The Psychopharmacology
of Alzheimer’s Disease
Bruce Kaster, MD
Instructor in Psychiatry Harvard
Medical school
Overview of Alzheimer’s
Disease
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Alzheimer’s is a progressive degenerative disease
Prevalence increases with age
Annual cost is estimated at $100 billion dollars3rd most costly disease in the U.S.
Approximately 4 million Americans have AD
14 million will have Alzheimer’s by 2050
Overview (cont)
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1:10 over age 65 has AD
Perhaps close to 1:2 has AD over age 85
50% of nursing home patients suffer from
dementia
Up to 50% of AD patients suffer from psychiatric
complications
Clinical Presentation
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Checklist published by the Alzheimer’s
Association
1. Memory loss
2. Difficulty with familiar tasks
3. Language problems
4. Disorientation to time and place
5. Poor judgement
Clinical Presentation (cont)
6. Problems with abstract thinking
7. Misplacing things
8. Changes in mood and behavior
9. Changes in personality
10. Loss of initiative
Diagnosis
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Complete history, physical, lab panels
Multiple sources of information
Neuroimaging
Neuropsycholgical battery
Approximately 90% accuracy
Treatment of Behavioral
Symptoms
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Whole variety of psychiatric symptoms are
present in AD
Depression, psychosis, anxiety, mania, aggression
Multiple agents can abate these symptoms
Behavioral Symptoms (cont)
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Depression
- usually seen in early AD
- can be present at any time, but usually not full
blown
- psychotherapy maybe helpful early
Depression (cont)
- trial of antidepressant is warranted
- all equally efficacious, but side effects may differ
- cost is also a factor
- generic vs brand
- compliance issues QD vs BID vs TID
Depression (cont)
- TCAs e.g. Elavil, Tofranil are older “dirtier”
drugs
- should be avoided in AD patients
- host of side effects including confusion,
constipation, dizziness
- unfortunately still prescribed for headache, pain
syndromes, urinary incontinence
Depression (cont)
SSRIs
- 1st line agents in depressed AD patients
- least toxic
- more favorable side effect profile
- Prozac, Zoloft,Paxil, Luvox, Celexa (recent FDA
warning), Lexapro
Depression (cont)
Other agents
- Remeron
- Effexor, Cymbalta
- Wellbutrin
- Viibryd
- MAOIs such as Emsam
- Stimulants e.g. Provigil, Ritalin
Behavioral Symptoms
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Psychosis
- 30 to 50% of AD patients have psychotic
symptoms
- delusions or hallucinations
- typically delusions of persecution and visual
hallucinations
Psychosis (cont)
-psychotherapy usually not helpful
- antipsychotic medications are needed
- multiple medications available
- typical vs atypical
- cost is a factor
- side effects are a factor
Psychosis (cont)
- typicals are older and less tolerable
- examples include Haldol, Stelazine,Thorazine,
Mellaril
- side effects include sedation, confusion,and
movement disorders
- difficult to justify using these meds today
Psychosis (cont)
- atypical or 2nd generation agents are better
tolerated, but not without their own side effects
- Risperdal, Zyprexa, Seroquel,Geodon, Abilify,
and Clozaril
- most have been used successfully in this
population
- different formulations are available
- FDA black box warning 2005
Behavioral Symptoms (cont)
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Mood lability
- extremes in mood, highs and lows
- possible mania
- mood stabilizers are used including Depakote,
Tegretol, and Lithium
- atypical antipsychotics are also used
Behavioral Symptoms (cont)
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Agitation
- encompasses combativeness, yelling, aggression
- maybe present in 50% of AD patients
- peaks in PM called sundowning
- variety of behavioral and pharmacologic options
available including Trazadone
Behavioral Symptoms (cont)
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Anxiety
- should investigate if this is a premorbid trait
- may use benzodiazepines, Buspar, Trazadone,
Neurontin, atypical antipsychotics
Behavioral Symptoms (cont)
Certain behaviors do not respond to
pharmacologic treatment
- wandering
- disrobing
- hoarding
- sexualizing
Cognitive Symptoms
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These include amnesia, apraxia, agnosia,
executive dysfunction
Also included are functional symptoms such as
ADLs and IADLs
Behavioral symptoms may also overlap
FDA approved AD treatments need to show
cognitive efficacy
Cholinesterase Inhibitors
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These meds prevent breakdown of acetylcholine
in the brain
Acetylcholine deficits are seen in AD patients
Acetylcholine probably plays a role in memory
4 FDA approved cholinesterase inhibitors
Cholinesterase Inhibitors (cont)
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Tacrine
- 1st available CEI approved in 1993
- fell out of favor because of hepatotoxicity, QID
dosing, and frequent blood monitoring
Cholinesterase Inhibitors (cont)
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Donepezil (Aricept)
- FDA approved in 1996
- long t1/2 allows once daily dosing
- side effects are usually GI in nature
- can also see vivid dreams, sleep problems, and
leg cramps
- available as a generic
Cholinesterase Inhibitors (cont)
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Rivastigmine (Exelon)
- FDA approved in 2000 for mild to moderate AD
- may tend to cause more GI upset therefore need
to titrate more slowly
- BID dosing
- also inhibits butyrylcholinesterase but benefit is
unclear
- Exelon patch better tolerated than capsules
Cholinesterase Inhibitors (cont)
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Galantamine (Reminyl)
- FDA approved 2001
- also acts as an allosteric modulator at nicotinic
receptors
- nicotine has shown effects in memory, attention,
and learning in AD patients
- BID dosed and needs to be titrated
- available as generic
Cognitive Symptoms
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Memantine (Namenda)
- NMDA receptor antagonist
- approved for moderate to severe AD
- patients required less caregiver time and showed a slower
rate of decline
- combination treatment may be better than monotherapy
- well tolerated, BID dosed, could possibly use QD due to
long t1/2
Memantine (cont)
- mechanism is related to receptor overactivation
by glutamate
- this can lead to cell death and cognitive deficits
- unclear if beneficial for mild to moderate
patients; studies are ongoing
- dose is 10mg bid
Cognitive Symptoms (cont)
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Vitamin E
- an antioxidant which may slow progression of AD
- Sano et al in NEJM ’97 showed vitamin E to delay
endpoints by 230 days
- Morris et al found dietary but not supplemental vitamin
E intake reduced risk of developing AD in patients
- has fallen out of favor, possible cardiac toxicity
Cognitive Symptoms (cont)
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Estrogen
- activates the cholinergic system
- has antioxidant properties
- women who were treated with estrogen postmenopause,
were found to have decreased risk of developing AD
- prospective studies have not shown supported this
finding
- treatment with estrogen may increase risk of heart
disease and breast cancer
Cognitive Symptoms (cont)
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Ginkgo Biloba
- an OTC anti-oxidant
- LeBars et al showed modest improvement in
patients taking ginkgo vs placebo
- not FDA approved substance
- need to watch for possible bleeding
Cognitive Symptoms (cont)
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Statins
- lipid lowering agents widely used to decrease cholesterol
- epidemiologic data suggest that increased cholesterol can
increase risk of developing AD
- one retrospective study showed patients treated with a
statin had a 30% reduced risk of developing dementia
- prospective studies are ongoing
- may cause confusion in some
Cognitive Symptoms (cont)
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Homocysteine
- an amino acid known as risk factor for cardiac
disease
- increased levels are associated with AD
- folate, vitamin B12, and vitamin B6 will lower
levels of homocysteine
Cognitive symptoms (cont)
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Clioquinol
- a copper and zinc chelater that has shown benefit
in mice models
- iron, copper, and zinc may have role in AD
pathogenesis
- 36 AD patients at various stages had decrease in
plasma AB
- trials continue
Cognitive Symptoms (cont)
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Secretase Inhibitors
- B-amyloid is formed from large Amyloid
precursor protein (APP)
- B-secretase and Gamma-secretase cleave APP
into the toxic AB42
- therapies are being developed to inhibit actions
of Beta and Gamma secretase
- Gamma secretase inhibitors are in clinical trials
Summary
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AD at this point is still being treated
symptomatically
Treatments are available for both cognitive and
noncognitive symptoms
“cocktail” approach for treatment
Patients may require polypharmacy
There are approximately 70 new compounds in
the Alzheimer’s pipeline so we need to be patient
References
1.Samuels SC, Grossman H. Emerging Therapeutics for
Alzheimer’s Disease. CNS Spectrums 8:834-845.
2.Farlow MR. Alzheimer’s Treatment Update. CNS/Long
Term Care Spring 2003. 11-13.
3.Sano,M. Noncholinergic Treatment Options for
Alzheimer’s Disease J Clin Psychiatry 64:23-28
4.Mintzer,J. The Search for Better Noncholinergic treatment
Options for Alzheimer’s Disease J Clin Psychiatry 64:
18-22
5.Grossberg,G. Daignosis and Treatment of Alzheimer’s
Disease. J Clin Psychiatry 64:3-6
References (cont)
6.Sano,M. Current Concepts in the Prevention of
Alzheimer’s Disease. CNS Spectrums. 8:846-853.
7.Jeste DV,Finkel SI. Psychosisof Alzheimer’s Disease and
Related Dis orders. Am J Geriatr Psychiatry 2000;8:2934
8.LeBars PL, Katz MM, Berman N, A placebo-controlled,
double-blind, randomized trial of an extract of ginkgo.
JAMA. 1997;278:1327-1332.
9.Leon J, Cheng C-K, Neumann,PJ. Alzheimer’s disease
care :costs and potential savings. Health Affairs
1998;17:206-216