Title: Pharmacy Medication Update: Dementia
1Pharmacy Medication Update Dementia
- Megan J. Ehret, PharmD, MS, BCPP
- Associate Professor University of Connecticut
2Objectives
- Describe the clinical presentation and diagnostic
criteria for dementia and mild cognitive
impairment. - Describe the treatment guidelines and landmark
clinical trials for the treatment of dementia. - Select an evidenced-based drug therapy regimen
for stabilizing symptoms of dementia. - Identify essential information to discuss during
patient education about the drug therapy of
dementia.
3Prevalence/Clinical Course
- 2-4 of population over 65 years old
- Increases with age
- AD accounts for 60 of all dementias in the
elderly - Gradual onset and is slowly progressive
- Cognition is affected early on with impairment in
motor, behavioral, and sensory functioning
occurring later - Time to onset to death 8-10 years
- Loss of 3-4 points/year on MMSE
4Risk Factors
- Degeneration of cholinergic neurons
- Cortical atrophy
- Presence of neurofibrillary tangles
- Accumulation of neuritic plaques
- Increasing age
- Down Syndrome
- Head trauma
- Depression
- Lower educational level
5DSM 5 Diagnostic Criteria- Alzheimers Disease
- Must meet criteria for major or mild
neurocognitive disorder - Cognitive decline from baseline in 1/5
Attention, Executive Function, Learning and
Memory, Language, Perceptual-Motor, or Social
Cognition) - Cognitive impairment is slow and gradual
DSM 5 2013
6Signs and Symptoms of AD
- Loss of early memory- progresses to loss of
long-term memory - Final stages gait abnormalities, motor
disturbances, decline in communication abilities,
dependent on others
7Objective Signs of AD
- Amyloid Beta Peptide-
- Imagining is appropriate in pts. with persistent
mild cognitive impairment, pts. with core AD with
atypical or unusual course, and progressive
dementia with early age onset (lt65) - MRI- Cortical atrophy
- MMSE- 3-4 point loss
- MoCA- Rapid screening instrument for mild
cognitive dysfunction - Total score is 30 gt26 is normal
- Genetic Testing- APOE4, presenilins 1 and 2
- Controversial
Alzheimers Association/Society of Nuclear
Medicine and Molecular Imagining 2013
8Mini-Mental State Exam (MMSE)
9(No Transcript)
10Other Rating Scales
- Alzheimers Disease Assessment Scale (ADAS)
- Evaluate the severity of dysfunction in
cognition, and non-cognitive behaviors over time - Severe Impairment Battery
- Used to detect cognitive function in severe
dementia - Neuropsychiatric Inventory
- Assesses behavioral problems in dementia
- Behavioral Pathology in Alzheimers Disease
(BEHAVE-AD) - Assess behavioral symptoms and measure outcomes
in treatment studies
11Treatment Guidelines
12Non-Pharmacological Treatment
13Therapies and Plans
- Increase enjoyable activities
- Redirect and refocus
- Increase social activities for the patient
- Eliminate sources of conflict and frustration
- Assess the pt.'s caregiver for signs and symptoms
of depression
14Pharmacological Treatment
15General Approach
- First line treatment Cholinesterase Inhibitors,
memantine can also be used in moderate to severe
dementia - Second line treatment addition of memantine to
cholinesterase inhibitors - Medications have been shown to only temporarily
slow the progression of the disease - Switching between cholinesterase inhibitors is
well tolerated and provides therapeutic benefit
if previous agent lacked efficacy or tolerability
16Cholinesterase Inhibitors
- Inhibit the cholinesterase (AChE)
- Enzyme responsible for hydrolysis of
acetylcholine - Elevates concentrations of acetylcholine for
synaptic transmission in the CNS - Thought to improve memory and cognition
17Donepezil (Aricept)
- Treatment of mild to severe AD
- Mild to moderate 5mg daily may increase to 10mg
daily after 4-6 weeks, may increase to 23mg daily
after gt3 months - Moderate to severe same as above
- 23mg greater benefit in cognition, but not global
functioning higher rates of GI adverse events
18Donepezil
- Warnings/Precautions
- Peptic ulcer disease and GI bleeding monitor for
GI bleeding especially in those who are higher
risk - Weight Loss
- Adverse Events
- Nausea, vomiting, and diarrhea administer
medication with food reduce dose - Vagotonic effects slows conduction through SA
and AV nodes resulting in bradycardia - Insomnia Give medication in morning
19Rivastigmine (Exelon)
- Treatment of mild, moderate, and severe AD,
treatment of Parkinsons Disease Dementia - 1.5mg twice daily, may increase by 3mg daily
every 2 weeks based on tolerability max dose
6mg twice daily - Patch 4.6mg/24hrs daily, may titrate to
9.5mg/24hrs, then to 13.3mg/24hrs (verify that
old patch has been removed prior to applying a
new patch) - If dosing is interrupted for more than 3 days,
pt. needs to be restarted on initial dose - Same warnings/precautions
20Galantamine (Razadyne)
- Mild to moderate AD
- IR or solution 4mg twice daily for 4 weeks,
then 8mg twice daily for gt4 weeks, if tolerated
than 12mg twice daily - ER 8mg once daily for 4 weeks, then 16mg daily
for gt4 weeks, if tolerated than 24mg daily - Same warnings/precautions
21Memantine (Namenda)
- Treatment of moderate to severe AD
- Low to moderate, uncompetitive,
N-methyl-D-aspartate (NMDA) receptor antagonist - Glutamate is an amino acid which may contribute
to the pathogenesis of AD by over-stimulating the
NMDA receptor - Short acting 5mg/day for 1 week, 5 mg twice
daily for 1 week, 5 mg in the AM and 10mg in the
PM for one week, then 10mg twice daily - Long acting 7mg/day for 1 week, 14mg/day for 1
week, 21mg/day for 1 week, then 28mg/day
22Memantine
- Use with caution in patients with seizure
disorders, hepatic impairment, or mild-moderate
renal impairment - Most common adverse effects dizziness, headache,
hallucinations, insomnia, confusion, and
constipation
23Duration of Therapy
- Controversial
- If no efficacy seen within 3 months of therapy at
maximum dose, switching should be attempted - Both immediate switching and a 7-14 day wash our
has been done good tolerability and efficacy
24Dietary Supplements
25Vitamin E
- Late 1990s recommended due to its antioxidant
effect - Decrease the accumulation of free radicals
- Evidence on prevention is mixed
- Adverse effects impaired hemostatis, fatigue,
nausea, diarrhea, abdominal pains, falls - Meta-analysis high-dose can increase mortality
- Not recommended
26Nutraceuticals/Supplements
- Ginkgo Biloba increase blood flow, decrease
blood viscosity, antagonize platelet-activating
factor receptors, increase anoxia tolerance,
inhibit monoamine oxidase, antioxidant - Side effects nausea, vomiting, diarrhea,
headaches, dizziness, palpitations, restlessness,
weakness
27Nutraceuticals/Supplements
- Omega-3 large, prospective, placebo-controlled
trial in AD subjects - Primary study endpoints negative
28Medical Food
- Axona
- Modification of medium-chain triglyceride
formulation - Contains mixtures of C5-C12 fatty acids
- Converted to betahydroxybutyrate oxidative
phosphorylation substrate by neuron mitochondria
supports brain bioenergetics - Supported by trials of 40 mg /day for 45 days
29Behavioral and Psychological Symptoms in Dementia
30Diagnostic Criteria
- No specific diagnostic criteria
- Could be met for impulse control disorders,
obsessive-control disorder, and bipolar disorder
31Signs and Symptoms
- Physically aggressive agitation pushing, biting,
kicking, spitting - Physically nonaggressive behavior pacing,
wondering, inappropriate voiding, undressing - Verbally aggressive behavior screaming, yelling,
cursing - Verbally nonaggressive behavior requesting
attention, repetitively calling out - Most common apathy, delusions,
aggression/agitation, anxiety, psychomotor
disturbance, irritability, sleep/wake
disturbance, depression, disinhibition,
hallucinations
32Risk Factors/ Prevalence
- Can occur in up to 60 of demented patients in
community dwelling and 80 in long term care
facilities - 1/3 of mildly-impaired dementia pts., 2/3 of
moderate impairment pts. - After 5 yrs. w/dementia 90 with have one BPSD
- Risk of developing varies
- Fronto-temporal dementias, LBD, vascular
dementia, Huntingtons disease more likely to
experience BPSD symptoms
33Clinical Course
- Depression, apathy, social withdrawal can be
noticed several years before diagnosis of
dementia - As dementia progresses frequency and intensity
of agitation and aggression worsen - At end stages of dementia, episodes of agitation
and aggression may diminish
34Treatment Guidelines
- Rule out psychological and psychosocial causes
for change in behavior - Elimination of causative factors and psychosocial
intervention are treatments of choice - Medication therapy can be recommended
- Hyperactivity syndrome and psychosis
risperidone, olanzapine, quetiapine,
aripiprazole, citalopram, trazodone, and
carbamazepine - Valproic acid and lithium should be avoided lack
of evidence
World Federation of Societies of Biological
Psychiatry 2011
35Non-Pharmacological Treatment
- Treatment of choice
- Recognizing, redirecting, and diffusing the
neuropsychiatric behavior - Intervene early
- Stay calm- avoid arguing or trying to reason with
the patient - Wondering
- Environmental modifications
- Providing activities
- Electronic alarms
- Safety Plans
36Non-Pharmacological Treatment
- Sleep disturbances
- Strive for consistent bedtimes
- Limit daytime napping
- Restrict use of alcohol and caffeinated beverages
- Reduce light levels, changes in temperature, and
nighttime noises - Avoid changes in daily routines
- Other therapies
- Music therapy
- Light therapy
- Massage therapy
- Multisensory Stimulation
37Pharmacological Treatment
38Antipsychotics
- Evidence is high to support the use of
antipsychotics for BPSD - Second Generation Antipsychotics
- Over 37 trials risperidone, olanzapine,
quetiapine, aripiprazole - Limited to no data clozapine, ziprasidone,
paliperidone, iloperidone, asenapine, lurasidone - Range 2 days to 1 year endpoints were not
standardized
Dementia Psychosis Agitation
Aripiprazole
Olanzapine /-
Quetiapine /- /-
Risperidone
39SHIFT IN RISK PERCEPTION OF ANTIPSYCHOTICS
Current Medical Realities
Past Areas of Concern
Diabetes
TD
Weight Gain
Prolactin
Tardive Dyskinesia
Hyperlipidemia
Insulin Resistance
Sedation
Weight Gain
Insulin Resistance
Hyper- lipidemia
Coronary Heart Disease
Sedation
CHD
Prolactin
40SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
CLOZ RIS OLZ QUE
ZIP ARIP
0/
0/
/0
Low Blood Pressure
Dry mouth, constipation
0
0
0
/
0
Tremors, stiffness, endocrine problems
0
/0
0
0/
/
0
0
0
/-
Sedation
-/
-/
Weight gain
0
0
Lipids
0
0
Blood sugar
CLOZ clozapine RIS risperidone OLZ
olanzapine QUET quetiapine ZIP ziprasidone
ARIP aripiprazole Adapted from Nasrallah HA,
Mulvihill T. Ann Clin Psychiatry.
2001(Dec)13(4)215-227
41WEIGHT GAIN ATYPICAL ANTIPSYCHOTICS
Data for Package Labels
42LIPID ABNORMALITIES
Data from product labels
43ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC
DRUGS AND OBESITY AND DIABETES SUMMARY
Drug Weight Gain Risk for Diabetes Worsening Lipid Profile
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Risperidone (Risperdal) Paliperidone (Invega) /- /-
Quetiapine (Seroquel) /-
Aripiprazole (Abilify) /- - -
Ziprasidone (Geodon) /- - -
increase effect - no effect D
discrepant results. Newer drugs with limited
long-term data.
44ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC
DRUGS AND OBESITY AND DIABETES SUMMARY
Baseline 4 wk 8 wk 12 wk Quarterly Annually Q5yr
Weight X X X X X X
BP X X X
Fasting Glucose X X X
Waist Circumference X X
Fasting Lipid X X X
45Antipsychotics
- Typical Antipsychotics
- 5 clinical trials comparing the efficacy of
haloperidol to a SGA - Average haloperidol dose per day 2-4 mg
- No difference in efficacy with haloperidol versus
a SGA
46Adverse Events- Black Box Warning
- WARNINGS INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY
AND ANTIDEPRESSANT DRUGS
47Black Box Warning Cerebrovascular Accidents
- Cerebrovascular Adverse Events, Including Stroke,
in Elderly Patients with Dementia-Related
Psychosis - In placebo-controlled trials with risperidone,
aripiprazole and olanzapine in elderly subjects
with dementia, there was a higher incidence of
cerebrovascular adverse events (cerebrovascular
accidents and transient ischemic attacks)
including fatalities compared to placebo-treated
subjects
48Risk Factors for Stroke
- Beyond Control
- Advancing age, risk doubles after age 55 years
- Male gender
- African-American
- Family history of diabetes
- Family history of stroke or
- TIA
- May be altered
- Medical
- Hypertension
- Atrial fibrillation
- Elevated cholesterol
- Coronary Heart Disease
- Sleep Apnea
- Lifestyle
- Smoking
- Obesity
- Excessive Alcohol
Source National Stroke Association
49Antidepressants
- Mixed studies
- Trazodone gt haloperidol
- Fluoxetine haloperidol
- Sertraline gt placebo agitation
- Citalopram- mixed studies
- Fluvoxamine perphenazine gt perphenazine alone
- All studies showed similar adverse event
profiles studies were relatively short in
duration, lacked randomization, and small number
of pts.
50Mood Stabilizers
- One meta-analysis and 5 RTCs did not support
efficacy of valproic acid in treating
aggression, agitation, or psychosis - Carbamazepine one meta-analysis and 3 trials
efficacy in treatment of agitation and aggression
compared to placebo placebo was better tolerated - Oxcarbazepine failed trial
- Lamotrigine, gabapentin, topiramate case reports
or case series
51Cholinesterase Inhibitors
- AChE inhibitors can improve BPSD
- If AChE inhibitors are tapered Worsening of
BPSD symptoms can occur
52Memantine
- Naturalistic, small, open-labeled studies
- Modest improvement in BPSD and overall good
tolerability
53General Recommendations
- Do not discontinue or change the dose of
treatment without discussion with health care
provider - Reduce/eliminate risk for strokes and diabetes
- What matters most
- Symptom relief
- Reduced care giver burden
- Increase quality of life
- Avoidance of unacceptable risks
- Improved functional status
- Risk reduction and cost of care
54Conclusion
55Key Concepts
- Etiology is unknown
- Current pharmacotherapy neither cures or arrests
the pathology - Pharmacotherapy focuses on 3 areas
- Cognition
- Behavioral and psychiatric symptoms
- Functional ability
- Pharmacotherapy may reduce the total cost of
treating AD by delaying cognitive decline and
time to nursing home placement