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 cholinesterase inhibitors in the treatment of dementias 2. Glutamate hypothesis and memantine 3. Treatment of behavioral symptoms 4. Prevention 5. Future Directions

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

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

Characteristics of Drugs for the Treatment of AD Donepezil Galantamine Rivastigmine Memantine 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 BuChE Non-competitive NMDA- allosteric nictotine receptor modulation inhibition receptor antagonist CYP450 metabolism Yes (CYP2D6 & CYP3A4) Yes (CYP2D6 & CYP3A4) No, hydrolysed by esterases No Half-life Long (70 hours) Short (7- 8 hours) Very short (~1 hour) Long (60 to 100 hours) Doses per day One Two IR or One ER Two Two Given with food Irrelevant Recommended Yes (increased bio-availability) Irrelevant Initial Dose 5mg/day 8mg/day 3mg/day 5mg/day Dose escalation 4-6 weeks every 4 weeks every 2-4 weeks every week Recommended clinically 10 mg/day 16-24mg/day 6-12mg/day 20mg/day efficient dose Adapted from Blennow, et al. Alzheimer’s Disease. Lancet 2006; 368: 387-403.

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

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)

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

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

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

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

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

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)

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% galantamine groupwere improved/stable vs 59% in placebo group AD-CVD subgroup similar effects to prior trials with AD patients

Galantamine and 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)

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

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)

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

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 donepezil vs placebo plus donepezil: memantine group had significant benefit in comparison

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

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

Treatment of behavioral Symptoms & Nonpharmacological Treatment Oh! Sorry! This not the case in this lecture!

Future directions to AD treatment

Normal Mild Cognitive Impairment Dementia

Early diagnosis: Impact on treatment Amyloid plaques 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

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

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)

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

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

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

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

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

Treatment Strategies to Lower AB/Plaque Load in DAT Mechanism of Action Secretase modulation [OM00-3]DR9 DAPT Bryostatin Beta secretase inhibitor Gamma secretase inhibitor PKC activator, alpha-secretase stimulator AB immunotherapy Pre-aggregated AB1-42+adjuvant Anti-AB antibodies Active immunization Passive immunization Neurotransmitter modulation Nicotine AF267B PEC Huperzine A Cholinergic stimulation Selective M1 receptor agonist Butyrylcholinesterase inhibitor Cholinesterase inhibition

Treatment Strategies to Lower AB/Plaque Load in DAT Mechanism of Action Anti-inflammatory NSAIDS Vitamin E Lipopolysaccharide Anti-inflammatory, gamma secretase inhibition? Anti-oxidative Immune system activation Miscellaneous Cerebrolysin Insulin-like growth factor 1 (IGF-1) Epigallocatechin-3-gallate (green tea) Rosiglitazone Neurotrophic Increased AB clearance   Possible alpha-secretase stimulation Increased insulin sensitivity? Cortisol lowering? Treatment Strategies to Lower AB/Plaque Load in DAT Treatment Mechanism of Action Secretase modulation [OM00-3]DR9 DAPT Bryostatin Beta secretase inhibitor Gamma secretase inhibitor PKC activator, alpha-secretase stimulator AB immunotherapy Pre-aggregated AB1-42+adjuvant Anti-AB antibodies Active immunization Passive immunization Neurotransmitter modulation Nicotine AF267B PEC Huperzine A Cholinergic stimulation Selective M1 receptor agonist Butyrylcholinesterase inhibitor Cholinesterase inhibition Anti-inflammatory NSAIDS Vitamin E Lipopolysaccharide Anti-inflammatory, gamma secretase inhibition? Anti-oxidative Immune system activation Miscellaneous Cerebrolysin insulin-like growth factor 1 (IGF-1) Epigallocatechin-3-gallate (green tea) Rosiglitazone Neurotrophic Increased AB clearance Possible alpha-secretase stimulation Increased insulin sensitivity? Cortisol lowering?

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