Transcript Current Management of Alzheimer’s Disease

Alzheimer’s Disease
The Cholinesterase Inhibitor
Medications
Diagnosed Dementia Patients
Diagnosis visits (millions)
2.5
2.0
1.5
1.0
0.5
0
1995
PCPs
1996
1997
Neurologists
1998
Psychiatrists
1999
All others
11/99 to
10/2000
Source: National Disease and Therapuetic Index (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904).
Cholinergic Hypothesis

Role
— Acetylcholine (ACh) is an important neurotransmitter
in brain regions involved in memory

Impact
— Loss of ACh in AD correlates with impairment of
memory

Treatment approach
— Enhancement of cholinergic function may stabilize
or improve cognitive function and may affect
behavior and daily functioning
Mayeux R et al. N Engl J Med. 1999;341:1670-1679.
Cholinergic 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)

Atrophy of the nucleus basalis of Meynert, the source
of choline acetyltransferase, causes deficit

Other neurochemical and neurohistologic
abnormalities contribute to the psychopathology of
AD

Cholinergic therapy may partially improve behavioral
symptoms of AD

Cholinergic therapy does not interrupt the disease
process
Current Medications Used to
Treat AD
*Paxil 3%
*Zyprexa 3%
Other
25%
*Zoloft 3%
Vitamin E 3%
*Ativan 4%
*Haldol 6%
Aricept
44%
*Risperdal 9%
*These uses are investigational.
Source: National Disease and Therapeutic Index, 1998.
Cholinesterase 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)

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
Hypothesized Treatment Effect
in Alzheimer’s Disease
Untreated
Cholinesterase Inhibitor (CI)
6–
Cognitive Function
(ADAS –Cog)
4–
2–
0–
-2 –
-4 –
-6 –
-8 –
-10 –
-12 –
-14 –
-16 –
1 year
2 years
Acetylcholinesterase Inhibitor
Development
1993
tacrine
(Cognex®)
1994
1995
1996
1997
donepezil
(Aricept®)
1998
1999
2000
2001
rivastigmine
(Exelon®)
galantamine
(Reminyl®)
Characteristics of
Cholinesterase Inhibitors
Drug
Binding
Dose
escalation
Dosing
tacrine
(Cognex®)
Noncompetitive,
reversible
6-week steps
qid
donepezil
(Aricept®)
Noncompetitive,
reversible
4-6-week step
qd
rivastigmine
(Exelon®)
Noncompetitive
reversible
2-week steps
bid
Davis KL, Powchik P. Lancet. 1995;345:625-630.
Aricept® package insert.
Exelon® package insert.
Tacrine (Cognex®)

Half-life of 3–5 hours (variable, affected
by food intake)

4-times-daily dosing of 10 to 40 mg
(40 to 160 mg/day)

Metabolized by the cytochrome P450
isoenzyme CYP1A2

Associated with hepatotoxicity
(monthly liver testing suggested)
Davis KL, Powchik P. Lancet. 1995;345:625-630.
Crimson ML. Pharmacotherapy 1998;18(2 pt 2):47S-54S.
Donepezil (Aricept®)

The first second-generation cholinesterase
inhibitor

Half-life of 70 hours

Once-a-day dosing of 5 to 10 mg

Metabolized by cytochrome P450 isoenzymes
CYP3A and CYP2D6

Higher doses associated with cholinergic side
effects, but generally well tolerated
Bryson HM, Benfield P. Drugs Aging. 1997;10:234-239.
Aricept® package insert.
Rivastigmine (Exelon®)

Newer second-generation cholinesterase
inhibitor

Half-life of 1.5 hours

Dosing (bid) of 3 to 12 mg/day

Metabolism is almost totally independent
of the hepatic cytochrome P450 system

Gastrointestinal adverse events are
common, including weight loss
Exelon® package insert.
Outcome Scales Used in
Phase III Trials of AD Drugs
Cognition
Alzheimer’s Disease Assessment ScaleCognitive Subscale (ADAS-cog)
Global change
Clinician Interview-Based Impression of
Change plus Caregiver Input (CIBIC-plus)
Activities of daily living
Interview for Deterioration in Daily Living
Activities in Dementia (IDDD)
Progressive Deterioration Scale (PDS)
Clinical Dementia Rating-Sum of Boxes
(CDR-SB)
(ADL)
Behavioral disturbances
Neuropsychiatric Inventory (NPI)
Alzheimer’s Disease Assessment
Scale-Cognitive Subscale (ADAS-cog)

Primary outcome measure
—
A validated, sensitive, and psychometric
measure
— Contains 11 items that measure cognitive
change
— Scoring range is 0–70; higher scores =
greater cognitive impairment
— Efficacy is measured as mean change
from baseline
Rosen WG et al. Am J Psychiatry. 1984;141:1356-1364.
Clinician Interview-Based
Impression of Change plus
Caregiver Input (CIBIC-plus)

Evaluates 4 areas: cognition, behavior, daily
functioning, general psychiatric symptoms

Scores range from 1 (markedly improved)
to 7 (markedly worse)
Schneider LS et al. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S22-32.
Tacrine Safety

Adverse gastrointestinal effects (somewhat
alleviated by concomitant food intake)

Elevated liver transaminase levels (ALT)
—

25%–30% of patients with ALT > 3 times
the upper limit of normal
Monitoring 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
Improvement in ADAS-cog (Rogers)
Change in ADAS-cog (LOCF*)
4
Treatment group
7
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.
 0†
Rogers SL et al.
Neurology. 1998;50:136-145.
Donepezil Safety

Individual adverse events that occurred
significantly more frequently with donepezil
10 mg than with placebo:
—
—
—
—
—
Nausea (17%)
Diarrhea (17%)
Vomiting (10%)
Fatigue (8%)
Muscle cramps (8%)
Rogers SL et al. Neurology. 1998;50:136-145.
Donepezil Safety (cont)

In the largest trial (N = 818), digestive system
and nervous system adverse events occurred
more frequently with donepezil
5 mg and 10 mg than with placebo
—
Digestive system = 36% vs 24%
— Nervous system = 38% vs 29%
Burns A et al. Dement Geriatr Cogn Disord. 1999;10:237-244.
Donepezil Summary

Donepezil (5* and 10 mg) improves cognition
and global function in patients with
mild-to-moderate AD

Long-term efficacy is maintained for up
to 50 weeks

ADL may be partially maintained by donepezil

Donepezil is generally safe and well tolerated
* In the largest trial, donepezil 5 mg was significantly better
than placebo using the ADAS-cog scale, but scores
worsened from baseline.
Rivastigmine Safety

During the maintenance phase,
adverse events with rivastigmine 6–12 mg
(1–4 mg)* compared with placebo were:
—
Dizziness, 14% (8%) vs 4%
— Nausea,
20% (8%) vs 3%
— Vomiting, 16% (5%) vs 2%
— Dyspepsia, 5% (6%) vs 1%
— Sinusitis,
4% (1%) vs 1%
* p < 0.05 vs placebo for all events except
rivastigmine 1–4 mg for dizziness and sinusitis
(not different from placebo).
Corey-Bloom J et al. Int J Geriatr
Psychopharmacol. 1998;1:55-65.
Rivastigmine Safety (cont)

Rivastigmine was generally safe and
well tolerated

There was no evidence of hepatotoxicity

Fewer adverse events were observed with
concomitant food administration versus
administration without food

In addition to nausea and vomiting,
rivastigmine was associated with significant
weight loss
Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.
Rivastigmine Summary

Rivastigmine (6–12 mg) improves cognition
and global function in patients with
mild-to-moderate AD

Positive effects on ADL have been observed
in some studies

Rivastigmine is generally safe and well
tolerated, although cholinergic side effects
occur at high doses
Galantamine (Reminyl®)

Galantamine has a dual mechanism of action
Competitive inhibition of acetylcholinesterase1
— Allosteric modulation of presynaptic and
postsynaptic nicotinic receptors2
—

Galantamine improves major aspects of AD
(eg, cognition, behavior, function)1

Galantamine is generally safe and well tolerated1
1. Tariot PN et al. Neurology. 2000;54:2269-2276.
2. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Dual Mechanism of Action
N = nicotinic
Presynaptic nerve
terminal
M = muscarinic
ACh = acetylcholine
M receptor
N receptor
Galantamine
ACh
Postsynaptic
nerve terminal
Galantamine
 ACh and other
neurotransmitters
• Choline
• Acetic acid
M receptor
N receptor
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Tariot PN et al. Neurology. 2000;54:2269-2276.
Galantamine: Potential Advantages
of Nicotinic Receptor Modulation

May increase release of ACh
—

Release of other neurotransmitters
also increases
May have a neuroprotective effect
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Galantamine Safety (cont)
Adverse events*
Placebo
(n = 286)
(%)
Galantamine Galantamine
16 mg/day
24 mg/day
(n = 279)
(n = 273)
(%)
(%)
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
*  5% of patients receiving galantamine and
more often than in patients receiving placebo.
Tariot PN et al. Neurology.
2000;54:2269-2276.
GI Adverse Events

Nausea: incidence related to treatment
initiation and dose escalation
—
Typically transient, resolving within 1 week
— Rarely severe

Weight loss: reported as an adverse event in
 5% of patients, with none discontinuing
treatment
Reminyl® package insert.
Comedication

Minimal potential for clinically relevant drug
interactions
—

No effect on kinetics of digoxin or warfarin
As with other cholinergics, galantamine should
be used with caution in patients with heart block
or sick sinus syndrome
Agents in Development

Memantine–NMDA receptor antagonist
—
Improvement in patients with severe AD
and VaD1
— Recent phase III trials indicate significant
improvement compared with placebo in
CIBIC-plus scores2
— Patients with moderately severe and severe
AD benefited the most
1. Winblad B, Portis N. Int J Geriat Psychiatry. 1999;14:135-146.
2. Reisberg B. World Alzheimer Congress, 2000.
Agents in Development (cont)






Immunization against b-amyloid1
Huprine X—acetylcholinesterase inhibitor2
Xanomeline patch—m1/m4 muscarinic receptor
agonist3
AIT-082 (purine hypoxanthine derivative)—
increases neurotransmission4
COX 2 inhibitors—neuroinflammation therapy5
Protease inhibitors—target g-secretases to prevent
amyloid formation6
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.
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.
Current Treatment Summary

Cholinergic agents initially improve and
transiently maintain cognitive abilities in
patients with mild-to-moderate AD

Cognitive abilities worsen over time,
indicating treatment does not stop (but may
delay) the progression of AD

New treatments that maintain cognitive ability
and stop the progression of AD are needed
Referrals
SHANDS at UF
Geriatric Psychiatry Inpatient Unit
Intake and Referral Line
352-265-5411
UF Psychiatry Clinical Trials Program
1-877-STUDY94