Update on Treatment of the Dementias

Transcription

1 Update on Treatment of the Dementias Mark Pippenger, MD Behavioral Neurology Associate Clinical Professor of Neurology University of Arkansas for Medical Sciences Disclosures I will be discussing off-label use of drugs Neither I (nor any family member) have any financial interest in pharmaceutical companies or other interested parties Drug reps don t like me Agenda What are the Dementias? Current treatments for dementias Treatment for behavioral symptoms Potential future treatments 1

2 What is Dementia? A syndrome in which there is decline in memory, general cognition, or behavior to the point that it interferes with function. The Dementias Alzheimer Disease Dementia with Lewy Bodies Vascular Dementia Fronto-Temporal Dementia Current Treatments for Dementia 2

3 General Statements about Drug Treatment for AD All approved drugs are symptomatic only All drugs show only modest effects in delaying symptomatic progression No drugs have been found which are neuroprotective No drugs slow disease progression Drug Treatments for Dementia Cholinesterase inhibitors (CEIs) Donepezil (Aricept ) Rivastigmine (Exelon ) Galantamine (Razadyne ) NMDA Antagonists Memantine (Namenda ) Donepezil (Aricept ) Two dose forms, regular and ODT (orally disintegrating tablet) Three doses, 5 mg, 10 mg, 23 mg* Once daily dosing Approved for mild, moderate, or severe AD 3

4 Rivastigmine (Exelon ) Available as oral capsules or transdermal patch Capsules are BID dosing, 1.5 mg, 3 mg, 4.5 mg, and 6 mg Patch: 4.6 mg/24 hrs; 9.5 mg/24hrs, and 13.3 mg/24 hrs Approved for mild, moderate, or severe AD Galantamine (Razadyne ) Immediate-release (4 mg, 8 mg, 12 mg) Twice-daily dosing Extended-release tablets (8 mg, 16 mg, 24 mg) Once-daily dosing Approved for mild or moderate AD CEI Effect Sizes 4

5 Donepezil 23 mg 1467 patients with AD, MMSE 0-20 Already taking 10 mg/day Randomized to 10 mg/day or 23 mg/day for 24 weeks Donepezil 23 mg Farlow et al, Clin Ther 2010, 32(7): Donepezil 23 mg Farlow et al, Clin Ther 2010, 32(7):

6 Rivastigmine Patch Transdermal IDEAL compared rivastigmine patch and capsules against placebo in 1195 patients Target doses: Patch 10, Patch 20, 12 mg/day capsules Capsule group s average dose: 9.7 mg/day Rivastigmine Patch Winblad et al, Neurology 2007;69(Suppl 1):S14-22 High-Dose Rivastigmine Patch 567 patients showing decline in open-label treatment with 9.5 mg/24 hr for wks Randomized to 9.5 mg/24 hr or 13.3 mg/24 hr for 48 weeks Primary endpoints: ADCS-IADL, ADAS-Cog 6

7 High-Dose Rivastigmine Patch Decline on ADAS-Cog Cummings et al, Dement Geriatr Cogn Disord 2012;33: Summary on CEIs Efficacy very similar at high doses, except for rivastigmine transdermal and possibly extendedrelease galantamine Adverse effects similar for all drugs, least for donepezil and galantamine, most for oral rivastigmine Cost is (currently) wildly different One Month Cost of Drugs 7

8 Memantine (Namenda ) 5 mg and 10 mg tablets Target dose is 10 mg BID Approved for moderate or severe AD Memantine for Mod-Sev AD: Add-On to Donepezil 404 patients with moderate-severe AD, already on donepezil, with MMSE 5-14 Randomized to continue donepezil and add memantine 20 mg/day or continue donepezil with placebo, for 24 weeks Primary efficacy measures: SIB, ADCS- ADL19 Memantine for Mod-Sev AD: Add-On to Donepezil SIB Score Tariot et al, JAMA 2004; 291:

9 Memantine for BPSD 369 Patients with AD and BPSD Herrmann et al, Int. Psychogeriatr 2013;25: Memantine for Mild AD Schneider et al performed meta-analysis of mild-moderate AD trials using memantine 3 trials, total of 431 mild (MMSE 20-23) AD patients and 697 moderate (MMSE 10-19) AD patients Memantine for Mild AD Drug-Placebo Difference Schneider et al, Arch Neurol 2011; 68:

10 Donepezil + Memantine 295 Community-dwelling AD patients with modsev dementia (MMSE 5-13) On donepezil 3 months Randomized to: donepezil + memantine, donepezil + placebo, placebo + memantine, placebo + placebo x 1 year Donepezil + Memantine Howard et al, NEJM 2012; 366: Memantine + CEIs: ADNI 402 MCI, 188 AD patients at entry 44% of MCI, 85% of AD patients received CEI 11% of MCI, 46% of AD patients received memantine Cognitive scores followed for two years 10

11 Memantine + CEIs: ADNI Change at 24 Months Schneider et al, Arch Neurol 2011; 68:58-66 Memantine Summary May give small additional benefit in moderatesevere dementia Ineffective in mild dementia and MCI No behavioral benefits in any monotherapy study No neuroprotective effect Vitamins for Dementia? 409 patients with AD randomized to receive folate/b6/b12 supplement or placebo for 18 months Main outcome was ADAS-Cog change 11

12 B Vitamins for AD Aisen et al, JAMA 2008;300: Vitamins for Dementia? 78 AD patients randomized to Vitamin E 800 IU daily/vitamin C 500 mg daily/alpha-lipoic acid 900 mg daily, or Co-enzyme Q mg TID, or placebo CSF markers and cognitive scores followed for 16 weeks Vit E/C/ALA, Co-Q10 for AD Galasko et al, Arch Neurol 2012;69:

13 Behavioral and Psychological Symptoms of Dementia (BPSD) What are BPSD? Non-cognitive symptoms of dementia 95% of persons with dementia will have BPSD at some point during their life More common as dementia progresses Often the cause of significant distress, and may lead directly to institutionalization What are BPSD? Depression Anxiety Apathy Insomnia Psychosis (delusions, hallucinations) Agitation Wandering Wandering 13

14 What causes BPSD? Drugs Intercurrent illness (infections, pain) Neurotransmitter changes Intellectual/cognitive changes Premorbid personality Unobservable behavior (e.g. prejudice) Instinctual behavior (e.g. defensiveness) Triggers of BPSD Drugs (esp. anticholinergic agents, opioids) Intercurrent illness (e.g., UTI) Pain Caregiver interactions Drugs Proven Effective for BPSD None 14

15 Drugs Used for BPSD Antipsychotics Benzodiazepines Antidepressants Anticonvulsants Cholinesterase inhibitors Divalproex for BPSD Tariot et al studied divalproex vs. placebo in 153 demented nursing home patients with agitation Randomized to divalproex 750 mg/day vs. placebo, for six weeks Primary outcomes: BPRS, CGIC, CMAI Divalproex for BPSD Tariot et al, Am J Geriatr Psychiatry 2005; 13:

16 Chronic Divalproex in AD 313 patients with mild-moderate Alzheimer disease randomized to divalproex or placebo for 24 months Annual percent changes in brain volume determined by MRI for whole brain, ventricle size, and hippocampal volume Clinical outcome measures determined at sixmonth intervals Chronic Divalproex in AD Fleisher et al, Neurology 2011; 77: Antipsychotics for BPSD 421 outpatients with AD and BPSD randomized to olanzapine, quetiapine, risperidone, or placebo for 36 weeks Primary outcomes: time to discontinue, change on CGIC 16

17 Antipsychotics for BPSD Schneider et al, N Engl J Med 2006; 355: Antipsychotics for BPSD Adverse Effects Schneider et al, N Engl J Med 2006; 355: Withdrawal of Antipsychotics: DART-AD 102 patients with AD treated with antipscyhotics for at least 3 months Randomized to continue treatment or switch to placebo for 12 months Primary outcome: SIB change Followed for another year 17

18 Withdrawal of Antipsychotics: DART-AD Probability of Survival Ballard et al, Lancet Neurol 2009; 8: Non-Pharmacological Management of BPSD Caregiver education Environmental modification Physical exercise Music Future Drugs for AD? 18

19 New Drug Targets in AD Deep Brain Stimulation Immunomodulators Anti-amyloid therapies (?) Anti-tau therapies 19