Pharmacy Medication Update: Dementia

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Pharmacy Medication Update Dementia

• Megan J. Ehret, PharmD, MS, BCPP
• Associate Professor University of Connecticut

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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.

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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

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Risk 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

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DSM 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
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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

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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 (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
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Mini-Mental State Exam (MMSE)
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(No Transcript)
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Other 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

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Treatment Guidelines
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Non-Pharmacological Treatment
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Therapies 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

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Pharmacological Treatment
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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
  

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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

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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 gt3 months
• Moderate to severe same as above
• 23mg greater benefit in cognition, but not global
  functioning higher rates of GI adverse events

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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

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Rivastigmine (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

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Galantamine (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

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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

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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

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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

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Dietary Supplements
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Vitamin 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

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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

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Nutraceuticals/Supplements

• Omega-3 large, prospective, placebo-controlled
  trial in AD subjects
• Primary study endpoints negative

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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

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Behavioral and Psychological Symptoms in Dementia
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Diagnostic Criteria

• No specific diagnostic criteria
• Could be met for impulse control disorders,
  obsessive-control disorder, and bipolar disorder

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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

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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, Huntingtons disease more likely to
  experience BPSD symptoms

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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

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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
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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
• Environmental modifications
• Providing activities
• Electronic alarms
• Safety Plans

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Non-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

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Pharmacological Treatment
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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
Olanzapine /-
Quetiapine /- /-
Risperidone
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SHIFT 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
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SIDE 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
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WEIGHT GAIN ATYPICAL ANTIPSYCHOTICS
Data for Package Labels
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LIPID ABNORMALITIES
Data from product labels
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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) /- /-
Quetiapine (Seroquel) /-
Aripiprazole (Abilify) /- - -
Ziprasidone (Geodon) /- - -
increase effect - no effect D
discrepant results. Newer drugs with limited
long-term data.
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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 X
BP X X X
Fasting Glucose X X X
Waist Circumference X X
Fasting Lipid X X X
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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

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Adverse Events- Black Box Warning

• WARNINGS INCREASED MORTALITY IN ELDERLY PATIENTS
  WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY
  AND ANTIDEPRESSANT DRUGS

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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

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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
• Hypertension
• Atrial fibrillation
• Elevated cholesterol
• Coronary Heart Disease
• Sleep Apnea
• Lifestyle
• Smoking
• Obesity
• Excessive Alcohol

Source National Stroke Association
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Antidepressants

• 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.

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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

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Cholinesterase Inhibitors

• AChE inhibitors can improve BPSD
• If AChE inhibitors are tapered Worsening of
  BPSD symptoms can occur

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Memantine

• Naturalistic, small, open-labeled studies
• Modest improvement in BPSD and overall good
  tolerability

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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
• Symptom relief
• Reduced care giver burden
• Increase quality of life
• Avoidance of unacceptable risks
• Improved functional status
• Risk reduction and cost of care

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Conclusion
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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