Clinical Update: Full Spectrum Treatment of Alzheimers Disease.

Clinical Update: Full Clinical Update: Full Spectrum Treatment of Spectrum Treatment of

Alzheimer’s DiseaseAlzheimer’s Disease

Alzheimer’s DiseaseAlzheimer’s DiseaseEconomic ConsequencesEconomic Consequences

► Third most expensive disease in the U.S.Third most expensive disease in the U.S.

► Costs over Costs over $100 billion$100 billion//yearyear

► Further Further $$3333 billion billion in in lost productivitylost productivity and other employer costsand other employer costs

► 3/4 of patients admitted to residential care 3/4 of patients admitted to residential care within 5 years of diagnosiswithin 5 years of diagnosis

Evans DA, Scherr PA, Smith LA, et al. Aging (Milano). 1990(Sept);2(3):298-302; Ernst RL, Hay JW. Am J Public Health. 1994(Aug);84(8):1261-1264; Alzheimer’s Association, 2002

Growth of the ProblemGrowth of the Problem

Alzheimer’s Prevalencein the U.S. by Age (1997)

Projected Dementia Patients in the U.S. (in Millions)

70

50

30

10

45 55 65 75 85 90

Pe

rce

nta

ge

2000 2010 2020 2030 20402050

4.05.8 6.8

8.7

11.8

14.3

Age (Years) Year

Guttman R, Altman RD, Nielsen NH. Arch Fam Med. 1999(July-Aug);8(4):347-353

0

Suggested Diagnostic Suggested Diagnostic Workup for DementiaWorkup for Dementia

► Diagnostic interview: Both the patient and a reliable Diagnostic interview: Both the patient and a reliable informantinformant

► Office-based clinical assessmentOffice-based clinical assessment Comprehensive physical examinationComprehensive physical examination Neurologic and mental status evaluationNeurologic and mental status evaluation Brief quantified cognitive function evaluation Brief quantified cognitive function evaluation

(MMSE)(MMSE)

► Laboratory evaluation and imaging: CBC, chemistries, liver Laboratory evaluation and imaging: CBC, chemistries, liver function, thyroid, vitamin Bfunction, thyroid, vitamin B12;12; CT head scan or non contrast CT head scan or non contrast MRIMRI

► Neuropsychologic testing or functional scan (PET) if Neuropsychologic testing or functional scan (PET) if diagnosis is uncleardiagnosis is unclear

Alva, Clin Geriatr Med 19 (2003)763-776

The Stages of Alzheimer’s DiseaseThe Stages of Alzheimer’s Disease

Mild Moderate Severe

Memory LossLanguage ProblemsMood and Personality ChangesDiminished Judgment

Behavioral, Personality ChangesUnable to Learn or Recall New InformationLong-Term Memory AffectedWandering, Agitation, Aggression, ConfusionRequire Assistance with ADLs

Unstable GaitIncontinenceMotor DisturbancesBedriddenDysphagiaMutePoor/No ADLsVacant

LTC Placement Common

Stage

Symptoms

ADL = activities of daily living ADL = activities of daily living LTC = long-term careLTC = long-term care

AP = amyloid plaques; NFT = neurofibrillary tangles

Courtesy of George T. Grossberg M.D.; St. Louis University

Neuropathological ChangesNeuropathological ChangesCharacteristic of ADCharacteristic of AD

Normal

AP

AD

NFT

AD

AS

-Co

g M

ean

C

ha

ng

e f

rom

Ba

sel

ine

Decline in ADAS-Cog scorebased on the natural history ofuntreated patients with moderate AD*

-6

0

6

12

180 6 12 14 26 38 50 62 74 85 98

Improvement

Decline

Model-Based Analysis: ADAS-Cog Score Model-Based Analysis: ADAS-Cog Score Mean Change from BaselineMean Change from Baseline

N=133

Rogers and Friedhoff, 1998; *Stern et al, 1994Rogers and Friedhoff, 1998; *Stern et al, 1994

Cognitive Decline in AD Correlates Cognitive Decline in AD Correlates with Rate of Cerebral Atrophywith Rate of Cerebral Atrophy

y = 0.48x + 0.34r = 0.8

Fall in MMSE Score

Lo

ss o

f B

rain

Vo

lum

e (

%)

Fox, DRG98

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18

UCI Brain Imaging CenterUCI Brain Imaging Center

Alzheimer’s Disease Normal Control

DecreasedTemporoparietal

OccipitalLobe

Cerebellum 0.00 19.36

FrontalLobe

mg/100g/min

Management of the AD PatientManagement of the AD Patient

► Maintain quality of lifeMaintain quality of life

► Maximize functionMaximize function

► Stabilize cognitionStabilize cognition

► Treat mood and behavior problemsTreat mood and behavior problems

► Ease caregiver burdenEase caregiver burden

Source: Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001.

Treatment GoalsTreatment Goals

Treatment Consideration:Treatment Consideration:When to Begin?When to Begin?

► Current guidelines (AAN) recommend that all Current guidelines (AAN) recommend that all patients with AD be treated at time of diagnosispatients with AD be treated at time of diagnosis

Well established rationale for ChEI treatment in patients Well established rationale for ChEI treatment in patients diagnosed with mild or moderate AD diagnosed with mild or moderate AD

Well established rationale for treating patients diagnosed Well established rationale for treating patients diagnosed with moderate to severe AD with memantinewith moderate to severe AD with memantine

Patients with severe AD have been shown to benefit from Patients with severe AD have been shown to benefit from treatmenttreatment1-31-3

► Establish realistic expectations of treatmentEstablish realistic expectations of treatment

Sources: 1. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. 2. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 3. Tariot P, et al. J Am Geriatr Soc. 2003;51(S4):S225-S226.

Neurotransmitter Basis for Current Neurotransmitter Basis for Current Dementia Drug Treatment InterventionsDementia Drug Treatment Interventions

► Acetylcholine and glutamate are 2 neurotransmitter Acetylcholine and glutamate are 2 neurotransmitter systems known to be important in learning and systems known to be important in learning and memorymemory

AcetylcholineAcetylcholine

Cholinergic neurons are lost in ADCholinergic neurons are lost in AD

Theory:Theory: increase available acetylcholine to improve or increase available acetylcholine to improve or maintain cognitive functionmaintain cognitive function

GlutamateGlutamate

Excessive or erratic glutamate stimulation impairs Excessive or erratic glutamate stimulation impairs learning and can cause neuronal toxicity learning and can cause neuronal toxicity

Theory:Theory: normalize glutamatergic neurotransmission to normalize glutamatergic neurotransmission to maintain or improve cognition and prevent maintain or improve cognition and prevent neurotoxicityneurotoxicity

ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor

Adapted from: Adem, 1992

Normal Cholinergic FunctionNormal Cholinergic Function

PostsynapticNeuron

AChE

AcetylCoA

CholineACh

Presynaptic Neuron

SynapticCleft

Cholinergic Receptors

Acetate

CholineCholine+

+

Astrocyte

AChACh

AChE

BuChE

BuChE

ChAT

Noncholinergic Action

MR NR MR NR

NR

MR

Pharmacotherapy for Mild to ModeratePharmacotherapy for Mild to ModerateAlzheimer’s DiseaseAlzheimer’s Disease

FDA Approved:FDA Approved:► Cholinesterase inhibitors (ChEIs)Cholinesterase inhibitors (ChEIs)

TacrineTacrine DonepezilDonepezil Galantamine Galantamine Rivastigmine Rivastigmine Monotherapy as standard treatmentMonotherapy as standard treatment

New Developments in Mild AD:New Developments in Mild AD:► NMDA-receptor antagonist (memantine)NMDA-receptor antagonist (memantine)

– MonotherapyMonotherapy Combination TherapyCombination Therapy

Important Considerations in Important Considerations in Alzheimer’s Disease Treatment*Alzheimer’s Disease Treatment*

Galantamine

Plasma protein binding

Rivastigmine

40%

Donepezil

96% 18%

NoneKnown†

No

ketoconazole, quinidine, and

other drugs metabolized by CYP2D6/3A4

None stated

amitriptyline, cimetidine, erythromycin, fluoxetine,

fluvoxamine, ketoconazole, paroxetine, quinidine, and other drugs

metabolized by CYP2D6/3A4

Yes

Listed drug-druginteractions

Dosage adjustment required for renal/hepatic impairment

Memantine

45%

carbonic anhydrase

inhibitors, sodium bicarbonate

Yes

Metabolism

Elimination pathway

Not Hepatic CYP450 CYP450 Partially Hepatic

Kidney(inactive

metabolite)

Liver50% Kidney50% Liver Kidney

*Data as listed in US prescribing information for rivastigmine, donepezil, galantamine, and memantine.†Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19 are expected.

ChEI Monotherapy in MildChEI Monotherapy in Mildto Moderate AD: Efficacyto Moderate AD: Efficacy

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

.2

.1

0

–.1

–.2

–.3

–.4

–.512 18 26

†

**

*

Week

PlaceboRivastigmine 1- 4 mgRivastigmine 6-12 mg

Global: CIBIC-PlusGlobal: CIBIC-Plus22

RivastigmineRivastigmine

Imp

rov

em

en

tIm

pro

ve

me

nt

De

clin

eD

ec

line

Time (Months)

–4

–2

0

–5

–3

–1

1

1 2 3 4 5

Galantamine 8 mg/dayGalantamine 16 mg/dayGalantamine 24 mg/dayPlacebo

†

†

Function: ADCS-ADLFunction: ADCS-ADL33

GalantamineGalantamine

*P<.05; †P<.01; ‡P≤.001.CIBIC-Plus = Clinician's Interview-Based Impression of Change with caregiver input; ADCS-ADL = Alzheimer's Disease Cooperative Study – Activities of Daily Living inventory.

Sources: 1. Winblad B, et al. Neurology. 2001;57:489-495. (Data represent change in least squares [LS] mean) 2. Corey-Bloom J, et al. Int J Geriatr Psychopharmacol. 1998;1550:55-65 3. Tariot PN, et al. Neurology. 2000;54:2269-2276

Cognition: MMSECognition: MMSE11

DonepezilDonepezil

–2.5

–2.0

–1.5

–1.0

–0.5

0

0.5

1.0

Donepezil

Placebo

Week52362412

‡

0 LOCF

‡

*‡

(LS

)(L

S)

ChEI Drug-Drug and ChEI Drug-Drug and Drug-Disease Interactions Drug-Disease Interactions

► PharmacodynamicPharmacodynamic Digoxin, Digoxin, ββ blockers — blockers — ChEIs may exert vagotonic ChEIs may exert vagotonic

effects on sinoatrial and atrioventricular nodeseffects on sinoatrial and atrioventricular nodes ChEIs may exaggerate succinylcholine-type muscle ChEIs may exaggerate succinylcholine-type muscle

relaxation during anesthesiarelaxation during anesthesia Concurrent anticholinergic or cholinergic Concurrent anticholinergic or cholinergic

pharmacotherapypharmacotherapy

► PharmacokineticPharmacokinetic None None — — rivastigminerivastigmine Minimal Minimal — — donepezildonepezil Moderate Moderate — — galantamine + CYP450 inhibitors (2D6, galantamine + CYP450 inhibitors (2D6,

3A4)3A4)

► Renal impairmentRenal impairment Clearance of galantamine decreased in renal Clearance of galantamine decreased in renal

insufficiencyinsufficiency

Source: Bentué-Ferrer D, et al. CNS Drugs. 2003;17:947-963.

Treatment Consideration: When to Treatment Consideration: When to Increase Dose or Switch Agents?Increase Dose or Switch Agents?

► Dose escalation may need to be slower than Dose escalation may need to be slower than suggested in suggested in Physicians’ Desk ReferencePhysicians’ Desk Reference

► Side effects to treatment are justifiableSide effects to treatment are justifiablereasons to switchreasons to switch

► Typically, switching ChEIs can be doneTypically, switching ChEIs can be donewithout washout period and with shorter titration without washout period and with shorter titration periodsperiods

► Evidence shows that memantine, a non-Evidence shows that memantine, a non-cholinergic agent, is effective as monotherapy cholinergic agent, is effective as monotherapy and in combination therapy with a ChEIand in combination therapy with a ChEI1,21,2

Sources: 1. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 2. Tariot P, et al. JAMA. 2004;291:317-324.

Treatment Consideration: Treatment Consideration: When to Stop?When to Stop?

► May not tolerate cholinergic side effects May not tolerate cholinergic side effects despite slow and careful escalationdespite slow and careful escalation

► When medication is prescribed, give it When medication is prescribed, give it time to work; gauge different domainstime to work; gauge different domains

► Establishing benefit in an individual patient Establishing benefit in an individual patient may be influenced by their stagingmay be influenced by their staging

► Studies suggest that most subjects benefit and Studies suggest that most subjects benefit and that long-term treatment is usefulthat long-term treatment is useful

► May see some deterioration when medication May see some deterioration when medication is stopped is stopped

MemantineMemantine in Mild to Moderate AD: in Mild to Moderate AD: Clinical TrialsClinical Trials

Monotherapy Trials:Monotherapy Trials:

US 24-week trialUS 24-week trial Statistically significant advantage of Statistically significant advantage of

memantine over placebo at end point on memantine over placebo at end point on cognitive and global measurescognitive and global measures

European 24-week trialEuropean 24-week trial Numerical advantage at end point for Numerical advantage at end point for

memantine (not statistically significant) over memantine (not statistically significant) over placebo for cognitive and global measuresplacebo for cognitive and global measures

Combination Therapy TrialsCombination Therapy Trials: :

US 24-week trial of patients on stable ChEI therapyUS 24-week trial of patients on stable ChEI therapyNumerical advantage at end point of Numerical advantage at end point of

memantine over placebo for cognitive, memantine over placebo for cognitive, functional, and global measures (not functional, and global measures (not statistically significant)statistically significant)

Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France. September 4-7, 2004; Paris, France.

Declin

eD

ecline

Memantine Monotherapy in Mild to Memantine Monotherapy in Mild to Moderate AD: US 24-Week Trial ResultsModerate AD: US 24-Week Trial Results

Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France. September 4-7, 2004; Paris, France.

Cognition: ADAS-CogCognition: ADAS-Cog

Imp

rovem

en

tIm

pro

veme

nt

LS

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(S

E)

LS

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(S

E)

*.003*.003 *.009*.009*.003*.003

*.002*.002

44 88 1212 1818 2424

-3-3

-2-2

-1-1

00

11

22

33

Treatment WeekTreatment Week

MemantineMemantinePlaceboPlacebo

195195 195195 195195 195195 191191n = 195n = 195198198 198198 198198 197197 195195n = 198n = 198

00

Imp

rovem

en

tIm

pro

veme

nt

Declin

eD

ecline

Treatment WeekTreatment Week

Me

an

Sc

ore

(S

E)

Me

an

Sc

ore

(S

E)

Global Change: Global Change: CIBIC-PlusCIBIC-Plus

44 88 1212 1818 2424

*.021*.021 *.024*.024*.015*.015

*.004*.004

3.53.5

44

4.54.5

55

MemantineMemantine

PlaceboPlacebo

196196 196196 196196 196196n = 194n = 194197197 197197 197197 197197n = 197n = 197

Intention-to-treat (ITT) population; last observation carried forward (LOCF); *P value for LS mean difference (memantine vs placebo)

Memantine/Rivastigmine CombinationMemantine/Rivastigmine CombinationTherapy in Mild to Moderate AD*Therapy in Mild to Moderate AD*

DesignDesign

► Multicenter (20), open-label, single-arm, Multicenter (20), open-label, single-arm,

historically controlled historically controlled

PopulationPopulation

► 95 outpatients with mild to moderate AD 95 outpatients with mild to moderate AD

(MMSE, 10-29) on stable rivastigmine (MMSE, 10-29) on stable rivastigmine

TreatmentTreatment

► Memantine 20 mg/d (10 mg bid) 4-week Memantine 20 mg/d (10 mg bid) 4-week

titrationtitration

(5 10 15 20 mg)(5 10 15 20 mg)

Duration:Duration: 12 weeks12 weeks

Assessments - Assessments - Primary: Primary: ADAS-CogADAS-Cog

*Memantine is not indicated for the treatment of mild AD. ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive Subscale.

Source: Riepe MW, et al. 17th U.S. Psychiatric and Mental Health Congress Research Abstract Presentation Book; Volume 1, #74, page 20; November 17-20, 2004; San Diego, Calif.

00

55

1010

1515

2020

2525

3030

-12-12 -8-8 -4-4 00 +4+4 +8+8

Change in ADAS-Cog Memory ScoreChange in ADAS-Cog Memory Score

Nu

mb

er o

f P

atie

nts

Nu

mb

er o

f P

atie

nts

Memantine Adverse EventsMemantine Adverse Events

► No clinically relevant differences between No clinically relevant differences between memantine- and placebo-treated groups were memantine- and placebo-treated groups were observed in: observed in:

Adverse event profileAdverse event profile Vital signs valuesVital signs values Laboratory parametersLaboratory parameters ECG valuesECG values

► Memantine at a dosage of 20 mg/d Memantine at a dosage of 20 mg/d Exhibits a safety profile similar to that of placeboExhibits a safety profile similar to that of placebo Is well tolerated and safe for the treatment of Is well tolerated and safe for the treatment of

patients with ADpatients with AD

Memantine: Drug-Drug and Memantine: Drug-Drug and Drug-Disease InteractionsDrug-Disease Interactions

► PharmacokineticPharmacokinetic Clearance via filtration Clearance via filtration andand secretion secretion——decreased renal decreased renal

clearance at alkaline urine pHclearance at alkaline urine pHPotential for decreased renal clearance drugs Potential for decreased renal clearance drugs

that undergo tubular secretion, eg, amantadine, that undergo tubular secretion, eg, amantadine, cimetidine, ranitidine, etc.cimetidine, ranitidine, etc.

Reduced bioavailability of hydrochlorothiazide (Reduced bioavailability of hydrochlorothiazide (↓↓20%) 20%)

► PharmacodynamicPharmacodynamic Avoid use with other NMDA antagonists: amantadine, Avoid use with other NMDA antagonists: amantadine,

ketamine, dextromethorphanketamine, dextromethorphan No interactions with ChEIs No interactions with ChEIs

► Renal ImpairmentRenal Impairment Consider decreased dose in moderate renal impairment; Consider decreased dose in moderate renal impairment;

memantine is not recommended in severe renal impairment memantine is not recommended in severe renal impairment

Sources: Guay D. The Consultant Pharmacist. 2003;18:625-634; Hartmann S, Mobius HJ. Int Clin Psychopharmacol. 2003;18:81-85; Namenda (memantine) package insert. Forest Laboratories, Inc.

Behavioral Symptoms in ADBehavioral Symptoms in AD

► CommonCommon

► Occur early in the diseaseOccur early in the disease

► May be part of the disease prodromeMay be part of the disease prodrome

► Symptoms emerge as disease progressesSymptoms emerge as disease progresses

► Once present, symptoms tend to persistOnce present, symptoms tend to persist

► Multiple types of symptoms that may occur Multiple types of symptoms that may occur simultaneously (eg, hallucinations, delusions, simultaneously (eg, hallucinations, delusions, depression, euphoria, agitation, aggression, depression, euphoria, agitation, aggression, abnormal vocalization, wandering, overactivity, abnormal vocalization, wandering, overactivity, sexual disinhibition, sleep disturbances,sexual disinhibition, sleep disturbances,and apathy)and apathy)

Interventions for Dementia-Related Interventions for Dementia-Related Behavioral SymptomsBehavioral Symptoms

NonpharmacologicNonpharmacologic

► Remove triggerRemove trigger

► Caregiver/familyCaregiver/familyeducationeducation

► Caregiver supportCaregiver support

► Increase staffing ratioIncrease staffing ratio

► Activity programsActivity programs

► Adult day careAdult day care

PharmacologicPharmacologic

► AntidepressantsAntidepressants

► Mood stabilizersMood stabilizers

► Antipsychotics*Antipsychotics*

► CholinesteraseCholinesteraseinhibitors inhibitors

► NMDA-receptor antagonist NMDA-receptor antagonist (memantine)(memantine)

*Public health advisory from FDA (April 2005): Clinical trials of antipsychotic drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate compared to placebo. Specific causes of death were primarily due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia)

Effects of Galantamine on BehaviorsEffects of Galantamine on Behaviors

*p<0.05 vs. placebo; N=978

Tariot PN, Solomon PR, Morris JC, et al. Neurology. 2000(June 27); 54(12):2269-2276

Ch

an

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in N

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core

Me

an (

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om

Bas

elin

eImprovement

Deterioration

Baseline 1 2 3 4 5

-2

-1

0

1

2

3

4

5

Time (Weeks)

*

PlaceboGalantamine 8 mg/dayGalantamine 16 mg/dayGalantamine 24 mg/day

Pharmacotherapy for ModeratePharmacotherapy for Moderateto Severe Alzheimer’s Disease to Severe Alzheimer’s Disease

FDA Approved:FDA Approved:

► Memantine Memantine MonotherapyMonotherapy Combination TherapyCombination Therapy

New Developments in Severe AD:New Developments in Severe AD:

► ChEIsChEIs MonotherapyMonotherapy Combination TherapyCombination Therapy

Increased Probability of Increased Probability of Institutionalization by Disease SeverityInstitutionalization by Disease Severity

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

Pro

bab

ility

of

Inst

itu

tio

na

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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

Effects of Donepezil on Behaviors in Effects of Donepezil on Behaviors in Nursing Home Patients at Week 24Nursing Home Patients at Week 24

ImprovementPlacebo (N=105)

Donepezil (N=103)

Mea

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*

Baseline

Decline

-3

-2

-1

0

1

2

3

4

*p<0.05 vs. placebo, secondary analysis ITT, LOCF analysis

Tariot PN, Cummings JL, Katz IR, et al. J Am Geriatr Soc. 2001;49:1590-1599

* *

* *** *

*

Behavioral Improvement with Rivastigmine: Behavioral Improvement with Rivastigmine: NPI-Mean Change from BaselineNPI-Mean Change from Baseline

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0

Agitation

Irritability

Anxiety

Aberr. Motor B

ehavior

Apathy

Depression

Delusions

Disinhibition

Hallucinations

Euphoria

Nighttime Behavior

Appetite

Mea

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*p<0.05 vs. baseline; **p<0.001 vs. baseline; Baseline MMSE = 9.2; OC analysis; N=98; Anand R, Kourmaras B, Hartman RD. Neurobiol Aging. 2000;21:S220; Cummings J. Presented at the American

Academy of Neurology. San Diego, Calif; April 26- May 6, 2000 (Poster presentation)

Imp

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26-Week U.S. Nursing Home Study

Memantine/Donepezil Combination Therapy in Memantine/Donepezil Combination Therapy in Moderate to Severe AD: EfficacyModerate to Severe AD: Efficacy

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

n =n =

Placebo + Donepezil

Memantine + Donepezil

Treatment Week

Me

an

Ch

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Fro

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Imp

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P<.001 P<.001

P=.006

P<.001

P=.03

P=.06

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

Design• US phase 3, multicenter

(37), randomized, double-blind, placebo-controlled study

Population• 404 outpatients with

moderate to severe AD on stable donepezil

• MMSE range, 5-14

Treatment• Memantine 20 mg/d

(10 mg bid) 4-week titration (5101520 mg)

Duration• 24 weeks

Cognition—SIBCognition—SIB

-4

-3

-2

-1

0

1

2

3

4

0 4 8 12 18 24 End Point(LOCF)

LOCF analysis; *P=.045; **P=.005; ***P=.001

Source: Cummings J, et al. Presented at: 56th Annual Meeting of the American Academy of Neurology; April 24–May 1, 2004; San Francisco, Calif.

Memantine in Patients Receiving Memantine in Patients Receiving Ongoing Donepezil: BehaviorOngoing Donepezil: Behavior

Del

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0.20.2

00

-0.2-0.2

-0.4-0.4 **********

**MemantinePlaceboNPI Single-Item DomainsNPI Single-Item Domains

Tolerability of Memantine/Donepezil Tolerability of Memantine/Donepezil Combination TherapyCombination Therapy

*Adverse events reported in 5% of either treatment group. Source: Tariot P, et al. JAMA. 2004;291:317-324.

Placebo + DonepezilPlacebo + Donepezil(n=201) n (%)(n=201) n (%)

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)

6 (3.0)6 (3.0)

16 (8.0)16 (8.0)

10 (5.0)10 (5.0)

10 (5.0)10 (5.0)

13 (6.5)13 (6.5)

5 (2.5)5 (2.5)

16 (8.0)16 (8.0)

24 (11.9)24 (11.9)

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

Memantine + Memantine + DonepezilDonepezil

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

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)

10 (5.0)10 (5.0)

4 (2.0)4 (2.0)

12 (5.9)12 (5.9)

10 (5.0)10 (5.0)

13 (6.4)13 (6.4)

14 (6.9)14 (6.9)

19 (9.4)19 (9.4)AgitationAgitation

Adverse Event*Adverse Event*

Evaluating ResponseEvaluating Response► Assess:Assess:

At baselineAt baseline

After reaching maximal tolerated dose After reaching maximal tolerated dose

Every 6 – 12 monthsEvery 6 – 12 months

If change in statusIf change in status

► Family/Patient/Nursing interviewFamily/Patient/Nursing interview

► Documentation in medical recordDocumentation in medical record Cooperation in activities, tolerance of groupsCooperation in activities, tolerance of groups

ADL abilities & tolerance with assistanceADL abilities & tolerance with assistance

Eating, toileting, dressing, showering, etc. Eating, toileting, dressing, showering, etc.

Routine and psychotropic medication usageRoutine and psychotropic medication usage

SummarySummary

► AD is an expensive illness in human and AD is an expensive illness in human and economic terms for patients, their caregivers, and economic terms for patients, their caregivers, and society.society.

► Diagnosis is often not made, especially in earlyDiagnosis is often not made, especially in earlyand mild AD; clinical nihilism can interfere with and mild AD; clinical nihilism can interfere with initiating or sustaining treatment. The long term initiating or sustaining treatment. The long term setting brings additional clinical challenges.setting brings additional clinical challenges.

► Cholinesterase inhibitors and NMDA receptor Cholinesterase inhibitors and NMDA receptor antagonists attenuate symptomatic decline and antagonists attenuate symptomatic decline and may modify disease progression.may modify disease progression.

► Early treatment pays off; delaying treatment has Early treatment pays off; delaying treatment has long-term consequences.long-term consequences.

► ChEls (mild to moderate AD) and memantine ChEls (mild to moderate AD) and memantine (moderate to severe AD) monotherapies are (moderate to severe AD) monotherapies are associated with less decline (vs placebo) in associated with less decline (vs placebo) in cognition and functioncognition and function

► Although not indicated, newer data support a role Although not indicated, newer data support a role for memantine in mild AD and ChEIs in severe ADfor memantine in mild AD and ChEIs in severe AD

► In moderate to severe AD, patients treated with In moderate to severe AD, patients treated with combination therapy (ie, memantine + ChEIs) combination therapy (ie, memantine + ChEIs) exhibited improved cognitive outcomes and exhibited improved cognitive outcomes and delayed functional decline (vs patients treated with delayed functional decline (vs patients treated with ChEI only)ChEI only)

SummarySummary