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Medication Therapies in the Treatment of Alzheimer’s Disease

Medication Therapies in the Treatment of Alzheimer’s Disease. Majid Barekatain , M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht 1392 April 16-17, 2013. LET’S HAVE LOOK!. 1. Cholinergic hypothesis and

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Medication Therapies in the Treatment of Alzheimer’s Disease

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  1. Medication Therapies in the Treatment of Alzheimer’s Disease MajidBarekatain, M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht 1392 April 16-17, 2013

  2. LET’S HAVE LOOK! • 1. Cholinergic hypothesis and cholinesterase inhibitors in the treatment of dementias • 2. Glutamate hypothesis and memantine • 3. Treatment of behavioral symptoms • 4. Prevention • 5. Future Directions

  3. The Cholinergic Hypothesis • Depletion of acetylcholine and nicotinic receptors thought to occur early and relate to memory impairment with AD • Focus on AD treatment with Acetylcholinesterase inhibitors: Recommended as first line treatment for patients with mild to moderate AD

  4. Cholinesterase Inhibitors • Trials in patients with mild to moderate disease (10-24 on MMSE) • On average these drugs seem to stabilize cognitive function and activities of daily living and may have benefits with QOL and behavioral disturbances for at least one year • Side Effects: GI problems

  5. Characteristics of Drugs for the Treatment of AD DonepezilGalantamineRivastigmineMemantine Indication Mild to moderate AD Mild to moderate AD Mild to moderate AD Moderate to severe AD Mode of action Selective AChE inhibition Selective AChE inhibition & Slowly reversible AChE and BuChENon-competitive NMDA- allostericnictotine receptor modulation inhibition receptor antagonist CYP450 metabolismYes (CYP2D6 & CYP3A4)Yes (CYP2D6 & CYP3A4)No, hydrolysed by esterasesNo Half-lifeLong (70 hours)Short (7- 8 hours)Very short (~1 hour)Long (60 to 100 hours) Doses per dayOneTwo IR or One ERTwoTwo Given with foodIrrelevant Recommended Yes (increased bio-availability) Irrelevant Initial Dose5mg/day 8mg/day3mg/day5mg/day Dose escalation4-6 weeksevery 4 weeksevery 2-4 weeksevery week Recommended clinically10 mg/day16-24mg/day6-12mg/day 20mg/day efficient dose Adapted from Blennow, et al. Alzheimer’s Disease. Lancet 2006; 368: 387-403.

  6. Donepezil (Aricept) • Three large RCT demonstrate modest effectiveness in stabilizing cognitive function • Well tolerated (no difference in adverse events compared to placebo) • Not hepatoxic, no significant drug-drug interactions • Single bedtime dose: start 5 mg, increase to 10 mg after 4-6 weeks • Most common side effects: sleep disturbance, GI

  7. Rivastigmine • May have increased selectivity for hippocampus and neocortex (areas affected by AD) • Modestly effective in treatment of mild to moderate AD (but only at high doses of 6-12 mg/day) • Recommended starting dose: 1.5 mg BID with breakfast and dinner • Minimize GI side effects with 4-6 week titration, increasing to 3 mg BID, 4.5 mg BID, 6 mg BID • More GI side effects, weight loss (dose dependent)

  8. Galantamine • Potential second mechanism: modulator at nicotinic cholinergic receptor • Three large RCTs indicate effectiveness in mild to moderate AD (same degree as other agents) at doses of 16, 24, 32 mg/day • Open label 6 month extension of US trial: Possible disease modifying effect • Starting dose: 4mg BID with meals, increase by 4mg BID every 4-6 weeks

  9. Cholinesterase inhibitors in moderate to severe dementia • RCT of donepezilvs placebo: 24 week international trial of 290 patients (MMSE 5-18) • 63 % of donepezil treated patients were stable/better vs 42% in placebo group

  10. Comparison of Cholinesterase Inhibitors… • Cochrane Dementia Group: 3 systematic reviews on efficacy of donepezil, rivastigmine, and galantamine • Each drug seems to have similar treatment effect at 6 months on global and cognitive rating scales • No double blind head to head trial

  11. Double-blind Open-Extension Improvement –4 –3 –2 Mean (± SE)Change From Baseline inADAS-cogScore –1 * 0 1 2 3 4 5 6 7 Deterioration 0 3 6 9 12 Months galantamine 24 mg/galantamine 24 mg(n = 212/116) *P < .05 vs placebo/galantamine and not statistically different from baseline. Placebo/galantamine 24 mg (n = 213/135) Historical placebo group Galantamine: Mean Change From Baseline in ADAS-cog Raskind et al. Neurology.2000.

  12. Cholinesterase Inhibitors and AD: • Approved for treatment of mild to moderate AD • Probably effective in treatment of more severe AD • Goal: stabilization (not miracle drugs) • Delay in nursing home placement, decline in ADLS • Probably benefits behavioral and functional status as well • Data suggest no big difference in efficacy among the 3 agents, although donepezil is easier to titrate and better tolerated

  13. Cholinesterase Inhibitors and Other Dementias… • Vascular dementia and Dementia with Lewy Bodies each account for 10-15% cases • Prominence of mixed pathology (especially vascular and AD in older population)

  14. Galantamine: Vascular and AD/Vascular Dementia • Placebo controlled trial, 6 months, 592 patients • 50% in study had AD plus radiological evidence of CVD, 41% had probable vascular dementia, 9% indeterminant • Results for the whole group were similar to previous trials in typical AD : 74% galantaminegroupwere improved/stable vs 59% in placebo group • AD-CVD subgroup similar effects to prior trials with AD patients

  15. Galantamineand Vascular Dementia • Patients with typical features of AD mixed with features of CVD or evidence of CVD on radiological tests seem to respond similarly to patients with AD alone • Subgroup with CVD alone does better over long term (even with placebo) • Surprise: patients with what appears to be only CVD also seem to have some benefit (these patients not traditionally felt to have specific degeneration of cortical cholinergic pathways)

  16. Cholinesterase Inhibitors and Other dementias • Lewy Body Dementia: may respond even more than AD patients • Frontal Lobe Dementia: often respond adversely to cholinesterase inhibitors with increased agitation and insomnia

  17. Memantine • NMDA (glutamate) receptor activation thought to be involved in neurodegeneration • Memantine: NMDA antagonist aimed at protecting neurons from glutamate mediated excitotoxicity • Approved in Europe in 2002 for treatment of severe AD (MMSE 3-14)

  18. Memantine • Randomized, double blind, placebo controlled study: 166 patients with severe dementia (AD and vascular, MMSE <10) • Cognitive and Behavioral Rating Scale significantly better with treatment, regardless of dementia type • Other European studies have looked at treatment for moderate-severe Vascular Dementia, demonstrating similar efficacy

  19. Memantine • 28 week RCT of 252 patients with severe AD (MMSE 3-14) in NEJM: memantine associated with less deterioration in cognitive and functional measures than placebo • Problem: small numbers, high drop out rate • Preliminary study: 400 patients with severe AD, 6 months RCT of memantine plus donepezilvs placebo plus donepezil: memantine group had significant benefit in comparison

  20. Cognitive Rx in AD • Efficacy of Cholinesterase Inhibitors • Donepezil, Rivastigmine, Galantamine • All of them work • Up to 80% of patients show no decline after 6 months of Rx and 50% no decline after 1 year • Need to give for at least 6 to 12 months to determine utility • Side effects: weight loss, diarrhea, nausea • Always titrate to highest dose

  21. Cognitive Rx in AD • NMDA Antagonists: Memantine • N-methyl-D-aspartate (NMDA) antagonists potentially prevent neuronal injury by reducing excitatory amino acid toxicity by glutamate • Side effects include headache, dizziness, fatigue, confusion • Titrate to 10 mg bid

  22. Treatment of behavioral Symptoms & NonpharmacologicalTreatment • Oh! Sorry! This not the case in this lecture!

  23. Future directions to AD treatment

  24. Normal Mild Cognitive Impairment Dementia

  25. Early diagnosis:Impact on treatment • Amyloidplaques probably start 20 years before clinical symptoms of AD • 16 million Americans projected to have AD by 2050 • Current AD meds work better if started earlier • Disease modifying agents are coming • Preventing or delaying AD could save billions of dollars and lead to improved quality of life for patients and families

  26. -amyloid precursor protein Extracellular space TM Cytoplasm A peptide COOH NH2 -secretase -secretase Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A Peptide Selkoe DJ et al. JAMA. 2000;283:1615-1617.

  27. Clinical Criteria for Definite, Probable, and Possible Alzheimer’s Diaease Definite Alzheimer’s Disease: 1. Clinical criteria for probable AD 2. Histopathological evidence of AD (autopsy or biopsy)

  28. Probable Alzheimer’s Disease: 1. Dementia established by clinical examination and documented by mental status exam 2. Dementia confirmed by neuropsychological testing 3. Deficits in two or more areas of cognition 4. Progressive worsening of memory and other cognitive functions 5. No disturbance of consciousness 6. Absence of systemic disorders or other brain diseases capable of producing a dementia

  29. Possible Alzheimer’s Disease: 1. Presence of a systemic disorder or other brain disease capable of producing dementia but not thought to be the cause of the dementia 2. Gradually progressive decline in a single intellectual function in the absence of any other identifiable cause

  30. Unlikely Alzheimer’s Disease 1. Sudden or apoplectic onset 2. Focal neurologic signs 3. Seizures or gait disturbance early in the course of the illness

  31. Immunization: Bapineuzumab (Phase III) • Passive immunotherapy • Monoclonal antibody against beta-amyloid peptide administered intravenously (IV) • Binds and removes beta-amyloid peptide that accumulates in plaques

  32. Future Rx Strategies • Anti-amyloid strategies • Combined drug treatments • Tau interventions (methylene blue: Phase II trials - disrupts tau aggregation) • Gene therapy • Brain transplants

  33. از توجه شما متشكرم

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