The Psychopharmacology of Alzheimer s Disease Bruce Kaster, MD Instructor in Psychiatry Harvard Medical school
Overview of Alzheimer s Disease Alzheimer s is a progressive degenerative disease Prevalence increases with age Annual cost is estimated at $100 billion dollars- 3 rd most costly disease in the U.S. Approximately 4 million Americans have AD 14 million will have Alzheimer s by 2050
Overview (cont) 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 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 Complete history, physical, lab panels Multiple sources of information Neuroimaging Neuropsycholgical battery Approximately 90% accuracy
Treatment of Behavioral Symptoms Whole variety of psychiatric symptoms are present in AD Depression, psychosis, anxiety, mania, aggression Multiple agents can abate these symptoms
Behavioral Symptoms (cont) 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 -1 st 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 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 2 nd 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) 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) 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) 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 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 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) Tacrine -1 st available CEI approved in 1993 - fell out of favor because of hepatotoxicity, QID dosing, and frequent blood monitoring
Cholinesterase Inhibitors (cont) 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) 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) 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 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) 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) 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) 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) 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) 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) 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) 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 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;8:29-34 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