Disclosures. Case: Ms. K. Case: Ms. K. Dementia: Considering When to Start, Stop, and Continue Medications 4/23/15. * Nothing to disclose

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1 Dementia: Considering When to Start, Stop, and Continue Medications * Nothing to disclose Disclosures Lianne Hirano, MD UW Division of Gerontology & Geriatric Medicine 4/23/15 Current Concepts in Drug Therapy * 76 yo woman w/ HTN but o/w relatively active and healthy, seen in f/u visit. * Pt s daughter concerned about pt s memory she is more forgetful, occasionally has trouble finding the right words, misplaces things around the house. This seems to be getting worse over the past year. Mini Mental Status Exam (MMSE) score = 26. * Labs are negative for reversible causes of dementia. Pt s daughter wants to start her on treatment for this ASAP as she is afraid her mother has Alzheimer s (AD). She informs you that her maternal grandmother also had AD and wonders if there is a medication or supplement for her mother and for her (she s already taking gingko biloba). What can you offer her? A. Start donepezil B. Start donepezil and memantine C. Watch and wait, this might not be AD D. Both pt and her daughter should start vitamin E 1

2 Mild Cognitive Impairment (MCI) * Currently, no treatment known to improve outcomes (cholinesterase inhibitors, gingko, NSAIDs, Vit E, phospholipids, for example) * Geriatrics rule of thirds * 10% per year risk of developing AD * Some guidelines suggest that if pt/family really insistent on starting a medication, can consider donepezil after good risk/benefit counseling. Pt s daughter wants to start her on treatment for this ASAP as she is afraid her mother has Alzheimer s (AD). She informs you that her maternal grandmother also had AD and wonders if there is a medication or supplement for her mother and for her (she s already taking gingko biloba). What can you offer her? A. Start donepezil B. Start donepezil and memantine C. Watch and wait, this might not be AD D. Both pt and her daughter should start vitamin E Cholinesterase Inhibitors Pt and her daughter return 8 months later for f/u AND because recently pt was driving and could not find her way home. Her car ran out of gas and she forgot her daughter s phone number so couldn t call for help. Her word- finding problems are worse. She repeats questions over and over. MMSE is now 21. Ms. K s daughter is stressed and frustrated. Ms. K does not want to be a burden, but she also does not want to end up in a nursing home. Mayeux R.N Engl J Med 2010; 362:

3 High- Dose Donepezil Ms. K returns after 8 weeks of being on donepezil for follow- up. She seems to be tolerating 10mg/day well without nausea or vomiting, but she has lost about 2lbs unintentionally (she isn t that hungry and her daughter thinks she just forgets to eat). Her daughter feels like the donepezil has helped a little and read on the internet about a 23mg dose. If it s working a little, wouldn t she do even better on a higher dose??? * For tx of mild- mod AD, donepezil 10mg/day demonstrated very modest benefits in activities of daily living (ADLs), cognition (0.8 difference in MMSE), and behavior. * Donepezil 23mg/day dose approved in * RCT, 1400 pts w/ mod- sev AD already on donepezil 10mg/day (for at least 3 months) * Only modest cognitive benefit, no change in global functioning. Significantly more adverse effects (N/V) 1. Birks JS, Harvey R. Cochrane Database Syst Rev. Donepezil for dementia due to Alzheimer s disease. 2003;CD Farlow MR, et al. Clin Ther. 2010;32: Ms. K returns for follow- up after 8 weeks of being on donepezil. She seems to be tolerating 10mg/day well without nausea or vomiting, but she has lost about 2lbs unintentionally (she isn t that hungry and her daughter thinks she just forgets to eat). Her daughter feels like the donepezil has helped a little and read on the internet about a 23mg dose. If it s working a little, wouldn t she do even better on a higher dose??? Ms. K continues on donepezil 10mg/day. Unfortunately, she gets the flu and is hospitalized with pneumonia. She has a bout of delirium during her hospitalization, but manages to recover. Upon discharge, her conscientious intern reviews her medications and in an effort to avoid any polypharmacy, wonders if Ms. K really needs to be on donepezil. If she does, shouldn t she also be on memantine as well for moderate AD? Her MMSE on day of discharge is 18. 3

4 Donepezil and Memantine in Moderate to Severe Alzheimer s Disease (DOMINO) Trial Memantine * 295 pts /w mod- severe AD already on donepezil randomized to continue donepezil alone, continue donepezil + memantine, discontinue donepezil, discontinue donepezil and take memantine alone. * Pts followed for 1 year * Pts who continued donepezil had better cognitive outcome than those that did not. * No significant benefit to combination of memantine and donepezil over donepezil alone. * Study ended early due to slow recruitment. * N- methyl- D- aspartate (NMDA) receptor antagonist * FDA approved since 2003 for mod- severe AD * Little (not really any) evidence for benefit in mild AD * However, fewer side effects than cholinergic agents. * May increase agitation and delusions but overall well- tolerated in general (might want to avoid in dementia w/ Lewy Bodies) Howard R, et al. NEJM 2012;366:893. Memantine * Possibly neuroprotective * Often prescribed with donepezil for mild- moderate AD * Combo donepezil- memantine capsule due out this year (according to UpToDate). Unfortunately, after her hospitalization, Ms. K s cognition has remained poor and when she sees you in follow- up her MMSE is now 16. Her daughter is wondering if there is anything else you can prescribe. Her neighbor mentioned Vitamin E and coconut oil. 4

5 Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM- AD VA cooperative randomized trial Coconut Oil * 613 pts (97% men) w/ mild to moderate AD randomized to vitamin E 2000IU/day, memantine 20mg/day, vit E + memantine, or placebo * Followed for up to 4 years * Primary outcome measure was ADLs * Vit E only group experienced the least decline in ADLs (no difference on cognitive results) * Benefits of vitamin E likely modest, possibly offset when combined w/ memantine * NO EVIDENCE! Dysken MW, et al. JAMA 2014;311:33 Discontinuing AD Medications Ms. K s cognition and her ability to do ADLs continue to decline. Her daughter places her in an adult family home. You discuss advanced directives with Ms. K s daughter. Fortunately, she has had a few discussions with her mother. A POLST is completed wherein Ms. K is DNR/DNI, comfort measures only, no antibiotics (treat infections symptomatically), no long- term artificial nutrition by tube. Ms. K s daughter asks if her mother still needs to take her AD medications (donepezil and memantine). * In general, can continue both medications until they are no longer tolerated or consistent with goals of care. * Several guidelines recommend tapering cholinesterase inhibitors over 2-4 weeks. 5

6 Antiamyloid Therapy for AD Bapineuzumab * Amyloid Hypothesis: Deposition of amyloid- beta in brain parenchyma is an early critical event in AD that promotes or accelerates downstream features of the disease. * 2 phase 3 trials of anti- AB antibodies: bapineuzumab and solanezumab Salloway, S, et al. NEJM 2014, 370;4:322. Doody, RS, et al. NEJM 2014, 370;4;311. * Humanized IgG1 antibody of mouse monoclonal antibody 3D6 that recognizes intact N- terminal of AB * Binds to AB plaque and activates phagocytic microglia to clear plaque * IV infusion every 13 weeks for 78 weeks (in APOE4 carriers and noncarriers) * ADAS- cog 11 (o- 70, higher scores = greater impairment) * Disability assessment for dementia (0-100, higher scores = less impairment) Solanezumab The Future of AD Treatment * Humanized IgG1 antibody of mouse monoclonal antibody 266 with affinity for mid- domain of AB and recognizes soluble but not plaque AB, driving equilibrium toward soluble form * IV every 4 weeks for 18 months * ADAS- cog11 and ADCS- ADL * No significant improvement in cognition or ADLs * Diagnosis of AD remains fundamentally clinical (despite advances in neuroimaging and measurement of biomarkers) * Most pharmaceutical companies are looking into disease- modifying treatments through AB therapeutics * Will need to figure out how clinical findings relate to biological findings in order to create treatment that results in cognitive and functional improvements. 6

7 Thank You! 7