Dementia in the LTC Environment: Choices in Management.

Dementia in the LTC Dementia in the LTC Environment: Choices in Environment: Choices in

ManagementManagement

““Doctor, just what Doctor, just what isis Dementia?” Dementia?”

“Globally decreasing cognitive function.”

Symptoms of Alzheimer’s DiseaseSymptoms of Alzheimer’s Disease

1.1. Memory loss affecting job skills or other Memory loss affecting job skills or other activitiesactivities

2.2. Difficulty performing familiar tasksDifficulty performing familiar tasks

3.3. Problems with languageProblems with language

4.4. Disorientation regarding time or placeDisorientation regarding time or place

5.5. Impaired judgmentImpaired judgment

6.6. Problems with abstract thinkingProblems with abstract thinking

7.7. Misplacing objectsMisplacing objects

8.8. Changes in mood or behaviorChanges in mood or behavior

9.9. Changes in personalityChanges in personality

10.10. Loss of initiativeLoss of initiative

1.1. Memory loss affecting job skills or other Memory loss affecting job skills or other activitiesactivities

2.2. Difficulty performing familiar tasksDifficulty performing familiar tasks

3.3. Problems with languageProblems with language

4.4. Disorientation regarding time or placeDisorientation regarding time or place

5.5. Impaired judgmentImpaired judgment

6.6. Problems with abstract thinkingProblems with abstract thinking

7.7. Misplacing objectsMisplacing objects

8.8. Changes in mood or behaviorChanges in mood or behavior

9.9. Changes in personalityChanges in personality

10.10. Loss of initiativeLoss of initiative

Alzheimer’s Disease in theAlzheimer’s Disease in theLong-Term Care (LTC) SettingLong-Term Care (LTC) Setting

Large patient population but overall low diagnosis Large patient population but overall low diagnosis and treatmentand treatment

1.8 million patients in skilled nursing1.8 million patients in skilled nursingfacilities facilities

70-90% incidence rate for AD70-90% incidence rate for AD22% of those with AD are diagnosed *22% of those with AD are diagnosed *30% of those diagnosed are treated 30% of those diagnosed are treated

with AChI’swith AChI’sThus, only 6-7% of potential patients Thus, only 6-7% of potential patients

treated with AChI’streated with AChI’s

*Beverly Nursing Home Analysis, 2002.

Know Thy Diagnostic Code$!Know Thy Diagnostic Code$!

► Alzheimer’s disease = 331.0Alzheimer’s disease = 331.0► Mild Cognitive Impairment = 780.93Mild Cognitive Impairment = 780.93

(Memory Loss)(Memory Loss)

► Frontotemporal / Picks = 331.11Frontotemporal / Picks = 331.11

► Senile degeneration of the brain = 331.2Senile degeneration of the brain = 331.2(useful for initial encounters when diagnosis uncertain)(useful for initial encounters when diagnosis uncertain)

► Dementia with Lewy bodies = 331.82Dementia with Lewy bodies = 331.82

► Parkinson’s disease = 332.0Parkinson’s disease = 332.0► Vascular Cognitive Impairment / Dementia = 438.0 Vascular Cognitive Impairment / Dementia = 438.0

(cognitive deficits causing late effects in cerebrovascular disease)(cognitive deficits causing late effects in cerebrovascular disease)

AAN Practice Parameters 2001AAN Practice Parameters 2001

Evidence supports the following tests in theEvidence supports the following tests in the

routine evaluation of the demented patient:routine evaluation of the demented patient:►Complete blood cell countComplete blood cell count►Serum electrolytesSerum electrolytes►Glucose: BUN/creatinineGlucose: BUN/creatinine►Serum BSerum B1212 levels levels►Liver function testsLiver function tests►Thyroid function testsThyroid function tests►Depression screening Depression screening

Knopman DS, DeKosky ST, Cummings JL, et al. Neurology. 2001(May 8);56(9):1143-1153

Short Geriatric Depression ScaleShort Geriatric Depression Scale► Are you basically satisfied with your life?Are you basically satisfied with your life?

► Do you often get bored?Do you often get bored?

► Do you often feel helpless?Do you often feel helpless?

► Do you prefer to stay at home, rather than Do you prefer to stay at home, rather than going out and doing new things?going out and doing new things?

► Do you feel pretty worthless the way you are Do you feel pretty worthless the way you are now?now?

2 or more “yes” answers [“no” to #1] may signal significant clinical

depression!

Hoyl MT, Alessi CA, Harker JO, et al. J Am Geriatr Soc. 1999(July);47(7):873-878

Scales and Evaluation Instruments to Monitor Scales and Evaluation Instruments to Monitor Natural History of Alzheimer’s DiseaseNatural History of Alzheimer’s Disease

► Mini-Mental State Examination (MMSE)Mini-Mental State Examination (MMSE)

► Function Activities Questionnaire Function Activities Questionnaire (FAQ)(FAQ)

► Physical Self-Maintenance Scale and Physical Self-Maintenance Scale and Instrumental Activites of Daily LivingInstrumental Activites of Daily Living

► Neuropsychiatric Inventory (NPI)Neuropsychiatric Inventory (NPI)

► Alzheimer’s Disease Assessment Alzheimer’s Disease Assessment Scale: Cognitive Section (ADAS-COG)Scale: Cognitive Section (ADAS-COG)

► Severe Impairment Battery (SIB)Severe Impairment Battery (SIB)

MMSE “Cutoff” Scores at Lower Quartile MMSE “Cutoff” Scores at Lower Quartile by Education and Age by Education and Age

252526262727272728281616

232323232525262627279-129-12

212122222222242424245-85-8

151516161818191919190-40-4

858580-8480-8475-7975-7970-7470-7465-6965-69

Age (Years)Age (Years)EducationEducation

(Years)(Years)

Crum RM, Anthony JC, Bassett SS, Folstein MF. JAMA. 1993(May 12);269(18):2386-2391

CognitiveCognitive

MildMild ModerateModerate SevereSevere

1. Santacruz KS, Swagerty D. Am Fam Physician. 2001;63(4):703-713.2. Alzheimer’s Society of Canada. Available at: www.alzheimer.ca/english/disease/progression-3stages.htm. Accessed 8/23/04.

EmotionalEmotional

BehavioralBehavioral

FunctionFunction

•Mood swings

•Personality changes

•Irritability

•Anxiety

•Depression

•Extreme personality changes

•Anxiety and apprehension

•Suspiciousness, paranoia, hostility, and anger

•Possible withdrawal

•Delusional behavioral

•Diminished short-term memory

•Language and speech difficulties (aphasia)

•Agnosia

•Limited attention span

•Diminished short-term and long-term memory

•Increased language and speech difficulties

•Declining ability to concentrate

•Severe memory impairment

•Severe impairment of verbal communication skills

•Inability to process information

•Misidentification

•Passiveness

•Restlessness

•Impaired judgment

•Repetitious behaviors

•Increased passivity

•Restlessness, pacing, wandering

•Disinhibition

•Increased potential for hostility and aggression

•Moaning and gesturing replace verbal communication

•Apraxia

•Impairment of coordination

•Initial signs of difficulties with ADLs

•Impaired ability to perform ADLs

•Urinary incontinence

•Sleep disruptions

•Perceptual disturbances

•Dependent on caregiver for ADL’s; bedridden

•Urinary & fecal incontinence

•Sleeps longer and more often

•Difficulty eating and swallowing

Stages of Alzheimer’s DementiaStages of Alzheimer’s Dementia

Unpaid Community Caregiver Time:Unpaid Community Caregiver Time:Relation to Alzheimer’s Dementia SeverityRelation to Alzheimer’s Dementia Severity

Hux MJ, et al. CMAJ. 1998;159(5):457-465.

0

1

2

3

4

5

6

7

SevereSevereModerateModerateMildMild

MMSE 21-26

MMSE 10-14

Ho

urs

pe

r H

ou

rs p

er

Da

yD

ay

Severity of Alzheimer’s Dementia

MMSE <10

MMSE <10

Nursing Time in Long-Term CareNursing Time in Long-Term Careper Patient, per 8-Hour Shiftper Patient, per 8-Hour Shift

► RN: 8 minutesRN: 8 minutes

► LPN: 12 minutesLPN: 12 minutes

► Nurse Aide: 40 minutesNurse Aide: 40 minutes

CMS: 1999 US national average.

Pathophysiologic Hypothesis of ADPathophysiologic Hypothesis of AD

Mitochondrial Mitochondrial DysfunctionDysfunction

InflammationInflammation

Other FactorsOther Factors

-Amyloid-Amyloid

GlutamateGlutamate

ExcitotoxicityExcitotoxicity

Cell Damage/Cell Damage/Loss (ACh deficit)Loss (ACh deficit)

DementiaDementia

NeurofibrillaryNeurofibrillaryTanglesTangles

Serotonin LossSerotonin Loss

NorepinephrineNorepinephrine LossLoss

Lipid MetabolismLipid Metabolism

HormonalHormonalChangesChanges

Other Other FactorsFactors

Cholinergic Hypothesis of ADCholinergic Hypothesis of AD

► Memory disturbance caused by loss of Memory disturbance caused by loss of

cholinergic neuronal functioningcholinergic neuronal functioning

► Muscarinic antagonists (scopolomine) Muscarinic antagonists (scopolomine)

produce memory disturbance in normalsproduce memory disturbance in normals

► Procholinergic agents reverse Procholinergic agents reverse

scopolomine and enhance memory in ADscopolomine and enhance memory in AD

Examples of Drugs with Examples of Drugs with Anticholinergic EffectsAnticholinergic Effects

► AntispasmodicsAntispasmodics

► Tricyclic antidepressantsTricyclic antidepressants

► AntihistaminesAntihistamines

► Low-potency conventional antipsychoticsLow-potency conventional antipsychotics

► Hyoscyamine (Cystospaz, Urised)Hyoscyamine (Cystospaz, Urised)

► Belladonna alkaloidsBelladonna alkaloids

► WarfarinWarfarin

► Furosemide, Nifedipine, Triamterene, Furosemide, Nifedipine, Triamterene, HCTZHCTZ

Lu & Tune, L.I. Am J Geriatr Psychiatry 11: 458-461: 2003.

Medications Reported to Cause Medications Reported to Cause Psychotic SymptomsPsychotic Symptoms

► Levodopa/carbidopa (Sinemet)Levodopa/carbidopa (Sinemet)

► Cimetidine (Tagamet)Cimetidine (Tagamet)

► Anti-inflammatory agentsAnti-inflammatory agents

► Antiparkinson agentsAntiparkinson agents

► AntihistaminesAntihistamines

► Tricyclic antidepressantsTricyclic antidepressants

► AnticonvulsantsAnticonvulsants

► AntiarrhythmicsAntiarrhythmics

Benadryl Use in the Inpatient ElderlyBenadryl Use in the Inpatient Elderly

► Prospective study of 426 hospitalized patients age Prospective study of 426 hospitalized patients age 70 and over70 and over

► 114 received Benadryl during hospital stay114 received Benadryl during hospital stay

► 68% for sleep, 21% for allergic reaction, 3% for 68% for sleep, 21% for allergic reaction, 3% for puritispuritis

► Cognitive decline observed in 42% of Benadryl Cognitive decline observed in 42% of Benadryl treated patients and 24% on non-Benadryl treated treated patients and 24% on non-Benadryl treated patientspatients

► Observed declines included delirium, disorganized Observed declines included delirium, disorganized speech, inattention, abnormal psychomotor activity speech, inattention, abnormal psychomotor activity and altered sleep-wake cyclesand altered sleep-wake cycles

Archives of Internal Medicine, 2001; 161:2091-2097

Normal Cholinergic FunctionNormal Cholinergic Function

AChE

AcetylCoA

CholineAChACh

Presynaptic neuron

Synaptic cleft

Postsynapticneuron Acetate

CholineCholine+

+

ACh

AChE

ChAT

MR NR

MR NR

Glial cell

BuChE

BuChE

ACh

ACh = acetylcholine; AChE = acetylcholinesterase;BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor.Adapted from Adem, 1992.

Flynn et al, 1995; Perry et al,1978; Rodriguez-Puertas et al, 1997; Whitehouse et al, 1982.

Major Cholinergic Changes in ADMajor Cholinergic Changes in AD

► Depletion of ACh: especially in moderate to Depletion of ACh: especially in moderate to severe disease stagessevere disease stages

► Decline in choline acetyltransferase (ChAT) Decline in choline acetyltransferase (ChAT) activityactivity

► Loss of cholinergic neuronsLoss of cholinergic neurons Loss of muscarinic (M2) receptorsLoss of muscarinic (M2) receptors Loss of nicotinic receptors (nAChR)Loss of nicotinic receptors (nAChR)

► AChEAChE

► BuChEBuChE

Dementia Symptom Continuum Dementia Symptom Continuum

MildMild Moderate Moderate Severe Severe

0 0.5 1 1.5 2 2.5 3 65.554.543.5 98.587.576.5Years from DiagnosisYears from Diagnosis

Min

imu

m

Min

imu

m

Maxim

um

M

aximu

m

Adapted from Mintzer J et al., 2002 AAGP Annual Meeting 2002Adapted from Doraiswarny PM et al. Neurology, 1997:48 1511-1517.

Cognitive Ability

Functional Ability

Behavioral Problems

Caregiver Time

► ImprovedImproved

► Unchanged (symptoms Unchanged (symptoms are no better or worse)are no better or worse)

► Slightly worse, but better Slightly worse, but better than expected with no than expected with no treatmenttreatment

► With no treatment, the With no treatment, the patient would be expected patient would be expected to decline more rapidlyto decline more rapidly

Goals of Alzheimer’s Disease TherapyGoals of Alzheimer’s Disease Therapy

Therapy may be working if the patient isTherapy may be working if the patient is

Mea

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ge

Mea

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han

ge

fro

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ine

fro

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ine

Exelon®6–12Exelon®6–12mg/daymg/dayPlaceboPlacebo

Pooled studies (OC analysis); *p<0.05; **p<0.02; ***p=0.003Potkin SG, et al. The World Alzheimer Congress 2000, July 9-13, 2000. Washington DC.‡ PDS = Progressive Deterioration Scale; GDS = Global Deterioration Scale

n=158n=158 n=180n=180 n=189n=189 n=193n=193 n=142n=142 n=149n=1491

0

–1

– 2

– 3

– 4

– 5

– 6

– 7

– 8 Mild Moderate SevereMild Moderate Severe

GDS GDS 33 GDS = 4GDS = 4 GDS GDS 55

***

***

Effect of Rivastigmine on ADL by Disease Effect of Rivastigmine on ADL by Disease Severity: PDSSeverity: PDS‡‡ Mean Change at Week 26 Mean Change at Week 26

Grossberg GT, et al. The Gerontological Society of America 52nd Annual Scientific Meeting, November 19-23, 1999. San Francisco, California.

Impact of Disease Severity on Response Impact of Disease Severity on Response of ADL to Rivastigmine Treatmentof ADL to Rivastigmine Treatment

Mild ADMild AD Moderate ADModerate AD Severe ADSevere AD ItemItem (GDS ≤3)(GDS ≤3) (GDS = 4)(GDS = 4) (GDS ≥5)(GDS ≥5)

Ability to Handle MoneyAbility to Handle Money Ability to Tell TimeAbility to Tell Time Time Spent on HobbiesTime Spent on Hobbies Participation in Family FinancesParticipation in Family Finances Ability to Dress ProperlyAbility to Dress Properly Reduced ForgetfulnessReduced Forgetfulness Time Rearranging ObjectsTime Rearranging Objects Ability to Use PhoneAbility to Use Phone Confusion in Different SettingsConfusion in Different Settings Proper Eating MannersProper Eating Manners

PCP-3

Rivastigmine Long-term Effects On Cognition In Moderately Severe Patients

-4

-2

0

2

4

6

8

0 13 26 39 52

6-12 mg

1-4 mg

Placebo

ADAS-Cog MEAN CHANGEStudy B352 (OC) patients with baseline GDS >5

*P<0.05 rivastigmine vs placebo. †A negative value indicates improvement.

Sohn et al. In: Proceedings of the CPNP. April 2000.

Study WeekStudy Week

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*

* ***

* ***

All Patients All Patients Receive RivastigmineReceive Rivastigmine

Donepezil Use in ModerateDonepezil Use in Moderateto Severe ADto Severe AD

► H. Feldman et al. H. Feldman et al.

► Double blind study of donepezil in moderate Double blind study of donepezil in moderate to severe AD patientsto severe AD patients

► Neurology: Aug 2001:57:613-620Neurology: Aug 2001:57:613-620

► MMSE 5-17 (Average MMSE = 11.7)MMSE 5-17 (Average MMSE = 11.7)

► All patients in community or assisted living All patients in community or assisted living settingsetting

► Average age 73.6Average age 73.6

Lease squares (LS) mean ± SE change from baseline scores for donepezil- and placebo-treated patients through 24 weeks of treatment, as measured using the standardized Mini-Mental State Examination (MMSE) and Severe Impairment Battery (SIB); LOCF = last observation carried forward.

Cognitive OutcomeCognitive Outcome

MMSEMMSE

LS M

ean

Cha

nge

LS M

ean

Cha

nge

Fro

m B

asel

ine

± S

EF

rom

Bas

elin

e ±

SE

Donepezil n=131 127 119 (131)

Placebo n=139 129 124 (139)

2.5

2.0

1.5

1.0

0.5

0.0

-0.5

-1.00 12 24 Week 24

LOCFStudy WeekStudy Week

PP=0.0004=0.0004

PP<0.0019<0.0019

PP<0.0001<0.0001

ClinicalClinicaldeclinedecline

BaselineBaseline

ClinicalClinicalimprovementimprovement

Placebo

Donepezil

Feldman et al. Neurology. 2001;57:613-620.

Behavior: NPI DomainsBehavior: NPI Domains

*P<0.05 vs placebo.

ClinicalClinicalImprovementImprovement

ClinicalClinicalDeclineDecline

BaselineBaseline

LS

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LS

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Item

Sco

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24 (

ITT

LO

CF

)It

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Wee

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(IT

T L

OC

F) -2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

*

*

*DonepezilDonepezil

Placebo Placebo

Delusio

ns

Delusio

ns

Hallucin

ations

Hallucin

ations

Agitatio

n/aggressio

n

Agitatio

n/aggressio

n

Elation

Elation

Disinhib

ition

Disinhib

ition

Irrita

bility

Irrita

bility

Aberrant m

otor b

ehavior

Night-t

ime b

ehavior

Night-t

ime b

ehavior

Appetite/eatin

g

Appetite/eatin

g

Depressio

n

Depressio

n

Anxiety

Anxiety

Apathy

Apathy

Feldman et al. Neurology. 2001;57:613-620.

Severe Impairment Battery (SIB)Severe Impairment Battery (SIB)

Clinicalimprovement

Clinicaldecline

Baseline

241812840 ITT LOCFStudy week

-6

-4

-2

0

2

4

6

LS

Mea

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ge

Fro

m

Bas

elin

e ±

SE

P=0.0078

P=0.0051

P<0.0001

P<0.0009 P<0.0001P=0.0001

Donepezil

Placebo

DAD Basic ADL ResultsDAD Basic ADL Results

ClinicalClinicalimprovementimprovement

ClinicalClinicaldeclinedecline

BaselineBaseline

2412

Study weekStudy week ITT LOCFITT LOCF

0-12

-10

-8

-6

-4

-2

0

2

4

LS

Me

an C

ha

ng

e F

rom

Ba

selin

e ±

SE

LS

Me

an C

ha

ng

e F

rom

Ba

selin

e ±

SE

P=0.0025

P=0.0011P<0.0001

Donepezil

Placebo

Donepezil Use in Nursing HomesDonepezil Use in Nursing Homes

► P. Tariot et al. P. Tariot et al.

► Placebo-Controlled, 6-Month, Multicenter, Placebo-Controlled, 6-Month, Multicenter, Nursing Home Study of DonepezilNursing Home Study of Donepezil

► MMSE range 5-26 (average 14.4)MMSE range 5-26 (average 14.4)

► J Am Geriatric Soc. 2001;49:1590-1599J Am Geriatric Soc. 2001;49:1590-1599

14

16

Baseline Week 24

PS

MS

PS

MS

Sco

re

Donepezil (n = 103) Placebo (n = 105)

Effect of Donepezil on ADLs in Nursing Effect of Donepezil on ADLs in Nursing Home Patients With Mild to Severe ADHome Patients With Mild to Severe AD

Decline

Improvement

► No statistically significant differences were seen between No statistically significant differences were seen between patients treated with donepezil and those given placebo at patients treated with donepezil and those given placebo at any time pointany time point

Mean MMSE=14.4 PSMS = Physical Self-Maintenance Scale.

Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599.

(MMSE 5-26)(MMSE 5-26)(MMSE 5-26)(MMSE 5-26)

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I-N

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Del

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Placebo (n = 105)

Donepezil (n = 103)

Improvement

Baseline

Decline

ITT, LOCF analysis. NPI-NH=Neuropsychiatric Inventory Nursing-Home Version.

*P 0.05 for second analysis; no significant difference on overall analysis.

Effects of Donepezil on ADLs in Nursing Home Effects of Donepezil on ADLs in Nursing Home Patients With Mild to Severe AD (MMSE 5-26)Patients With Mild to Severe AD (MMSE 5-26)

-3

-2

-1

0

1

2

3

4

*

Total NPI score at baseline

Total NPI score at Week 24

Change from baseline in total NPI score

20.5

15.6

- 4.9

21.0

18.7

-2.3

Placebo Donepezil

Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599. Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599.

Donepezil in the LTC Setting in MildDonepezil in the LTC Setting in Mildto Severe AD (MMSE 5-26)to Severe AD (MMSE 5-26)

Study Week

*

* *

*

0.8

24201612840

0.6

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

-1

MM

SE

: M

ean

Ch

ang

eF

rom

Bas

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e

Mean MMSE = 14.4.*P<0.05 vs placebo.

.

Donepezil

Placebo

Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599

Rivastigmine Use in the Nursing HomeRivastigmine Use in the Nursing Home

► 173 patients173 patients

► Multicenter nursing home trialMulticenter nursing home trial

► 52 week study52 week study

► Open-labelOpen-label

► Patients begun at 1.5 mg bid with titration to 6 Patients begun at 1.5 mg bid with titration to 6 mg bid or max. tolerated dosemg bid or max. tolerated dose

► Mean NPI-NH score = 15.8Mean NPI-NH score = 15.8

► Mean MMSE 9.3Mean MMSE 9.3

Cummings J et al. Presented at American Psychiatric Association 2000 Annual Meeting. May 13 -18, 2000. Chicago, Ill.

Improve

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

Agitatio

n

Irrita

bility

Anxiety

Aberr. m

otor

behavior

Apathy

Depressio

n

Delusio

n

Disinhib

ition

Hallucin

ations

Euphoria

Night-t

ime b

ehavior

AppetiteM

ean

Ch

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e fr

om

Bas

elin

e

†

††

† **

† †

†

Cummings J et al. Presented at American Psychiatric Association 2000 Annual Meeting. May 13 -18, 2000. Chicago, Ill.

Effects of Rivastigmine on Behavior Effects of Rivastigmine on Behavior Following 52 Weeks of Therapy*Following 52 Weeks of Therapy*

* In patients with symptoms at baseline.† P<0.05 vs baseline.**P<0.001 vs baseline.

* In patients with symptoms at baseline.† P<0.05 vs baseline.**P<0.001 vs baseline.

0

5

10

15

20

25

30

35

Increaseddose

Terminatedmedication

Antipsychotics

(n = 55)

Anxiolytics (n = 33)

Antidepressants

(n = 57)

Reduced dose

Pat

ien

ts t

akin

g p

sych

otr

op

ic d

rug

s d

uri

ng

riv

asti

gm

ine

trea

tmen

t (%

)Nursing Home Patients at Week 52

Anand, Koumaras, Hartman 2000.

Effects of Rivastigmine on Effects of Rivastigmine on Psychotropic Medication UsePsychotropic Medication Use

Antipsychotic Drug Use Among Nursing Antipsychotic Drug Use Among Nursing Home Residents Taking RivastigmineHome Residents Taking Rivastigmine

► MDS data from 452 US nursing facilities from MDS data from 452 US nursing facilities from

2000-20022000-2002

► Pts. With diagnosis of AD given rivastigmine Pts. With diagnosis of AD given rivastigmine

vs those diagnosed but not given a vs those diagnosed but not given a

cholinesterase inhibitorcholinesterase inhibitor

► All patients began study antipsychotic naïve All patients began study antipsychotic naïve

Narayanan et al. Antipsychotic Drug Use Among Nursing Home Residents Taking Rivastigmine. JAMDA 2006; Vol 7 No 1: 12-16.

Comparison of Baseline Comparison of Baseline Characteristics Between Study GroupsCharacteristics Between Study Groups

RivastigmineRivastigmine

(n=845) %(n=845) %

ControlControl

(n=517) %(n=517) % P ValueP Value

SexSex

MaleMale 3434 2727 .007.007

FemaleFemale 6666 7373 <.0001<.0001

AgeAge

<<7474 1212 66

75-8475-84 4848 3232

>>8585 4040 6262

MDS dist.MDS dist.

Verbal dist.Verbal dist. 3131 1919 <.0001<.0001

Sleep issuesSleep issues 1212 55 <.0001<.0001

SadSad 4040 2727 <.0001<.0001

Loss of interestLoss of interest 88 44 .0093.0093

Behav. sxBehav. sx 4545 3636 .0003.0003


Usage Pattern of First Antipsychotic Drug Usage Pattern of First Antipsychotic Drug After Index DateAfter Index Date

Antipsychotic DrugAntipsychotic Drug RivastigmineRivastigmine

(n=845) %(n=845) %

ControlControl

(n=517) %(n=517) %

Any antipsychoticAny antipsychotic 8.68.6 17.017.0

HaloperidolHaloperidol 0.20.2 2.72.7

RisperidoneRisperidone 4.44.4 7.17.1

OlanzapineOlanzapine 3.23.2 5.65.6

QuetiapineQuetiapine 0.80.8 1.51.5

Each antipsychotic drug was initiated approximately twice as frequently in the control group than in the rivastigmine group.


Reasons for ChangingReasons for ChangingChE InhibitorsChE Inhibitors

Tolerability concernsTolerability concerns► Sleep disturbances

► Muscle cramps, weakness

► Acute cholinergically mediated AEs, eg, nausea and vomiting

► Cardiovascular problems

► Extrapyramidal symptoms

Safety concerns► Drug-drug interaction

► Drug-disease interaction

Declining long-term efficacyDeclining long-term efficacy

Rationale for ChangingRationale for ChangingCholinesterase Inhibitor TherapyCholinesterase Inhibitor Therapy

Adapted from Emre. 2002; Inglis. 2001.

Aricept/Exelon Switching StudyAricept/Exelon Switching Study

► 382 outpatients with mild to moderately severe AD 382 outpatients with mild to moderately severe AD who failed to show sustained benefit within who failed to show sustained benefit within previous 12 monthsprevious 12 months

► Median treatment period of 14 months at 10 Median treatment period of 14 months at 10 mg/day, 5 mg/day if poorly toleratedmg/day, 5 mg/day if poorly tolerated

► 80% failed due to lack of efficacy, 11% due to 80% failed due to lack of efficacy, 11% due to tolerability problems, 9% for bothtolerability problems, 9% for both

► Lack of benefit defined by minimum of 6 month Lack of benefit defined by minimum of 6 month decline of MMSE or noticeable loss of functiondecline of MMSE or noticeable loss of function

► Exelon begun at 1.5 mg bid and titrated every four weeks Exelon begun at 1.5 mg bid and titrated every four weeks to max dose of 6 mg bidto max dose of 6 mg bid

► 56.2% responded via stabilization (30.1%) or improving 56.2% responded via stabilization (30.1%) or improving (26.1%) based on Clinicians’ Global Impression of Change(26.1%) based on Clinicians’ Global Impression of Change

► MMSE improved or stabilized in 48.9%MMSE improved or stabilized in 48.9%

► Instrumental Activities of Daily Living Scale improved or Instrumental Activities of Daily Living Scale improved or stabilized in 57%stabilized in 57%

► Serious adverse events were reported in 2.4%Serious adverse events were reported in 2.4%

► 84.6% who were intolerant to donepezil tolerated 84.6% who were intolerant to donepezil tolerated rivastiminerivastimine

► 54.5% who discontinued donepezil for lack of efficacy 54.5% who discontinued donepezil for lack of efficacy responded to rivistigmineresponded to rivistigmine

Aricept/Exelon Switching StudyAricept/Exelon Switching Study

Nausea

Vomiting

Anorexia

Diarrhea

GalantamineDonepezil

12

6

3

11

Adverse Event (%)

Placebo(n=868)

Physicians’ Desk Reference®, 2002; Wilcock GK, et al, 2000.

47

31

17

19

6-12 mg/d(n=1189)

12

4

0

7

Placebo(n=215)

37

20

10

7

24 mg/d(n=220)

6

3

2

5

Placebo(n=315)

19

8

7

15

10 mg/d(n=315)

Rivastigmine

Most Frequent Adverse Events with Most Frequent Adverse Events with 1-Week Titration1-Week Titration

Role of Role of GlutamateGlutamate in AD in AD

► The normal activity of the neurotransmitter The normal activity of the neurotransmitter glutamate plays an integral role in the glutamate plays an integral role in the neural pathways associated with learning neural pathways associated with learning and memoryand memory

► In AD, abnormal glutamatergic may impair In AD, abnormal glutamatergic may impair learning and may contribute to neuronal learning and may contribute to neuronal toxicitytoxicity

Greenamyre JT, et al. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:421-430.

Normal NMDA Receptor TransmissionNormal NMDA Receptor Transmission

MagnesiumMagnesiumGlutamateGlutamate

CalciumCalcium

NormalNormal

RestRest

CaCa2+2+

NMDANMDAReceptorReceptor

NoiseNoise

Cognitive ActivityCognitive Activity

SignalSignalDetectedDetected

NoiseNoiseSignalSignal

Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantineis a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier.

SignalSignal NoiseNoise

Chronic NeurodegenerationChronic NeurodegenerationImpairment of Signal Impairment of Signal DetectionDetection

Signal NotSignal NotDetectedDetected

Pathological Activation Pathological Activation of NMDA Receptorsof NMDA Receptors

NoiseNoise

Rest

Rest

Ab

no

rmal

Ab

no

rmal


CalciumCalcium


Pathological Activation ofNMDA Receptors

Memantine Voltage DependentMemantine Voltage DependentReceptor Blocking Receptor Blocking

MagnesiumMagnesium

PhysiologicalPhysiologicalMagnesium BlockMagnesium Block

MinorMinorDepolarizationDepolarization

SynapticSynapticActivityActivity

RestingRestingStateState

CaCa2+2+ CaCa2+2+

––70 mV70 mV ––50 mV50 mV ––20 mV20 mV

Low to Moderate AffinityLow to Moderate AffinityAntagonist MemantineAntagonist Memantine(Ki = 0.5 (Ki = 0.5 µM)µM)

MemantineMemantine

MMMM

CaCa2+2+ MM

MM

Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier.

Pathological Activation Pathological Activation of NMDA Receptorsof NMDA Receptors

CaCa2+2+

Memantine Blocks Memantine Blocks Pathological Glutamatergic ActivationPathological Glutamatergic Activation

Memantine Allows Memantine Allows Signal DetectionSignal Detection

NoiseNoise NoiseNoise

CaCa2+2+

SignalSignal NoiseNoise

Rest

Rest

Ab

no

rmal

Ab

no

rmal


CalciumCalcium

MemantineMemantineMM

MM

MM

Memantine Selectively Blocks Pathological Activation of NMDA Memantine Selectively Blocks Pathological Activation of NMDA Receptors, but Does Not Impair Normal TransmissionReceptors, but Does Not Impair Normal Transmission


Pivotal TrialsPivotal Trials

Study DesignStudy Design

Monotherapy Monotherapy in Moderate in Moderate to Severe ADto Severe AD11

Combination Combination Memantine and Memantine and Donepezil in Mod. To Donepezil in Mod. To Severe ADSevere AD22

Nursing Home Nursing Home Patients With Severe Patients With Severe DementiaDementia33

Memantine doseMemantine dose 10 mg bid10 mg bid 10 mg bid10 mg bid(plus donepezil)(plus donepezil) 10 mg qd10 mg qd

Duration in weeksDuration in weeks 2828 2424 1212

MMSE rangeMMSE range 3-143-14 5-145-14 <10<10

Principal Efficacy MeasuresPrincipal Efficacy Measures

Global changeGlobal change CIBIC-PlusCIBIC-Plus CIBIC-PlusCIBIC-Plus CGI-CCGI-C

CognitionCognition SIBSIB SIBSIB

FunctionFunction ADCS-ADLADCS-ADL1919 ADCS-ADLADCS-ADL1919 BGP-CareBGP-Care

1. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 2. Tariot P, et al. JAMA. 2004;291:317-324.3. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

Memantine Monotherapy inMemantine Monotherapy inMod-Severe ADMod-Severe AD

► Male or female outpatients aged Male or female outpatients aged 50 years50 years

► Diagnosis of probable AD consistent with DSM- Diagnosis of probable AD consistent with DSM- IV, NINCDS-ADRDA criteria IV, NINCDS-ADRDA criteria

► CT or MRI scan consistent with ADCT or MRI scan consistent with AD

► MMSE scores of 3 to 14 at screeningMMSE scores of 3 to 14 at screening and baseline and baseline

► Global Deterioration Scale (GDS), Global Deterioration Scale (GDS), stages 5 or 6 stages 5 or 6

► Functional Assessment StagingFunctional Assessment Staging (FAST), (FAST), 6a 6a

Reisberg B, et al. N Engl J Med. 2003;348:1333-1341.

Withdrawal design

TimeTime

Per

form

ance

Per

form

ance

RandomizedRandomizedphasephase

PlaceboPlacebophasephase

Placebo

Active

Symptomatic effect

Disease-modifyingeffect

Leber, 1997

Discrimination Between Disease Discrimination Between Disease Modification and Symptomatic BenefitModification and Symptomatic Benefit

Staggered-start design

TimeTime

Per

form

ance

RandomizedRandomizedphasephase

PlaceboPlacebophasephase

Placebo

Active

Disease-modifyingeffect

Symptomatic effect

Patients who switched from placebo to memantine improved relative to their projected rate of decline *p=0.048; ITT-OC analysis

Cognition: SIBCognition: SIBin Mod-Severe Monotherapyin Mod-Severe Monotherapy

Double-Blind Phase Open-Label Extension

-20

-15

-10

-5

0

SIB

Sco

re M

ean

Ch

an

ge

fro

m B

ase

line

Wo

rsenin

gW

orsen

ing

Imp

rovem

ent

Imp

rovem

ent

12 28 40 524

*

Week 0

N=80

N=95 N=95

N=80

N=94

N=74

N=79N=75

N=66

N=70

5

Memantine

Placebo-memantinePlacebo

Reisberg B et al. N Engl J Med. 2003;348: 1333-1341. Ferris S et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; Honolulu, Hawaii; March 1-4, 2003; Forest Laboratories, Inc. (Data on file)

AD

CS

-AD

L (

Mo

dif

ied

)A

DC

S-A

DL

(M

od

ifie

d)

Sc

ore

Me

an

Ch

an

ge

Sc

ore

Me

an

Ch

an

ge

fro

m B

ase

line

fro

m B

ase

line

Open-Label Extension

Patients who switched from placebo to memantine improved relative to their projected rate of decline *p=0.018; ITT-OC analysis

-12

-10

-8

-6

-4

-2

0

2

N=80

N=95N=95

N=80

N=95

N=75

N=80N=75

N=66

N=71

0 12 28 40 52WeekDouble-Blind Phase4

*

Memantine

Placebo-memantinePlacebo

Imp

rovem

ent

Imp

rovem

ent

Wo

rsenin

gW

orsen

ing


Function: ADCS-ADL Effect in Memantine Monotherapy for Mod-Severe AD

Patients who switched from placebo to memantine improved relative to their projected rate of decline; *p<0.001; ITT-OC analysis

Double-Blind Phase Open-Label Extension

3.4

3.6

3.8

4.0

4.2

4.4

4.6

4.8

5.00 12 28 40 52

CIB

IC+

Glo

bal

Sco

re M

ean

C

IBIC

+ G

lob

al S

core

Mea

n

Ch

ang

e fr

om

Bas

elin

eC

han

ge

fro

m B

asel

ine

N=95

N=79

N=95

N=95

N=75

N=80

N=65

N=74N=69

N=79

Memantine

Placebo-memantine

Week

Placebo

*

Imp

rovem

ent

Imp

rovem

ent

Wo

rsenin

gW

orsen

ing


Global Impression: CIBIC+ Effect inMemantine Monotherapy for Mod-Severe AD

Completedn=172 (85%)*

Withdrewn=30(15%)

Completedn=150(75%)

Withdrewn=51(25%)

Memantine+Donepezil n=202

Placebo+Donepezil n=201

Patients Randomized**Patients Randomized**

n=404 n=404

Patients TreatedPatients Treatedn=403n=403

*P=.011; a significantly higher number of patients taking memantine/donepezil completed the study, compared with those taking placebo/donepezil. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc.

Combination Memantine + DonepezilCombination Memantine + Donepezilin Mod. to Severe (MMSE 5-14) AD Studyin Mod. to Severe (MMSE 5-14) AD Study

**Ave. 2 yrs on donepezil**Ave. 2 yrs on donepezil Ave. > 9 mg/dAve. > 9 mg/d

Results: CognitionResults: Cognition——SIBSIB

*OC analysis. †LOCF analysis. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc.

Memantine + Donepezil Combination Memantine + Donepezil Combination Therapy in Moderate to Severe AD Therapy in Moderate to Severe AD

-4

-3

-2

-1

0

1

2

3

4

n =n =

Placebo+Donepezil

Memantine+Donepezil

0 4 8 12 18

Treatment Week

24

Mea

n C

ha

ng

e F

rom

M

ean

Ch

an

ge

Fro

m

Bas

elin

e in

SIB

Sco

reB

asel

ine

in S

IB S

core

End Point

Imp

rovem

ent

Imp

rovem

ent

Deterio

ration

Deterio

ration

*P<.001†P<.001P=.006P<.001P=.030P=.057

198198 192192 190190 185185 181181 171171 198198n =n = 197197 194194 180180 169169 164164 153153 196196

Results: FunctionResults: Function——ADCS-ADLADCS-ADL1919

*OC analysis. †LOCF analysis. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc.

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

0 4 8 12 18 24

Mea

n C

ha

ng

e F

rom

M

ean

Ch

an

ge

Fro

m

Bas

elin

e in

AD

CS

-AD

LB

asel

ine

in A

DC

S-A

DL

1919

Sco

re S

core

End Point

Deterio

ration

Deterio

rationPlacebo+Donepezil

Memantine+Donepezil

Treatment Week

n =n = 198198 198198 190190 185185 181181 172172 198198

n =n = 197197 195195 182182 170170 163163 152152 197197

†P=.028*P=.020P=.027P=.020P=.012P=.028

Imp

rovem

ent

Imp

rovem

ent


Results: Global ChangeResults: Global Change——CIBIC-PlusCIBIC-Plus

*OC analysis. †LOCF analysis. Data on file, Forest Laboratories, Inc.

Deterio

ration

Deterio

ration

Imp

rovem

ent

Imp

rovem

ent

3.6

3.8

4.0

4.2

4.4

4.6

0 4 8 12 18 24

Memantine+Donepezil Placebo+Donepezil

4.8End Point

Mea

n C

IBIC

-Plu

s S

core

Mea

n C

IBIC

-Plu

s S

core

Treatment Week

n =n = 198198 197197 190190 182182 180180 172172 198198

n =n = 196196 194194 181181 170170 164164 152152 196196

††P=P=.027.027*P=*P=.028.028P=.P=.008008P=.P=.123123P=.P=.014014P=.P=.032032


Memantine in Nursing Home Patients Memantine in Nursing Home Patients With Severe DementiaWith Severe Dementia

DesignDesign

► Eastern European, phase 3, multicenter (7), randomized, double-blind, placebo-Eastern European, phase 3, multicenter (7), randomized, double-blind, placebo-controlled study controlled study

PopulationPopulation

► 167 nursing home patients with severe primary dementia 167 nursing home patients with severe primary dementia (AD or VaD), MMSE score <10(AD or VaD), MMSE score <10

TreatmentTreatment

► Memantine 10 mg/d or placeboMemantine 10 mg/d or placebo

► 2-week titration (52-week titration (510 mg)10 mg)

DurationDuration

► 12 weeks12 weeks

Principal Efficacy MeasuresPrincipal Efficacy Measures

► BGP-Care, CGI-C, D-Test BGP-Care, CGI-C, D-Test

Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

Disposition of Patients: AD PopulationDisposition of Patients: AD Population

Memantine n=82

Completedn=78

(95.1%)

Withdrewn=4

(4.9%)

Completedn=80

(95.2%)

Withdrewn=4

(4.8%)

Placebon=84

Patients RandomizedPatients Randomizedn=166n=166

Completedn=41

Completedn=38

Total Total PopulationPopulation

AD AD PopulationPopulation

Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. Data on file, Forest Laboratories, Inc.

Memantine in Moderate toMemantine in Moderate toSevere Dementia StudySevere Dementia Study

Memantine Significantly Reduces Care Dependence in Nursing Home Memantine Significantly Reduces Care Dependence in Nursing Home Patients With DementiaPatients With Dementia

MemantineMemantine Monotherapy in Nursing Monotherapy in NursingHome Patients with Severe Dementia Home Patients with Severe Dementia

†P=.012*P=.010P=.093P=.109P=.983

Imp

rovem

en

tW

orsen

ing

n = n = 8282 8282 8282 8080 7878 8282

n = n = 8484 8484 8484 8282 8080 8484

PlaceboMemantine

Treatment Week

-6

-5

-4

-3

-2

-1

0

1

20 1 4 8 12 End

Point

Mea

n (

SE

M)

Ch

ang

e F

rom

Bas

elin

e

*OC analysis. †LOCF analysis. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

Function: BGP-Care

Results: Global ChangeResults: Global Change—CGI-C—CGI-C

2.42.62.83.03.23.43.63.84.04.24.44.6

0 4 12 End Point

Mea

n (

SE

M)

Ch

ang

e F

rom

Bas

elin

e

n = n = 8282 8282 7878 8282

n = n = 8484 8484 8080 8484

†P<.001*P<.001P=.006

Treatment Week

PlaceboMemantine

Imp

rovem

en

tW

orsen

ing

*OC analysis. †LOCF analysis. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

MemantineMemantine Monotherapy in Nursing Monotherapy in NursingHome Patients with Severe Dementia Home Patients with Severe Dementia

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10a 10b 11 12 13 14 15 16

Memantine

Placebo

Results: FunctionResults: Function——D-TestD-Test

Fre

qu

enc

y o

f Im

pro

vem

ent

(%)

Fre

qu

enc

y o

f Im

pro

vem

ent

(%)

Mo

bility W

hen

Bed

Is Mad

e

Ab

ility of

Stan

din

g U

p

Ab

ility to M

ove

Ab

ility to W

ash

Ab

ility to T

ake

a Sh

ow

er/Bath

Ab

ility to D

ressA

bility to

Eat

Flu

id In

take

To

ilet Use

Co

mm

un

ication

Un

derstan

din

g

Co

mm

un

ication

Exp

ression

Orien

tation

in S

pace

Reco

gn

ition

of P

erson

s

Gro

up

Activities

Ho

bb

ies/

Interest

Un

distu

rbed

Sleep

Beh

avior

** ****

**

**

*

** **

OC analysis, n=151. *Trend to treatment difference. Assessed by Wilcoxon rank sum test on the detailed scale of change (P<.10).**Statistically significant treatment difference (P<.05). Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

**

Memantine Monotherapy in NursingMemantine Monotherapy in NursingHome Patients with Severe DementiaHome Patients with Severe Dementia

Memantine Clinical PharmacokineticsMemantine Clinical Pharmacokinetics

► Bioavailability: Bioavailability: 100%100%

► TTmaxmax: : 3 to 7 hours3 to 7 hours

► Protein binding: Protein binding: 45%45%

► TT½½: : 60 to 80 hours60 to 80 hours

► PharmokineticsPharmokinetics LinearLinear

► Time to [CTime to [CSSSS]: ]: within 21 dayswithin 21 days

► CSF/serum ratio = 0.52CSF/serum ratio = 0.52

► MetabolismMetabolism No CYP450No CYP450► EliminationElimination 57-82% Renal57-82% Renal

Source: Namenda package insert, Forest Pharmaceuticals, Inc.

Memantine Clinical PharmacokineticsMemantine Clinical Pharmacokinetics► Can be administered with or without foodCan be administered with or without food

► Limited metabolismLimited metabolism——eliminated mostly in urine as eliminated mostly in urine as parent drug, metabolites inactiveparent drug, metabolites inactive

► No or minimal effects on CYP450 isoenzymesNo or minimal effects on CYP450 isoenzymes

► No interactions with cholinesterase inhibitorsNo interactions with cholinesterase inhibitors

► Dose reduction in patients with moderate renal Dose reduction in patients with moderate renal impairment should be consideredimpairment should be considered

► Effect of severe renal impairment has not Effect of severe renal impairment has not been evaluated and is not recommendedbeen evaluated and is not recommended

HCTZ/TA = hydrochlorothiazide/triamtereneSource: Namenda package insert, Forest Pharmaceuticals, Inc.

Tolerability Profile From Double-Blind,Tolerability Profile From Double-Blind,Placebo-Controlled Monotherapy TrialsPlacebo-Controlled Monotherapy Trials

Adverse Events Reported in Adverse Events Reported in 5% of Either Treatment Group5% of Either Treatment Group

AgitationAgitation

Accidental injuryAccidental injuryFallFallConstipationConstipation

ConfusionConfusionHeadacheHeadache

Adverse EventAdverse Event

Any adverse eventAny adverse eventDizzinessDizziness

PlaceboPlacebo(n=922)(n=922)n (%)n (%)

624 (67.7)624 (67.7)

98 (10.6)98 (10.6)42 (4.6)42 (4.6)31 (3.4)31 (3.4)28 (3.0)28 (3.0)50 (5.4)50 (5.4)64 (6.9)64 (6.9)

49 (5.3)49 (5.3)

Memantine Memantine (n=940)(n=940)n (%)n (%)

662 (70.4)662 (70.4)

63 (6.7)63 (6.7)58 (6.8)58 (6.8)54 (5.7)54 (5.7)50 (5.3)50 (5.3)48 (5.1)48 (5.1)44 (4.7)44 (4.7)

64 (6.8)64 (6.8)

Data on file, Forest Laboratories, Inc.

No adverse event was reported at an incidence of5% in the memantine group and 2x placebo

9 (4.5)9 (4.5)

10 (5.0)10 (5.0)

15 (7.4)15 (7.4)

15 (7.4)15 (7.4)

16 (7.9)16 (7.9)

11 (5.4)11 (5.4)

12 (5.9)12 (5.9)

4 (2.0)4 (2.0)

10 (5.0)10 (5.0)

10 (5.0)10 (5.0)

13 (6.4)13 (6.4)

14 (6.9)14 (6.9)

19 (9.4)19 (9.4)

Memantine+DonepezilMemantine+Donepezil

% (n=202)% (n=202)

17 (8.5)17 (8.5)

8 (4.0)8 (4.0)

14 (7.0)14 (7.0)

13 (6.5)13 (6.5)

4 (2.0)4 (2.0)

13 (6.5)13 (6.5)

10 (5.0)10 (5.0)

10 (5.0)10 (5.0)

16 (8.0)16 (8.0)

6 (3.0)6 (3.0)

5 (2.5)5 (2.5)

16 (8.0)16 (8.0)

24 (11.9)24 (11.9)

Placebo+DonepezilPlacebo+Donepezil

% (n=201)% (n=201)

DiarrheaDiarrhea

Peripheral edemaPeripheral edema

FallFall

Influenza-like symptomsInfluenza-like symptoms

ConfusionConfusion

Urinary incontinenceUrinary incontinence

Accidental injuryAccidental injury

Fecal incontinenceFecal incontinence

Urinary tract infectionUrinary tract infection

Upper respiratory tract infectionUpper respiratory tract infection

HeadacheHeadache

DizzinessDizziness

AgitationAgitation

Adverse EventAdverse Event

Tolerability Profile of Tolerability Profile of Combination Therapy StudyCombination Therapy Study

Adverse Events Reported in Adverse Events Reported in 5% of Either Treatment Group5% of Either Treatment Group

Adapted from Tariot P, et al. JAMA. 2004;291:317-324.

► Treat comorbid conditions conservativelyTreat comorbid conditions conservatively11

● Consider risk vs. benefit ratioConsider risk vs. benefit ratio● Mortality rate increased in demented patients with comorbid Mortality rate increased in demented patients with comorbid

hospitalizationhospitalization22

► Stress importance of preparing for increasing caregiver Stress importance of preparing for increasing caregiver burdenburden

● financial planningfinancial planning● durable power of attorney for finances and healthcaredurable power of attorney for finances and healthcare● ““expanded” advanced directivesexpanded” advanced directives

● Include thresholds for hospitalization, feeding tube placement, Include thresholds for hospitalization, feeding tube placement, treatment of infections, intubation and resuscitation effortstreatment of infections, intubation and resuscitation efforts

► Be vigilant of overall patient/caregiver needs and Be vigilant of overall patient/caregiver needs and capabilitiescapabilities

1. Tariot PN. J Am Geriatr Soc. 2003 May;51(5 Suppl Dementia):S305-S313.2. Morrison RS, Siu AL.. JAMA. 2000;284(1):47-52.

General Guidelines for Care of Institutionalized General Guidelines for Care of Institutionalized Patients with Moderate to Severe DementiaPatients with Moderate to Severe Dementia

Dementia in the LTC Environment: Dementia in the LTC Environment: Choices in ManagementChoices in Management

► Minimize anticholinergic loadMinimize anticholinergic load

► Be aware of and treat depressionBe aware of and treat depression

► Use psychotropics (antipsychotics, Use psychotropics (antipsychotics, antiepileptics, benzodiazepines etc.) antiepileptics, benzodiazepines etc.) cautiously and only to treat definable cautiously and only to treat definable symptomssymptoms

► Obtain history of prior AChI use and continue Obtain history of prior AChI use and continue treatment unless no further treatment treatment unless no further treatment interventions desiredinterventions desired

Dementia in the LTC Environment: Dementia in the LTC Environment: Choices in Management Choices in Management (cont)(cont)

► Consider switching AChI in patients who are Consider switching AChI in patients who are declining on current therapydeclining on current therapy

► For patients with mod. to severe dementia on no For patients with mod. to severe dementia on no therapy consider beginning memantine therapy consider beginning memantine monotherapymonotherapy

► For patients already receiving AChI’s consider For patients already receiving AChI’s consider adding memantine if patient has mod to severe adding memantine if patient has mod to severe dementia and has active caregiver burden issuesdementia and has active caregiver burden issues

► Consider discontinuing AChI’s and memantine only Consider discontinuing AChI’s and memantine only

with thorough documentation of family goalswith thorough documentation of family goals

Dementia in the LTC Environment: Choices in Management.

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