The Psychopharmacology of Alzheimer ’ s Disease

1. The Psychopharmacology of Alzheimer’s Disease Bruce Kaster, MD Instructor in Psychiatry Harvard Medical school

2. Overview of Alzheimer’s Disease • Alzheimer’s is a progressive degenerative disease • Prevalence increases with age • Annual cost is estimated at $100 billion dollars- 3rd most costly disease in the U.S. • Approximately 4 million Americans have AD • 14 million will have Alzheimer’s by 2050

3. 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

4. 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

5. 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

6. Diagnosis • Complete history, physical, lab panels • Multiple sources of information • Neuroimaging • Neuropsycholgical battery • Approximately 90% accuracy

7. Treatment of Behavioral Symptoms • Whole variety of psychiatric symptoms are present in AD • Depression, psychosis, anxiety, mania, aggression • Multiple agents can abate these symptoms

8. Behavioral Symptoms (cont) • Depression - usually seen in early AD - can be present at any time, but usually not full blown - psychotherapy maybe helpful early

9. 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

10. 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

11. 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

12. Depression (cont) Other agents - Remeron - Effexor, Cymbalta - Wellbutrin - Viibryd - MAOIs such as Emsam - Stimulants e.g. Provigil, Ritalin

13. Behavioral Symptoms • Psychosis - 30 to 50% of AD patients have psychotic symptoms - delusions or hallucinations - typically delusions of persecution and visual hallucinations

14. 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

15. 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

16. 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

17. 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

18. 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

19. Behavioral Symptoms (cont) • Anxiety - should investigate if this is a premorbid trait - may use benzodiazepines, Buspar, Trazadone, Neurontin, atypical antipsychotics

20. Behavioral Symptoms (cont) Certain behaviors do not respond to pharmacologic treatment - wandering - disrobing - hoarding - sexualizing

21. 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

22. 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

23. Cholinesterase Inhibitors (cont) • Tacrine - 1st available CEI approved in 1993 - fell out of favor because of hepatotoxicity, QID dosing, and frequent blood monitoring

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. References (cont) 6.Sano,M. Current Concepts in the Prevention of Alzheimer’s Disease. CNSSpectrums. 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