Alzheimer’s DiseaseAlzheimer’s Disease

The Cholinesterase Inhibitor The Cholinesterase Inhibitor MedicationsMedications

Diagnosed Dementia PatientsDiagnosed Dementia Patients

PCPs Neurologists Psychiatrists All others

Source: National Disease and Therapuetic Index (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904).

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Mayeux R et al. N Engl J Med. 1999;341:1670-1679.

Cholinergic HypothesisCholinergic Hypothesis

RoleRole— Acetylcholine (ACh) is an important neurotransmitterAcetylcholine (ACh) is an important neurotransmitter

in brain regions involved in memory in brain regions involved in memory

ImpactImpact— Loss of ACh in AD correlates with impairment of Loss of ACh in AD correlates with impairment of

memorymemory

Treatment approachTreatment approach— Enhancement of cholinergic function may stabilize Enhancement of cholinergic function may stabilize

or improve cognitive function and may affect or improve cognitive function and may affect behavior and daily functioning behavior and daily functioning

Cholinergic HypothesisCholinergic Hypothesis

• Cholinergic deficiency contributes to cognitive decline in AD

• It may contribute to behavioral symptoms of AD

– Psychosis-agitation– Apathy-indifference– Disinhibition– Aberrant motor behavior

Cholinergic Hypothesis (cont’d)Cholinergic Hypothesis (cont’d)

Atrophy of the nucleus basalis of Meynert, the source Atrophy of the nucleus basalis of Meynert, the source of choline acetyltransferase, causes deficit of choline acetyltransferase, causes deficit

Other neurochemical and neurohistologic Other neurochemical and neurohistologic abnormalities contribute to the psychopathology of abnormalities contribute to the psychopathology of ADAD

Cholinergic therapy may partially improve behavioral Cholinergic therapy may partially improve behavioral symptoms of AD symptoms of AD

Cholinergic therapy does not interrupt the disease Cholinergic therapy does not interrupt the disease processprocess

Current Medications Used to Current Medications Used to Treat ADTreat AD

Other25%

Aricept44%

*Risperdal 9%

*Paxil 3%

*Zyprexa 3%

*Zoloft 3%

Vitamin E 3%

*Ativan 4%

*Haldol 6%

*These uses are investigational. Source: National Disease and Therapeutic Index, 1998.

Cholinesterase InhibitorsCholinesterase Inhibitors

• FDA-approved agents: tacrine, donepezil, rivastigmine

• Doses

– Tacrine: 80 to 160 mg/d– Donepezil: 5 and 10 mg/d– Rivastigmine: 6 to 12 mg/d– Galantamine: 20 to 50 mg/d

• Efficacy in mild/moderate AD

• Limited information on long-term treatment and in late-stage disease

• May be helpful in Lewy body disease

Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother. 1999.

Cholinesterase Inhibitors (cont’d)Cholinesterase Inhibitors (cont’d)

Side-effect profiles are similar— Tacrine: liver toxicity, nausea, vomiting,

diarrhea— Donepezil: nausea, vomiting, diarrhea,

muscle cramps— Rivastigmine: nausea, vomiting, diarrhea,

headache, dizziness— Galantamine: nausea, vomiting, agitation,

sleep disturbances

6 –

4 –

2 –

0 –

-2 –

-4 –

-6 –

-8 –

-10 –

-12 –

-14 –

-16 –

Cognit

ive F

unct

ion

(A

DA

S –

Cog)

UntreatedCholinesterase Inhibitor (CI)

1 year 2 years

Hypothesized Treatment Effectin Alzheimer’s Disease

Acetylcholinesterase Inhibitor Acetylcholinesterase Inhibitor DevelopmentDevelopment

1993 1994 1995 1996 1997 1998 2000

rivastigmine(Exelon®)

tacrine(Cognex®)

1999

donepezil(Aricept®)

2001

galantamine(Reminyl®)

Characteristics ofCharacteristics ofCholinesterase InhibitorsCholinesterase Inhibitors

Dose Drug Binding escalation Dosing

tacrine Noncompetitive, 6-week steps qid (Cognex®) reversible

donepezil Noncompetitive, 4-6-week step qd(Aricept®) reversible

rivastigmine Noncompetitive 2-week steps bid(Exelon®) reversible

Davis KL, Powchik P. Lancet. 1995;345:625-630.Aricept® package insert.Exelon® package insert.

Tacrine (CognexTacrine (Cognex®®))

Half-life of 3–5 hours (variable, affected Half-life of 3–5 hours (variable, affected by food intake)by food intake)

4-times-daily dosing of 10 to 40 mg 4-times-daily dosing of 10 to 40 mg (40 to 160 mg/day)(40 to 160 mg/day)

Metabolized by the cytochrome P450 Metabolized by the cytochrome P450 isoenzyme CYP1A2isoenzyme CYP1A2

Associated with hepatotoxicity Associated with hepatotoxicity (monthly liver testing suggested)(monthly liver testing suggested)

Davis KL, Powchik P. Lancet. 1995;345:625-630.Crimson ML. Pharmacotherapy 1998;18(2 pt 2):47S-54S.

Bryson HM, Benfield P. Drugs Aging. 1997;10:234-239.Aricept® package insert.

Donepezil (AriceptDonepezil (Aricept®®))

The first second-generation cholinesterase The first second-generation cholinesterase inhibitorinhibitor

Half-life of 70 hoursHalf-life of 70 hours

Once-a-day dosing of 5 to 10 mgOnce-a-day dosing of 5 to 10 mg

Metabolized by cytochrome P450 isoenzymes Metabolized by cytochrome P450 isoenzymes CYP3A and CYP2D6CYP3A and CYP2D6

Higher doses associated with cholinergic side Higher doses associated with cholinergic side effects, but generally well tolerated effects, but generally well tolerated

Rivastigmine (ExelonRivastigmine (Exelon®®))

Newer second-generation cholinesterase Newer second-generation cholinesterase inhibitorinhibitor

Half-life of 1.5 hoursHalf-life of 1.5 hours

Dosing (bid) of 3 to 12 mg/dayDosing (bid) of 3 to 12 mg/day

Metabolism is almost totally independent Metabolism is almost totally independent of the hepatic cytochrome P450 systemof the hepatic cytochrome P450 system

Gastrointestinal adverse events are Gastrointestinal adverse events are common, including weight losscommon, including weight loss

Exelon® package insert.

Outcome Scales Used in Outcome Scales Used in Phase III Trials of AD DrugsPhase III Trials of AD Drugs

Cognition Cognition Alzheimer’s Disease Assessment Scale- Alzheimer’s Disease Assessment Scale- Cognitive Subscale Cognitive Subscale (ADAS-cog)(ADAS-cog)

Global change Global change Clinician Interview-Based Impression of Clinician Interview-Based Impression of Change plus Caregiver Change plus Caregiver Input (CIBIC-plus)Input (CIBIC-plus)

Activities of daily living Activities of daily living Interview for Deterioration in Daily LivingInterview for Deterioration in Daily Living

Activities in Dementia (IDDD)Activities in Dementia (IDDD) Progressive Deterioration Scale (PDS)Progressive Deterioration Scale (PDS)

Clinical Dementia Rating-Sum of Boxes Clinical Dementia Rating-Sum of Boxes

(CDR-SB)(CDR-SB)

Behavioral disturbances Behavioral disturbances Neuropsychiatric Inventory (NPI)Neuropsychiatric Inventory (NPI)

(ADL)(ADL)

Rosen WG et al. Am J Psychiatry. 1984;141:1356-1364.

Alzheimer’s Disease Assessment Scale-Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog)Cognitive Subscale (ADAS-cog)

Primary outcome measurePrimary outcome measure— A validated, sensitive, and psychometric A validated, sensitive, and psychometric

measuremeasure— Contains 11 items that measure cognitive Contains 11 items that measure cognitive

changechange— Scoring range is 0–70; higher scores = Scoring range is 0–70; higher scores =

greater cognitive impairmentgreater cognitive impairment— Efficacy is measured as mean change Efficacy is measured as mean change

from baseline from baseline

Schneider LS et al. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S22-32.

Clinician Interview-Based Impression of Clinician Interview-Based Impression of Change plusChange plus

Caregiver Input (CIBIC-plus)Caregiver Input (CIBIC-plus) Evaluates 4 areas: cognition, behavior, daily Evaluates 4 areas: cognition, behavior, daily

functioning, general psychiatric symptomsfunctioning, general psychiatric symptoms

Scores range from 1 (markedly improved) Scores range from 1 (markedly improved) to 7 (markedly worse)to 7 (markedly worse)

Tacrine SafetyTacrine Safety

Adverse gastrointestinal effects (somewhat Adverse gastrointestinal effects (somewhat alleviated by concomitant food intake)alleviated by concomitant food intake)

Elevated liver transaminase levels (ALT)Elevated liver transaminase levels (ALT)— 25%–30% of patients with ALT > 3 times 25%–30% of patients with ALT > 3 times

the upper limit of normalthe upper limit of normal

Monitoring of liver function requiredMonitoring of liver function required

Farlow M et al. JAMA. 1992;268:2523-2529.Knapp MJ et al. JAMA. 1994;271:985-991.

Donepezil: Percentage of Patients With Donepezil: Percentage of Patients With Improvement in ADAS-cog (Rogers)Improvement in ADAS-cog (Rogers)

Rogers SL et al.Neurology. 1998;50:136-145.

Change in ADAS-cog (LOCF*)

Treatment group 7 4 0†

Placebo 7.8% 26.8% 57.7%

Donepezil 5 mg/day 15.4% 37.8% 78.7%

Donepezil 10 mg/day 25.2% 53.5% 81.1%

* Last observation carried forward.† Includes patients who did not improve or decline.

Donepezil SafetyDonepezil Safety

Individual adverse events that occurred Individual adverse events that occurred significantly more frequently with donepezil significantly more frequently with donepezil

10 mg than with placebo: 10 mg than with placebo: — Nausea (17%)Nausea (17%)— Diarrhea (17%)Diarrhea (17%)— Vomiting (10%)Vomiting (10%)— Fatigue (8%)Fatigue (8%)— Muscle cramps (8%)Muscle cramps (8%)

Rogers SL et al. Neurology. 1998;50:136-145.

Donepezil Safety (cont)Donepezil Safety (cont)

In the largest trial (N = 818), digestive system In the largest trial (N = 818), digestive system and nervous system adverse events occurred and nervous system adverse events occurred more frequently with donepezil more frequently with donepezil 5 mg and 10 mg than with placebo5 mg and 10 mg than with placebo— Digestive system = 36% vs 24% Digestive system = 36% vs 24% — Nervous system = 38% vs 29% Nervous system = 38% vs 29%

Burns A et al. Dement Geriatr Cogn Disord. 1999;10:237-244.

* In the largest trial, donepezil 5 mg was significantly betterthan placebo using the ADAS-cog scale, but scoresworsened from baseline.

Donepezil SummaryDonepezil Summary

Donepezil (5* and 10 mg) improves cognition Donepezil (5* and 10 mg) improves cognition and global function in patients with and global function in patients with mild-to-moderate ADmild-to-moderate AD

Long-term efficacy is maintained for up Long-term efficacy is maintained for up to 50 weeksto 50 weeks

ADL may be partially maintained by donepezil ADL may be partially maintained by donepezil

Donepezil is generally safe and well toleratedDonepezil is generally safe and well tolerated

Rivastigmine SafetyRivastigmine Safety

During the maintenance phase, During the maintenance phase, adverse events with rivastigmine 6–12 mg adverse events with rivastigmine 6–12 mg (1–4 mg)* compared with placebo were:(1–4 mg)* compared with placebo were:— Dizziness, 14% (8%) Dizziness, 14% (8%) vs 4%vs 4%— Nausea, 20% (8%) vs 3%Nausea, 20% (8%) vs 3%— Vomiting, 16% (5%) Vomiting, 16% (5%) vs 2%vs 2%— Dyspepsia, 5% (6%) Dyspepsia, 5% (6%) vs 1%vs 1%— Sinusitis, 4% (1%) Sinusitis, 4% (1%) vs 1%vs 1%

Corey-Bloom J et al. Int J GeriatrPsychopharmacol. 1998;1:55-65.

* p < 0.05 vs placebo for all events except rivastigmine 1–4 mg for dizziness and sinusitis (not different from placebo).

Rivastigmine Safety (cont)Rivastigmine Safety (cont)

Rivastigmine was generally safe andRivastigmine was generally safe andwell toleratedwell tolerated

There was no evidence of hepatotoxicityThere was no evidence of hepatotoxicity

Fewer adverse events were observed with Fewer adverse events were observed with concomitant food administration versus concomitant food administration versus administration without foodadministration without food

In addition to nausea and vomiting, In addition to nausea and vomiting, rivastigmine was associated with significant rivastigmine was associated with significant weight lossweight loss

Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.

Rivastigmine SummaryRivastigmine Summary

Rivastigmine (6–12 mg) improves cognitionRivastigmine (6–12 mg) improves cognitionand global function in patients withand global function in patients withmild-to-moderate ADmild-to-moderate AD

Positive effects on ADL have been observed Positive effects on ADL have been observed in some studiesin some studies

Rivastigmine is generally safe and well Rivastigmine is generally safe and well tolerated, although cholinergic side effects tolerated, although cholinergic side effects occur at high dosesoccur at high doses

1. Tariot PN et al. Neurology. 2000;54:2269-2276.2. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.

Galantamine (ReminylGalantamine (Reminyl®®) )

Galantamine has a dual mechanism of actionGalantamine has a dual mechanism of action— Competitive inhibition of acetylcholinesteraseCompetitive inhibition of acetylcholinesterase11

— Allosteric modulation of presynaptic and Allosteric modulation of presynaptic and postsynaptic nicotinic receptorspostsynaptic nicotinic receptors22

Galantamine improves major aspects of AD Galantamine improves major aspects of AD (eg, cognition, behavior, function)(eg, cognition, behavior, function)11

Galantamine is generally safe and well toleratedGalantamine is generally safe and well tolerated11

Dual Mechanism of ActionDual Mechanism of Action

Postsynaptic nerve terminal

M receptorM receptor N receptorN receptor

Presynaptic nerve terminal

Galantamine ACh and other

neurotransmitters

M receptorM receptor N receptorN receptor

ACh• Choline• Acetic acid

GalantamineGalantamine

N = nicotinic

M = muscarinic

ACh = acetylcholine

Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170. Tariot PN et al. Neurology. 2000;54:2269-2276.

Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.

Galantamine: Potential Advantages of Galantamine: Potential Advantages of Nicotinic Receptor ModulationNicotinic Receptor Modulation

May increase release of AChMay increase release of ACh— Release of other neurotransmitters Release of other neurotransmitters

also increases also increases

May have a neuroprotective effectMay have a neuroprotective effect

Galantamine Safety (cont)Galantamine Safety (cont)Galantamine Galantamine

Placebo 16 mg/day 24 mg/day (n = 286) (n = 279) (n = 273)

Adverse events* (%) (%) (%)

Nausea 4.5 13.3 16.5

Vomiting 1.4 6.1 9.9

Anorexia 3.1 6.5 8.8

Agitation 9.4 10.0 8.1

Diarrhea 5.9 12.2 5.5

Tariot PN et al. Neurology. 2000;54:2269-2276.

* 5% of patients receiving galantamine and more often than in patients receiving placebo.

GI Adverse EventsGI Adverse Events

Nausea: incidence related to treatment Nausea: incidence related to treatment initiation and dose escalationinitiation and dose escalation— Typically transient, resolving within 1 weekTypically transient, resolving within 1 week— Rarely severeRarely severe

Weight loss: reported as an adverse event in Weight loss: reported as an adverse event in 5% of patients, with none discontinuing 5% of patients, with none discontinuing treatmenttreatment

Reminyl® package insert.

ComedicationComedication

Minimal potential for clinically relevant drug Minimal potential for clinically relevant drug interactionsinteractions— No effect on kinetics of digoxin or warfarinNo effect on kinetics of digoxin or warfarin

As with other cholinergics, galantamine should As with other cholinergics, galantamine should be used with caution in patients with heart block be used with caution in patients with heart block or sick sinus syndromeor sick sinus syndrome

Agents in Development Agents in Development

Memantine–NMDA receptor antagonistMemantine–NMDA receptor antagonist— Improvement in patients with severe AD Improvement in patients with severe AD

and VaDand VaD11

— Recent phase III trials indicate significant Recent phase III trials indicate significant improvement compared with placebo in improvement compared with placebo in CIBIC-plus scoresCIBIC-plus scores22

— Patients with moderately severe and severe Patients with moderately severe and severe AD benefited the most AD benefited the most

1. Winblad B, Portis N. Int J Geriat Psychiatry. 1999;14:135-146. 2. Reisberg B. World Alzheimer Congress, 2000.

4. Lahiri DK et al. Ann NY Acad Sci. 2000;903:387-393.5. O’Banion K. World Alzheimer Congress, 2000.

6. Dovey HF et al. J Neurochem. 2001;76:173-181.

Agents in Development (cont)Agents in Development (cont)

Immunization against Immunization against -amyloid-amyloid11

Huprine X—acetylcholinesterase inhibitorHuprine X—acetylcholinesterase inhibitor22

Xanomeline patch—m1/m4 muscarinic receptor Xanomeline patch—m1/m4 muscarinic receptor agonistagonist33

AIT-082 (purine hypoxanthine derivative)—AIT-082 (purine hypoxanthine derivative)—increases neurotransmissionincreases neurotransmission44

COX 2 inhibitors—neuroinflammation therapyCOX 2 inhibitors—neuroinflammation therapy55

Protease inhibitors—target Protease inhibitors—target -secretases to prevent -secretases to prevent amyloid formationamyloid formation66

1. Schenk DB et al. Nature. 1999;400:173-177.2. Camps P et al. Mol Pharmacol. 2000;57:409-417.3. Shannon HE et al. Schizophr Res. 2000;42:249-259.

Current Treatment SummaryCurrent Treatment Summary

Cholinergic agents initially improve and Cholinergic agents initially improve and transiently maintain cognitive abilities in transiently maintain cognitive abilities in patients with mild-to-moderate ADpatients with mild-to-moderate AD

Cognitive abilities worsen over time, Cognitive abilities worsen over time, indicating treatment does not stop (but may indicating treatment does not stop (but may delay) the progression of ADdelay) the progression of AD

New treatments that maintain cognitive ability New treatments that maintain cognitive ability and stop the progression of AD are needed and stop the progression of AD are needed

ReferralsReferrals

SHANDS at UFSHANDS at UF

Geriatric Psychiatry Inpatient UnitGeriatric Psychiatry Inpatient Unit

Intake and Referral LineIntake and Referral Line

352-265-5411352-265-5411

UF Psychiatry Clinical Trials ProgramUF Psychiatry Clinical Trials Program

1-877-STUDY941-877-STUDY94