 mg/d

Galantamine 16 mg/d

Galantamine 24 mg/d

Time (Months)

Improvement

Deterioration

–3

–2

–1

0

1

2

3

4Mea

n C

han

ge

fro

m B

asel

ine

NP

I-N

H In

div

idu

al It

em S

core

at

Wee

k 24

Delusions

Hallucinatio

ns

Agitatio

n/aggression

Depression/dysphoria

Anxiety

Elation/euphoria

Apathy/indiffe

rence

Disinhibition

Irrita

bility/la

bility

Aberrant m

otor behavior

Night-tim

e behavior

Appetite/eatin

g

Placebo (n = 105)

Donepezil (n = 103)Improvement

Baseline

Decline

ITT, LOCF analysisNPI-NH=neuropsychiatric inventory-nursing home version Tariot et al, 2001

Donepezil Behavioral Effects in Nursing Home Patients at Week 24: Mean Change from Baseline in NPI-NH Individual Items

******

**

*

Mea

n c

han

ge

fro

m b

asel

ine

-3

-2

-1

0

1

2

3

4

*P<.05 vs baseline; **P<.001 vs baseline; OC analysis

Imp

rove

me

nt

Ag

itat

ion

Irri

tab

ility

An

xiet

yA

ber

ran

t m

oto

rb

ehav

ior

Ap

ath

yD

epre

ssio

nD

elu

sio

ns

Dis

inh

ibit

ion

Hal

luci

nat

ion

sE

up

ho

ria

Nig

ht-

tim

eb

ehav

ior

Ap

pet

ite

Cummings et al, 2002.

N=99

Rivastigmine: Change on NPI-NH at Week 52 for Patients Who Had the Symptom at Baseline

–3

–2

–1

0

1

2

3

Mea

n C

han

ge

fro

m B

asel

ine

n=234 n=212n=103

n=103

n=98

Imp

rove

men

t

Pla

ceb

o

Gal

anta

min

e(2

4 m

g/d

ay

Pla

ceb

o

Do

nep

ezil

(10

mg

/d)

Op

en-l

abel

Riv

asti

gm

ine

(3–1

2 m

g/d

)

MMSE=17.7 MMSE=14.4 MMSE=11.8 MMSE=9.2 MMSE=10.8NPI-101 NPI-122 NPI-123 NPI-124 NPI-125

OC analysis ITT, LOCF analysis OC analysis OC analysis OC analysisOutpatients Nursing home Community/ Nursing home Nursing home

assisted living

Adapted from Tariot et al,1 2000; Tariot et al,2 2001; Feldman et al,3 2001; Cummings et al,4 2000; Bullock et al,5 2001.

Pla

ceb

o

Do

nep

ezil

(10

mg

/d)

n=125n=119

Baseline

n=113

Op

en-l

abel

Riv

asti

gm

ine

(3–1

2 m

g/d

)

NPI Improvement following AChE Inhibitors and Dual AChE and BuChE Inhibitors Treatment in Five Studies (Mean Change per Item after Approximately 6 Months)

IncreasedDose

TerminatedMedication

Antipsychotics (n=55)

Anxiolytics (n=33)

Antidepressants (n=57)

Reduced Dose

Nursing Home AD Patients at Week 26

Anand R, et al. Neurobiol Aging. 2000;21:5220

0

5

10

15

20

25

30

35

Effects of Rivastigmine on Psychotropic Medication Use

Pat

ien

ts T

akin

g P

sych

otr

op

ic D

rug

s D

uri

ng

Riv

asti

gm

ine

Tre

atm

ent

(%)

Rivastigmine and Donepezil Administration Increases Basal ACh Release in Aged Rats

Chronic (21 Days)

Ach

(fm

ol/

µL

)

18 hours after the last administration; N=4–8; *P<.005 vs controlsScali et al. J Neural Transm. 2002;109(7-8):1067-1080

Most Frequent Adverse Events with 1-Week Dose Titration of ChE Inhibitors

Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268

Donepezil Galantamine Rivastigmine

AdverseEvent (%)

Placebo(n=315)

10 mg/Day(n=315)

Placebo(n=213)

24 mg/Day(n=212)

Placebo(n=868)

6–12 mg/Day

(n=1,189)

Nausea 6 19 13 37 12 47

Vomiting 3 8 8 21 6 31

Anorexia 2 7 6 14 3 17

Diarrhea 5 15 10 12 11 19

Adverse Events with 1- vs 4-Week Titration of Galantamine

Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268

1-Week Titration (%) 4-Week Titration (%)

AdverseEvent (%)

Placebo(n=213)

24 mg/Day(n=212)

Placebo(n=286)

24 mg/Day(n=273)

Nausea 13 37 5 17

Vomiting 8 21 1 10

Diarrhea 10 12 6 6

Anorexia 6 14 3 9

Tolerability of Donepezil: Incidence of Common Adverse Events by Titration Rate

Physicians’ Desk Reference, 2003.

No Titration 1-wk Titration 6-wk Titration

AdverseEvent (%)

Placebo(n=315)

5 mg/Day(n=311)

10 mg/Day (n=315)

10 mg/Day(n=269)

Nausea 6 5 19 6

Diarrhea 5 8 15 9

Insomnia 6 6 14 6

Fatigue 3 4 8 3

Vomiting 3 3 8 5

Muscle cramps 2 6 8 3

Anorexia 2 3 7 3

Slow (4 Weeks)-Dose Titration with Rivastigmine Provides Low Potential for AEs

Shua-Haim et al, 2001.

N=212

Adverse Event N %

Nausea/vomiting 8 3.8

Abdominal pain 1 0.5

Diarrhea 5 2.4

Agitation 7 3.3

Confusion 4 1.9

Hallucinations 1 0.5

Total 26 12.4

Acute Titration-Related AEs with ChE Inhibitor Therapy

Cholinergically mediated AEs include nausea, vomiting, abdominal pain, dizziness, diarrhea, weight loss/anorexia

Tend to be transient, most frequent during dose escalation and of mild to moderate intensity

Nausea and vomiting are centrally mediated, caused by too rapid an increase in brain ACh levels

Slow-dose escalation and administration with food are proven ways to reduce the incidence of these AEs, especially with rivastigmine and galantamine

Go slowly; give with food with Exelon and Reminyl

Erythrocyte:GlobularDimer G2

Muscle:AsymmetricA12

CNS: Brain

PNS: Skeletal muscleErythrocyte

Globular TetramerG4

GlobularMonomerG1

Darvesh S. et al. Nature Reviews. 2003: 4:131-138.

Molecular Forms of AChE

Cortex Hippocampus

Rivastigmine

Heptylphysostigmine

Human Brain AChE

7

6

5

4

3

2

1

0

Rat

io IC

G4/

G1 5

07

Inhibitory Influence of ChE Inhibitors on Molecular Forms

Human Control Cortex G1/G416.0

S11.4

S

G1G4

Ratio G4/G1: 2.1

Ch

E A

ctiv

ity

nm

ol

x m

in–

1 x

ml–

1 F

ract

ion

4.8S

75

50

25

0

Physostigmine

Donepezil

0 5 10 15 20 25 30 35

Enz et al, 1993.

Ratio G4/G1: 2.1

G1G4

16.0S 11.0S

4.8S

Fraction Nr.0 5 10 15 20 25 30 35

75

50

25

0

Human Alzheimer Cortex G1/G4 G1 preferring

G4 preferring

Enz, et al. Prog Brain Res. 1993;98:431-8.

Number of Fraction

0 10 20 300.00

0.50

1.00

0 10 20 300

25

50

0 10 20 300

25

50

0 10 20 300

25

500 10 20 30

0

25

50

Caudate nucleus

Normal Adult Brain AD

AC

hE

(µ

mo

l/M

in.

x m

L F

ract

ion

)

Frontal cortex

Nucleus basalis

G1G4G1G4

0 10 20 300.00

0.50

1.00

AChE Isoforms in Normal and AD Brains

ChE Inhibitors: Tolerability

**Clinical significance is unclear; CV=cardiovascular; EPS=extrapyramidal symptoms; +/- little or none; + mild; ++ moderateInglis, 2002.

Donepezil Rivastigmine Galantamine

Cholinergically mediatedacute AEs Yes Yes Yes

Drug–drug interactionsYes* None known Yes*

Chronic AEs Sleep disturbances ++ +/– +/–

CV problems + +/– +

EPS ++ +/– +/–

Behavioral disturbances + +/– +

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7Rivastigmine

Donepezil

*P<.05; **P<.01 vs rivastigmineRizzo et al, 2001.

Ad

vers

e E

ven

ts

per

100

,000

Pre

scri

pti

on

s

All Adverse Serious Adverse Major Reactions Reactions Reactions from Clinical Trials

*

**

Adverse Events per 100,000 Prescriptions for Rivastigmine and Donepezil

2C9/10/19

1A2

3A4

2D6

31%

54%

11% 4%

CYP450=cytochrome P450AAnzenbacher P, Anzenbacherova E. Cell Mol Life Sci. 2001(May);58(5-6):737-747; Scordo MG, Spina E. Pharmacogenomics. 2002(March);3(2):201-218; Grossberg GT, et al. Int J Geriatr Psychiatry. 2000(March);15(3):242-247

Significance of Drug-Drug Interaction

5 CYP450 isoenzymes account for ~99% of all drug metabolism

~85% of drug metabolism is mediated by 2 members of the CYP450 system: CYP3A4 and CYP2D6

Safety of rivastigmine:no clinically relevant interactions with 22 therapeutic classes of drugs

ChE Inhibitors: Pharmacokinetic Characteristics

Physicians’ Desk Reference, 2002; Nordberg and Svensson, 1998; Polinsky, 1998; Inglis, 2002.

AChE InhibitorsDual AChE/

BuChE Inhibitor

Characteristic Donepezil Galantamine Rivastigmine

Plasma half-life (hour)Brain half-life

~7070

~66

~112

Eliminationpathway Liver

50% kidney50% liver Kidney

Metabolism by2D6/3A4 isoenzymes Yes Yes Minimal

Administer with food? No Yes Yes

Enhanced G1 inhibition No Unknown Yes

Anand, et al, 2000.

Last Prescribed Dose ofRivastigmine (mg/d)

Imp

rove

men

t

LimitsPredicted response

–2.0

–1.0

0.0

1.0

2.0

3.0

4.00 2 4 6 8 10 12

1.5

1.0

0.5

0.0

–0.5

–1.0

–1.5

Last Prescribed Dose (mg/day)

Mea

n c

han

ge

fro

mb

asel

ine

on

MM

SE

0 2 4 6 8 10 12

Predicted responseLimits

Imp

rove

men

t

Predicted responseLimits

2.01.00.0

–1.0–2.0–3.0–4.0–5.0–6.0–7.0–8.0

Last Prescribed Dose (mg/day)0 2 4 6 8 10 12

Imp

rove

men

t

Mea

n c

han

ge

fro

m

bas

elin

e o

n P

DS

Mea

n C

han

ge

fro

m

Bas

elin

e o

n A

DA

S-C

og

ADAS-Cog PDS

MMSE

Linear Dose Response of Rivastigmine in ADAS-Cog, PDS, and MMSE Mean Change from Baseline at Week 26

6–12 mg/d 1–4 mg/d Placebo

–3

–2

–1

0

1

2

3

4

5

AD

AS

-Co

g S

core

Mea

n C

han

ge

fro

m B

asel

ine MHIS = 0 MHIS >0

***

**

*

Improvement

Decline

OC analysis, week 26*P<.002 vs placebo; **P=.02 vs 6–12 mg/day (MHIS = 0); ***P<.001 vs placeboMHIS=modified Hachinski ischemic scaleAdapted from Kumar, et al, 2000.

(n = 287) (n = 244)

Effects of Rivastigmine on Cognition in Patients With AD (MHIS score = 0) and AD with Vascular Risk Factors (MHIS >0)

-7

-6

-5

-4

-3

-2

-1

0

OC analysis, week 26*P<.05 vs placebo; **P<.001 vs placebo Adapted from Kumar, et al, 2000.

Improvement

Decline

PD

S S

core

Mea

n

Ch

ang

e fr

om

Bas

elin

e

MHIS=0 MHIS >0(n=287) (n=244)

6–12 mg/d 1–4 mg/d Placebo

*

**

Effects of Rivastigmine on ADL in Patients with AD (MHIS score=0) and AD With Vascular Risk Factors (MHIS >0)

VAD=vascular dementia MID=multi-infarct dementia

Evolution of VAD Syndrome

Alzheimer: (1895) arteriosclerotic brain degeneration

Tomlinson: (1967) volume of brain infarction Hachinski: (1967) MID cumulative multiple

small strokes Roman: (1967) VAD

– Infarcts—size, location, and number

– Risk factors—DM, hypertension, hyperlipidemia

Other=(AD + CVD DLB, FTD, unknown); CVD=cerebrovascular disease; DLB=Lewy bodydementiaFTD=frontotemporal dementiaLobo, et al, Neurology. 2000.

AD53.7%

VAD15.8%

Other 30.5%

Prevalence of Dementias:European Study of 2346 Cases

Vascular Risk Factors

Hyperlipidemia Hypertension Diabetes Obesity Smoking history Alcohol history

TIA FHx, Hx: Strokes,

cardiac/periph vas disease

Coagulopathy EKG abnormalities Atrial fib or

arrhythmias

Scheltens, 2001.

VAD: MRI Required for Clinical Diagnosis

*P<0.01Sakurada, et al, 1990.

00.20.40.60.8

11.21.41.61.8

Control AD AD/MID MID

Control AD AD/MID MID

** *

9 9 6 4n =

Hippocampal ChAT Activity

0

50

100

150

200

250

300

350

Control AD AD/MID MID

QNP (pmol/g protein)

*P<.05Sakurada, et al, 1990.

*

9 9 6 4n =

Hippocampal Muscarinic Receptors

*P<.05 vs placeboErkinjuntti, et al, 2002.

Placebo

Galantamine 24 mg/d

3

2

1

0

–1

–2

–3

–4

–5

AD

AS

-Co

g S

core

Mea

n C

han

ge

fro

m B

asel

ine

*

VAD AD + CVD(n=188) (n=239)

Improvement

Effects of Galantamine Treatment for 26 Weeks on Cognition in VAD and AD Patients With CVD

*P<.001 vs cardioaspirin and P<.05 vs baselineMoretti, et al, 2002.

Rivastigmine (3–6 mg/d)Cardioaspirin

-4.0

-3.0

-2.0

-1.0

0

1.0

Improvement

Decline0 1 3 8 12 16 22

Months

Ch

ang

e fr

om

Bas

elin

e in

N

PI

Sco

re a

t 22

Mo

nth

s *

Rivastigmine in Subcortical VAD: Efficacy up to 22 Months in an Open-label Study

*P<.001 improvement vs cardioaspirin and P<.01 vs baselineTPC=ten point clock drawingMoretti, et al, 2002.

Rivastigmine (3–6 mg/day)Cardioaspirin

4.0

3.0

2.0

1.0

0

-1.0

Improvement

Decline0 1 3 8 12 16 22

Months

Ch

ang

e fr

om

bas

elin

e in

T

PC

sco

re a

t 22

mo

nth

s

*

Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

*P<.01 vs cardioaspirin and P<.05 vs baselineRSS=relative stress scaleMoretti, et al, 2002.

Rivastigmine (3–6 mg/day)Cardioaspirin

-10.0

-7.5

-5.0

-2.5

0

-2.5

Improvement

Decline0 1 3 8 12 16 22

Months

Ch

ang

e fr

om

bas

elin

e in

R

SS

sco

re a

t 22

mo

nth

s *

Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

15

10

5

0

15

10

5

0

4

3

2

1

0

*Lewy body variant of ADPerry, et al, 1985, 1994.

NC AD DLB PD NC AD DLB PD NC AD DLB* PD

Normal controls (NC)

AD

DLB

Parkinson’s disease (PD)

Parietalcortex

Temporalcortex

Occipitalcortex

Decreased Cholinergic Activity Associated With Neuropathology of AD, DLB, and PD

Ch

AT

(n

mo

l/h/m

gP

)

Brain Infarction and the Clinical Expression of Alzheimer disease: The Nun Study (N=61)

Participants with AD pathology and brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts (OR 20.7)

Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter

Cerebrovascular disease can play an important role in determining the presence and severity of the clinical symptoms of AD

Campbell, Stephens, Ballard, 2001.

Dementia With Lewy Bodies

15%–25% of all dementia in the elderly Onset ~75–80 years Duration ~3.5 years (<1–20) Slight male predominance Characterized by

– Fluctuating cognitive impairment (~80%)– Persistent visual hallucinations (>60%)– Systematized delusions (~70%)– Depression (38%)– Parkinsonism (65%–70%)– Neuroleptic sensitivity (>50%)

Dementia With Lewy Bodies (cont’d)

DLB is underdiagnosed and may constitute 15% of all dementias

Supportive Features

Transient loss of consciousness 40%

Falls and syncope 50%

Systematized delusions 70%

Neuroleptic sensitivity 50%

Depression 50%

REM sleep behavior disorder 25%

*

**

*

*P<.05Ballard C, Walker M. Curr Psychiatry Rep. 1999(Oct);1(1):49-60

0

10

20

30

40

50

60

70

80 DLBAD

Visual

Hallu

cinat

ions

Auditory

Hallu

cinat

ions

Delusi

ons

Mis

iden

tific

atio

n

Depre

ssio

n

Per

cen

tag

e o

f P

atie

nts

Per

cen

tag

e o

f P

atie

nts

wit

h S

ymp

tom

sw

ith

Sym

pto

ms

Neuropsychiatric Symptoms in DLB vs AD

Ranked by Frequency of Occurrence (% of Patients)

McKeith IG, Ballard CG, Perry RH, et al. Neurology. 2000(March 14);54(5):1050-1058

Apathy/indifference 72.5 Appetite; eating disorder 34.2Anxiety 70.0 Elation/euphoria 18.3Depression/dysphoria 65.8 Disinhibition 16.7Delusions 58.3Agitation/aggression 55.0Irritability/lability 55.0Aberrant motor behavior 53.3

Symptoms in >50% of Patients (%) Symptoms in <50% of Patients (%)

Behavioral Symptoms at Baseline (NPI)

0

1

2 AD (n=12)

DLB (n=4)

Ave

rag

e B

EH

AV

E-A

D

Sco

re

Baseline 6 months Baseline 6 months

P=NS

P=NS

0

1

2

Incr

ease

in

M

MS

E S

core

AD DLB

3

4

5

P=NS

P=NS

NS=nonsignificantSamuel, et al, 2000.

Behavioral and Cognitive Responses to Donepezil in AD and DLB (Open-label, 5 mg/d for 6 Months)

*P<.01 vs placebo; **P<.001 vs placebo†Responder definition recommended by NPI author (J Cummings)Adapted from McKeith, et al, 2000.

Baseline

Imp

rove

men

t

NPI 10-Item Score

*

Mea

n C

han

ge

fro

m B

asel

ine

–8

–7

–6

–5

–4

–3

–2

–1

0

Rivastigmine

Placebo

12 20

Weeks Rivastigmine 3–12 mg/d (n=59)Placebo (n=61)

NPI 10-Item Score—Percentage of Patients Improving by 30% from Baseline†

* *70

60

50

40

30

20

10

0

Pat

ien

ts Im

pro

vin

g (

%)

Week 20

Effects of Rivastigmine on Behavioral Symptoms in DLB (Double Blind)

Perry, et al, 1985; Korczyn, 2001.

PD and Dementia

At least one-third of PD patients develop dementia

Patients with PD have degeneration of the nucleus basalis of Meynert and low brain ChAT levels

The dementia of PD is not improved by dopaminomimetic drugs

ChE inhibitor therapy in PD is indicated

Baseline

Rivastigmine 3–12 mg/d

*P<.02; **P<.015; OC analysisReading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174

8

6

4

2

0

NP

I H

allu

cin

atio

n a

nd

Sle

ep S

core

s

IncreasingSymptoms

*

N=12

N=12

**

8

6

4

2

0Hallucination Sleep

NPI Hallucination and Sleep Scores in PD Patients Receiving Rivastigmine

*

**

*P<.05; **P<.01 vs baseline; OC analysis; Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174

0

5

10

15

20

25

30

35

MMSE UPDRS

10

15

20

25

30

35

Imp

rove

men

t

Imp

rove

men

t0

2

4

6

8

10

12

NPI Caregiver Distress

0

5Im

pro

vem

ent

Baseline

Rivastigmine 3–12 mg/d

Rivastigmine in PD: Cognition, Motor Function, and Caregiver Burden

Effects of Rivastigmine Treatment on ADAS-Cog and UPDRS Motor Scores in PDD

N=28*P=.004 vs baseline Giladi, et al, 2003.

Baseline Week 12 Week 26

Mean rivastigmine dose (mg/d) 7.2 7.5

ADAS Cog total score 30.8 23.6 23.5*

UPDRS motor 43.9 42.9 43.6

ADAS-Cog Subscores Showing Statistically Significant Improvement from Baseline at Week 26 P

Naming 0.05

Recognition 0.007

Word finding 0.02

Remembering instructions 0.008

Concentration 0.0005

Effects of Rivastigmine Treatment on Clinical Global Impression of Change from Baseline

*P<.0001CGIC=clinical global impression of changeCGIC Scale: 3=marked improvement, 2=moderate improvement, 1=mild improvement, 0=no change,-1=mild worsening, -2=moderate worsening, -3=marked worsening; N=28Giladi, et al, 2002.

Week 12 Week 26

Mean dose (mg/d) 7.3 7.5

Patient perspective 1.6* 1.5*

Caregiver perspective 1.7* 1.3*

Neurologist perspective 1.8* 1.7*

Emre, 2002.

Reasons to Consider Switching ChE Inhibitors

Switching should be considered whenthere is– A lack of initial response to treatment

– Loss of response during long-term treatment Switching should not be considered in

patients responding to current treatment

Switching: Medical Rationale

Therapeutic strategy performed routinely in daily medical practice

Employed across a spectrum of medical conditions– Depression (SSRIs)– Migraine (triptans)– Microbial infection (antibiotics)– Heart failure (ACE inhibitors)

Purpose of switching is to maximize the benefits of treatment

N=17; 12-month, open-label extension of a 6-week open-label trial; week 18 vs baseline; Rasmusen L, et al. Clin Ther. 2001;23(suppl A):A25-A30; Bullock R, Connolly C. Int J Geriatr Psychiatry. 2002(March);17(3):288-289

No

. of

Do

nep

ezil

No

nre

spo

nd

ers

Wh

o R

esp

on

ded

to

Gal

anta

min

e1

Per ADAS-

cog

Per ADCS/ADL

9 8

0

20

40

60

80

100

Side EffectsDonepezil

Group (n=18)

Lack/Loss of Efficacy Group

(N=22)

Pat

ien

ts in

Wh

om

Sw

itch

Was

Ben

efic

ial (

%)2

0

4

8

12

16

20

Changing from Donepezil to Galantamine and Rivastigmine

15.4

74.4

11.5

54.5

Rivastigmine Responders

Auriacombe S, Pere JJ, Loria-Kanza Y, Vellas B. Curr Med Res Opin. 2002;18(3):129-138

Discontinued Rivastigmine

Due to AEs

0

20

40

60

80

Pat

ien

ts (

%)

0

20

40

60

80

Pat

ien

ts (

%)

Lack of efficacy of donepezil (n=304)Unable to tolerate donepezil (n=78)

Rivastigmine Responders

Discontinued Rivastigmine

Due to AEs

Lack of Tolerability and Efficacy With Donepezil Do Not Preclude Response to Rivastigmaine

Emre, 2002; Morris, 2002.

*Patients may derive clinical benefit from escalating the dose further to 9 mg daily(4.5 mg twice daily), and 12 mg daily (6 mg twice daily), at intervals of no less than 4 weeks.

No washout periodrequired

Washout for 7 days oruntil symptoms resolve

Initiate rivastigmine therapy at

3 mg daily (1.5 mg twice daily)

Minimum of 4 weeks

Monitor patient for efficacy, safety, and tolerability,as with standard dosing guidelines

Escalate dose to 6 mg daily (3 mg twice daily) and recheck in 4 weeks*

Safety or tolerabilityproblem

Unsatisfactory treatment on donepezil

Patient experiencing lack

of response or loss of efficacy

Donepezil or galantamineto rivastigmine

Donepezil or rivastigmineto galantamine

NO

Is the patient stabilized on

current therapy (ie, no tolerability

problems)?

YES

No washout period required

Initiate galantamine therapy at 8 mg daily (4 mg twice daily)

4 weeks

Monitor patient for efficacy, safety, and tolerability, as with standard dosing guidelines Escalate dose to 16 mg daily (8 mg twice daily)

and recheck in 4 weeks

7-day washout is recommended or until symptoms

resolve

Guidelines for Switching ChEIs

Medical Rationale for Switching

Switching is a relatively new concept in AD treatment

Many physicians stop ChE inhibitor treatment altogether if patient fails to show response or loses response to current agent

However, evidence suggests that switching between ChE inhibitors represents a valuable therapeutic option to maximize treatment benefits over a longer period

Reisberg B, Doody R, Stoffler A, et al. N Engl J Med. 2003(April 3);348(14):1333-1341

Memantine in Moderate-to-Severe AD

252 patients randomly assigned to placebo or 20 mg of memantine for 28 weeks

Memantine superior to placebo on– CIBIC-plus

– ADCS-ADL severe

– Severe Impairment Battery (SIB) No AEs observed Memantine recently FDA approved for

moderate to severe AD

Summary

AChE inhibitors and dual ChEIs are proven effective in the treatment of the ABC of AD

Patients with severe AD maintain robust behavioral responses to ChEI

Behavioral disturbances often result in patient institutionalization

As AD progresses, the number and severity of behavioral disturbances increases

ChE inhibitors can reduce the need for concomitant antipsychotics, antidepressants and anxiolytic medications

Summary

AD associated with vascular risk factors, cerebral vascular disease, and vascular angiopathy

Cholinergic deficits in VAD, AD, and mixed dementias

There is increasing evidence of efficacy for ChEIs in PDD, DLB, and VAD, which may result in an extended role for these agents

All ChEIs have differing modes of action and pharmacokinetic profiles; therefore, switching can be efficacious