Transcript Pharmacy Medication Update: Dementia

Pharmacy Medication
Update: Dementia
Megan J. Ehret, PharmD, MS, BCPP
Associate Professor
University of Connecticut
Objectives
• 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.
Prevalence/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
Risk Factors
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Degeneration of cholinergic neurons
Cortical atrophy
Presence of neurofibrillary tangles
Accumulation of neuritic plaques
Increasing age
Down Syndrome
Head trauma
Depression
Lower educational level
DSM 5 Diagnostic CriteriaAlzheimer’s 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
Signs 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
Objective 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 (<65)
• MRI- Cortical atrophy
• MMSE- 3-4 point loss
• MoCA- Rapid screening instrument for mild cognitive
dysfunction
• Total score is 30; >26 is normal
• Genetic Testing- APOE4, presenilins 1 and 2
• Controversial
Alzheimer’s Association/Society of Nuclear Medicine and
Molecular Imagining 2013
MINI-MENTAL STATE EXAM (MMSE)
Other Rating Scales
• Alzheimer’s Disease Assessment Scale (ADAS)
• Evaluate the severity of dysfunction in cognition, and noncognitive behaviors over time
• Severe Impairment Battery
• Used to detect cognitive function in severe dementia
• Neuropsychiatric Inventory
• Assesses behavioral problems in dementia
• Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD)
• Assess behavioral symptoms and measure outcomes in treatment
studies
TREATMENT GUIDELINES
NON-PHARMACOLOGICAL TREATMENT
Therapies and Plans
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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
PHARMACOLOGICAL TREATMENT
General 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
Cholinesterase 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
Donepezil (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 >3 months
• Moderate to severe: same as above
• 23mg greater benefit in cognition, but not global functioning;
higher rates of GI adverse events
Donepezil
• 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
Rivastigmine (Exelon)®
• Treatment of mild, moderate, and severe AD, treatment of
Parkinson’s 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
Galantamine (Razadyne)®
• Mild to moderate AD
• IR or solution: 4mg twice daily for 4 weeks, then 8mg twice
daily for >4 weeks, if tolerated than 12mg twice daily
• ER: 8mg once daily for 4 weeks, then 16mg daily for >4 weeks,
if tolerated than 24mg daily
• Same warnings/precautions
Memantine (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
Memantine
• 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
Duration 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
DIETARY SUPPLEMENTS
Vitamin E
• Late 1990’s: recommended due to it’s 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
Nutraceuticals/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
Nutraceuticals/Supplements
• Omega-3: large, prospective, placebo-controlled trial in AD
subjects
• Primary study endpoints: negative
Medical 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
Behavioral and
Psychological
Symptoms in
Dementia
Diagnostic Criteria
• No specific diagnostic criteria
• Could be met for impulse control disorders, obsessive-control
disorder, and bipolar disorder
Signs 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
Risk 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,
Huntington’s disease more likely to experience BPSD
symptoms
Clinical 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
Treatment 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
Non-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:
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Environmental modifications
Providing activities
Electronic alarms
Safety Plans
Non-Pharmacological
Treatment
• Sleep disturbances
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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:
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Music therapy
Light therapy
Massage therapy
Multisensory Stimulation
PHARMACOLOGICAL TREATMENT
Antipsychotics
• 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
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Olanzapine
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+/-
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Quetiapine
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+/-
Risperidone
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++
SHIFT IN RISK PERCEPTION
OF ANTIPSYCHOTICS
Current Medical Realities
Past Areas of
Concern
Weight
Gain
Tardive
Dyskinesia
Sedation
Insulin
Resistance
CHD
Prolactin
Hyperlipidemia
Diabetes
Weight Gain
Prolactin
TD
Hyperlipidemia
Insulin
Resistance
Sedation
Coronary Heart
Disease
SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
CLOZ
RIS
OLZ
QUE
ZIP
ARIP
Low Blood Pressure
+++
+
+/0
++
0/+
0/+
Dry mouth,
constipation
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0
+/++
0
0
0
0
+/++
0/+
0
+/0
0
+++
+/-
++
+++
0
0
++++
+
++++
++
-/+
-/+
Lipids
+++
+
+++
++
0
0
Blood sugar
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+
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++
0
0
Tremors, stiffness,
endocrine problems
Sedation
Weight gain
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
WEIGHT GAIN ATYPICAL
ANTIPSYCHOTICS
Data for Package Labels
LIPID ABNORMALITIES
Aripiprazole,
Ziprasidone,
Paliperidone
Risperidone
Quetiapine
Olanzpine,
Clozapine
Data from product labels
ADA/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)
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+/-
+/-
Quetiapine (Seroquel)
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+/-
+
Aripiprazole* (Abilify)
+/-
-
-
Ziprasidone* (Geodon)
+/-
-
-
+ = increase effect; - = no effect; D = discrepant
results. *Newer drugs with limited long-term data.
ADA/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
BP
X
X
X
Fasting
Glucose
X
X
X
X
Waist
X
Circumf
erence
Fasting
Lipid
X
X
X
X
Antipsychotics
• 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
Adverse Events- Black Box
Warning
WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY AND
ANTIDEPRESSANT DRUGS
Black 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
Risk 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
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Hypertension
Atrial fibrillation
Elevated cholesterol
Coronary Heart Disease
Sleep Apnea
• • Lifestyle
• Smoking
• Obesity
• Excessive Alcohol
Source: National Stroke Association
Antidepressants
• Mixed studies
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Trazodone > haloperidol
Fluoxetine = haloperidol
Sertraline > placebo; agitation
Citalopram- mixed studies
Fluvoxamine + perphenazine > perphenazine alone
• All studies showed similar adverse event profiles; studies were
relatively short in duration, lacked randomization, and small
number of pts.
Mood 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
Cholinesterase Inhibitors
• AChE inhibitors can improve BPSD
• If AChE inhibitors are tapered: Worsening of BPSD symptoms
can occur
Memantine
• Naturalistic, small, open-labeled studies
• Modest improvement in BPSD and overall good tolerability
General 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:
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Symptom relief
Reduced care giver burden
Increase quality of life
Avoidance of unacceptable risks
Improved functional status
Risk reduction and cost of care
CONCLUSION
Key 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