Medication Therapies in the Treatment of Alzheimer’s Disease

Majid Barekatain, M.D.,Associate Professor of Psychiatry

NeuropsychiatristIsfahan University of Medical Sciences

27-28 Ordibehesht 1392April 16-17, 2013

LET’S HAVE LOOK!

• 1. Cholinergic hypothesis andcholinesterase 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

Raskind et al. Neurology. 2000.

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/galantamineand not statistically different from baseline.

Improvement

Deterioration

0 3 6 9 12

Mean (± SE)

Change From

Baseline in

ADAS-cogScore

–4

–3

–2

–1

0

1

2

3

45

6

7

Months

Placebo/galantamine 24 mg (n = 213/135)

*

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

Selkoe DJ et al. JAMA. 2000;283:1615-1617.

-amyloid precursor protein

-secretase

A peptide

-secretase

Extracellular space

TM Cytoplasm

COOHNH2

Clinical Criteria for Definite, Probable, and Possible Alzheimer’s Diaease

Definite Alzheimer’s Disease:1. Clinical criteria for probable AD2. 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 DATTreatment Mechanism of Action

Secretase modulation [OM00-3]DR9

DAPTBryostatin

Beta secretase inhibitorGamma secretase inhibitorPKC activator, alpha-secretase stimulator

AB immunotherapy Pre-aggregated AB1-42+adjuvant Anti-AB antibodies

Active immunization

Passive immunization Neurotransmitter modulation

NicotineAF267B

PEC

Huperzine A

Cholinergic stimulationSelective M1 receptor agonistButyrylcholinesterase inhibitorCholinesterase inhibition

Treatment Strategies to Lower AB/Plaque Load in DATTreatment Mechanism of Action

Anti-inflammatory NSAIDS

Vitamin ELipopolysaccharide

Anti-inflammatory, gamma secretase inhibition?Anti-oxidativeImmune system activation

Miscellaneous CerebrolysinInsulin-like growth factor 1 (IGF-1)Epigallocatechin-3-gallate (green tea)Rosiglitazone

Neurotrophic Increased AB clearance Possible alpha-secretase stimulationIncreased insulin sensitivity? Cortisol lowering?

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