pharmacy medication update: dementia megan j. ehret, pharmd, ms, bcpp associate professor university...
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Pharmacy Medication Update: DementiaMegan J. Ehret, PharmD, MS, BCPPAssociate 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 • 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 Criteria- Alzheimer’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 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 Alzheimer’s Disease (BEHAVE-AD)• Assess behavioral symptoms and measure outcomes in
treatment studies
TREATMENT GUIDELINES
NON-PHARMACOLOGICAL TREATMENT
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
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:• Environmental modifications• Providing activities• Electronic alarms• Safety Plans
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
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 ++ + +
Olanzapine + +/- ++
Quetiapine + +/- +/-
Risperidone ++ ++ ++
Past Areas of Concern
Current Medical Realities
SHIFT IN RISK PERCEPTION OF ANTIPSYCHOTICS
SedationWeight
GainInsulin
Resistance
CHD
Hyper-lipidemia
Weight Gain
Diabetes
Prolactin
Insulin Resistance
Sedation
Hyperlipidemia
Coronary HeartDisease
Tardive Dyskinesia
TD
Prolactin
SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
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
00+++++++++Blood sugar
00 +++++++++Lipids
-/+-/++++++++++++Weight gain
00++++++/-+++Sedation
0+/000/++/++0Tremors, stiffness, endocrine problems
000+/++0+++Dry mouth, constipation
0/+0/++++/0++++Low Blood Pressure
CLOZ RIS OLZ QUE ZIP ARIP
WEIGHT GAIN ATYPICAL ANTIPSYCHOTICS
Data for Package Labels
LIPID ABNORMALITIES
Data from product labels
Drug Weight Gain
Risk for Diabetes
Worsening Lipid Profile
Clozapine (Clozaril) +++ ++ ++
Olanzapine (Zyprexa)
+++ ++ ++
Risperidone (Risperdal)Paliperidone (Invega)
++ +/- +/-
Quetiapine (Seroquel)
++ +/- +
Aripiprazole* (Abilify) +/- - -
Ziprasidone* (Geodon)
+/- - -
ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC DRUGS AND OBESITY AND DIABETES SUMMARY
+ = 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 X
BP X X X
Fasting Glucose
X X X
Waist Circumference
X X
Fasting Lipid
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• Hypertension• Atrial fibrillation• Elevated cholesterol• Coronary Heart Disease• Sleep Apnea
• • Lifestyle• Smoking• Obesity• Excessive Alcohol
Source: National Stroke Association
Antidepressants• Mixed studies• 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:• 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
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