Alzheimer’s Disease:Update on Evidence-

BasedTreatment Guidelines

Debra Cherry, PhDFreddi Segal-Gidan, PA-C, PhD

Bradley R. Williams, PharmD, CGPOn behalf of the California Workgroup on Guidelines for

Alzheimer’s Disease Management

ObjectivesIdentify the typical signs and symptoms associated with Alzheimer’s disease and other dementias. Discuss the roles of cholinergic manipulation and NMDA inhibition in the treatment of Alzheimer’s disease symptoms. Recognize behavior disturbances commonly displayed by patients with dementia.Develop a therapeutic strategy for treating agitated behaviors in Alzheimer’s disease.

Mrs. R. L.

Mrs. R. L. is a retired librarian who visits her physician for a routine follow-up for her osteoarthritis, GERD, and glaucoma. She has enjoyed her 3 years of retirement, but reports that recently her husband has been worried about her memory. Mrs. L. states that she had started writing reminder notes, “which don’t always help.” She admits to reading less than she used to; she also drives less because “traffic is such a problem.”

Mrs. R. L.

Mr. L. reports that his wife often returns from grocery shopping having forgotten to pick up several things that she intended to buy. At other times she will wander through the house, looking in drawers or closets for items that she had put away for safe-keeping. Although they used to go out to dinner at least once a week, they now go much less frequently because Mrs. L. states that “I just never know what to order, and it’s not as much fun as it used to be.”

Mrs. R. L.

Mrs. R. L.’s medications include:Xalcom Drops 1 drop in each eye HS

(Latanoprost 0.005% + Timolol 0.5%)

Esomeprazole (Nexium) 20 mg dailyAcetaminophen 1 gm PRN arthritis painUnisom 2-3 times/week for insomnia

Dementia Warning Signs

Task Example

Memory decline Forgetfulness

Difficulty performing familiar tasks

Bill paying, shopping

DisorientationGetting lost in familiar places

Impaired judgmentInviting strangers into the home

Impaired abstract thinking, problem-solving

Driving skills

Dementia Warning Signs

Task Example

Misplacing thingsLosing valuable items in the home

Mood or behavior change

New-onset irritability, unusual habits or activities

Personality changeWithdrawn, increased socialization

Loss of initiative Lost interest in hobbies

What signs and symptoms are present in Mrs. R. L. that suggest that she may have a dementia?

AD Management

AssessmentTreatmentPatient & Family Education & SupportLegal Considerations

Assessment

Cognitive statusDaily functionConcurrent medical conditionsMedicationsBehavior symptoms and moodLiving arrangementsSupport system

Assessing Cognition

TestItems/Score

Domains

Folstein Mini-Mental Status Exam

19 items30 points

Multi-dimensional

Mini-Cog 2 items5 points

3-item recallClock drawing

Blessed Orientation-Concentration-Memory

6 items28 points

Orientation, concentration, recall

Cognitive Assessment Screening Instrument

25 items100 points

Multi-dimensional

Assessing Function: Activities of Daily Living (ADL)

Self-feedingDressingAmbulationToileting

BathingTransfer from bed to toiletContinenceGroomingCommunication

Assessing Function:Instrumental ADL (IADL)

WritingReadingCookingCleaningShoppingDoing laundry

Climbing stairsUsing telephoneManaging medicationManaging moneyAbility to perform outside workAbility to travel (public transportation)

Concurrent Conditions

Chronic diseaseAbility to manage

Impact on functionDeliriumNew problems

InfectionCancer

Medications & CognitionAnticholinergicsBenzodiazepinesSleep aidsAntipsychoticsNarcoticsMuscle relaxants

NSAIDsAnti-arrhythmicsAntihypertensivesCimetidineCorticosteroidsHypoglycemic agents

Behavior and MoodAgitation

RestlessnessIrritabilityAggression

PsychosisDelusionsParanoiaHallucinations

DepressionWithdrawalSleep disturbancesAppetite changes

ApathyLoss if interest

Living ArrangementsDeclining ability for self-care

Patient autonomy vs. need for care

Safety issuesRugs, appliancesDriving

Abuse and neglectDependenceCaregiver stress

Support SystemSpouse

Ability to care for patient

FamilyCommunity support

Alzheimer’s AssociationReligious or other groups

Health care resourcesAdvance directives

How would you evaluate Mrs. R. L. regarding her condition?

What concerns do you have regarding her care and situation?

Treatment Strategies

Early diagnosisFamily education Early treatment interventionEffective management of concurrent conditionsOngoing caregiver support

Pharmacists Can…

Serve as an information resourceLocal Alzheimer’s Association chapters

www.alz.org1.800.272.3900MedicAlert + Safe Return program

Social service agenciesSenior centersAdult day care

Helping Families Manage Meds

Evaluate risk for additional, drug-induced cognitive impairment (e.g., anticholinergics)Explain potential adverse effects

Instruct families how to monitor

Assess the ability of patients and caregivers to adhere to a medication regimen

Adherence aidsSimplify medication regimen

Disease Modifying Approaches

Cholinergic manipulationCholinesterase inhibitors

All agents block acetylcholinesterase activityRivastigmine also blocks butyrylcholinesteraseGalantamine stimulates cholinergic receptors

NMDA antagonistReduces glutamate activityRegulates calcium entry into cells

Available AgentsDonepezil (Aricept®)

Starting dose is therapeuticCYP1A2 substrate

Galantamine (Razadyne®)Initial dose is not therapeuticProbably first to go generic

Rivastigmine (Exelon®)Patch reduces GI effectsRenal excretion

ChEI Adverse Reactions (%)

Donepezil Rivastigmine Galantamine

Nausea 4-24 8-58 6-37

Vomiting 1-15 5-38 4-21

Diarrhea 4-17 7-17 2-12

Wt/App 2-19 3-18 6-12

Dizziness NR 6-27 4-19

Insomnia 8-18 NR NR

Musc 6-8 NR NR

Headache

9-12 7-20 6-11

-Kaduszkiewicz, et al., BMJ 2005;331:321-327

Principles for ChEI UseInitial treatment upon diagnosis or 6-months duration of AD symptomsEvaluate for ADR after 2-4 weeks

Evaluate for effectiveness every 6 months

Switch if poor tolerance, or continued decline

Discontinue prior to surgery

Is Mrs. R. L. an appropriate candidate for treatment with a cholinesterase inhibitor?

How should her treatment (both drug and non-drug) be started and monitored?

Counseling Points

Effects on cognition are very mildMay stabilize or slow decline for 6-12 months

May improve independence, self-careGastrointestinal effects are prominentMay slow heart rate

The Evidence Suggests…

-Kaduszkiewicz, et al., BMJ 2005;331:321-327

Memantine

Uncompetitive NMDA receptor antagonist

Increased glutamate release in CNS produces excitotoxic reactions and cell death

Prominent in areas affected by dementias

Calcium ion channels are affected

Moderate affinity for receptor avoids toxicity associated with ketamine, etc.

Memantine (Namenda®)Approved for use in moderate, severe AD

MonotherapyWith ChEI

Availability5 & 10 mg tablets10 mg/5 mL solution

Dosing5 mg/day for 1 weekIncrease by 5 mg/day in weekly intervals to 10 mg twice daily10 mg/day maximum with renal impairment

May be taken without regard to mealsRenal elimination as unchanged drug

Memantine Adverse Effects

> 5% incidence in clinical trialsAgitation (less than for placebo)DiarrheaInsomnia

5% incidenceDizzinessHeadacheHallucinations

Memantine

Effects in moderate ADSlower decline in overall function and in loss of activities of daily livingNo significant effect on cognition

Systematic reviews have reported small to no clinically relevant effect

Principles for Memantine UseTreat upon reaching mild to moderate AD symptoms

Typically used as adjunct to ChEI

Evaluate for ADR after 2-4 weeks

Evaluate for effectiveness every 6 monthsDiscontinue prior to surgery

Behavior Symptoms

Most difficult for both patients and caregiversBehavior symptoms contribute to:

Patient distressCaregiver burnoutExcess disabilityInstitutionalization

Treatment Recommendations

Treat behavioral symptoms and mood disorders using:

Non-pharmacologic approaches, such as environmental modification, task simplification, appropriate activities, etc.IF non-pharmacological approaches prove unsuccessful, THEN use medications, targeted to specific behaviors, if clinically indicated. Note that side effects may be serious and significant.

Treatment: Increase Level of Function and Delay Disease Progression

Behavioral interventionsAdult day servicesExercise and recreationMedications

Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081.

Agitation

Diurnal Rhythm

Irritability

Wandering Aggression

Hallucinations

Mood Change

Socially Unacceptable

Delusions

Sexually InappropriateAccusatorySuicidal

Ideation

Paranoia

Depression

100

80

60

40

20

0–40 –30 –20 –10 0 10 20 30

Months Before Diagnosis Months After Diagnosis

Pre

vale

nce

(%

of

pat

ien

ts)

AnxietySocial Withdrawal

Behavioral Symptoms as AD Progresses

Mrs. R. L.

Mrs. R. L. starts to realize she has Alzheimer’s disease. She becomes depressed. She is dysphoric, has lost her appetite, and feels helpless and hopeless. Her husband reports that he is becoming frustrated and doesn’t know how to help her.

What is your assessment of Mrs. L.’s condition?

Is she a candidate for antidepressant treatment?

What should be done to assist her & her husband?

Mood Changes

Depressed moodDysphoria secondary to dementiaConcurrent major depressionCognition, behavior, co-morbid conditions influence managementConnect her to the Alzheimer’s Association for support & activities

Antidepressants

Drug Start Max/day

Citalopram 10 mg 30 mg

Escitalopram 5 mg 20 mg

Paroxetine 10 mg 30 mg

Sertraline 25 mg 150 mg

Mirtazapine 7.5 mg 30 mg

Trazodone 25 mg 100 mg

Mrs. R. L.

Some time has passed and Mr. L. is concerned about changes in his wife’s behavior. She becomes agitated, especially in the late afternoon and leaves the house. She says she is going home and gets more agitated when he reminds her that she is in her home.

Evaluating Behaviors

Rapid onset requires search for medical cause

Pain, infection, adverse drug effect

Identify problemA – Antecedents / triggersB - Behavior – be specificC – Consequences / reinforcers

What may be triggering Mrs. L.’s behavior?

What does this behavior mean to her?

How should these symptoms be managed?

Common Causes of Behaviors

HealthDifficult tasksConfusing environmentCommunication breakdownPatient’s perceptions of the situation

Behavior Management Principles

Non-drug management generally provides better resultsAssess likelihood that pharmacotherapy will be beneficial

Target medication to specific behaviorAvoid caregiver interpretation of PRN ordersConsider the patient's health statusConsider drug pharmacokinetic and pharmacodynamic properties

Non-drug Strategies

Avoid startling patientDon’t argue incorrect statementsEmploy distractionsSafety-proof living areasOne-step commands

Specific BehaviorsProblem Strategy

ApathyStimulation/ActivitiesSimple tasks

IrritabilityAgitation

Breakdown tasks to simple stepsRedirection and distraction

WanderingVisual cuesExercise in safe places to wanderEnroll in Medic-Alert® + Safe Return ®

Mood disorders

Exercise

Specific BehaviorsProblem Strategy

Disturbed sleepSleep hygiene practicesDaytime stimulationReduced evening stimulation

Psychotic symptoms

ReassuranceDistraction, rather than confrontationRemove triggers (e.g., mirrors)

Appetite problems

Offer simple, finger foodsRemove distractions from dining areaSoothing music during meals

Mrs. R. L.

Mrs. R. L. has begun a daily exercise program and late afternoon agitation is now less of an issue. However, at night she awakens and becomes agitated. She believes someone is trying to break into the house. When her husband tries to reassure her, she gets angry and strikes out at him.

What non-drug strategies are appropriate to manage Mrs. L.’s current behaviors?

Is drug therapy appropriate, and if so, how should it be initiated?

Managing Anxiety

Reassure, don’t ignoreDistract - engage person in other activities

Music, simple tasks, hobby-type activities

Simplify the environmentCover windows and mirrors; use night lights

AnxiolyticsShort-term use for anxiety in early stagesBenzodiazepine use is discouraged

Use short-acting agents, if necessary

Trazodone 25 mg is an effective agent for anxiety or insomniaPeriodically re-assess need

Taper BZDP downward to avoid seizures

Managing AggressionIdentify the cause (noise, fear, etc.)Focus on the person’s feelingsAvoid getting angry or upsetSimplify the environment to limit distractionsMusic, exercise, etc. as a soothing activityShift the focus to another activity

Antipsychotic Agents

Effective for acute aggressive episodesSome benefit for delusions, hallucinationsBedtime dose for initial treatmentVery low doses often sufficientDiscontinue periodically to assess continued needIncreased risk for stroke, weight gain

Antipsychotic Agents

Drug Start (HS) Max/day

Aripiprazole 5 mg 20 mg

Clozapine 10-25 mg 100 mg

Haloperidol 0.5 mg 4 mg

Olanzapine 2.5 mg 15 mg

Quetiapine 25 mg 200 mg

Risperidone 0.25 mg 3 mg

Atypical Agents

DivalproexUseful for aggression or anger unrelated to anxiety, psychosis or depressionStarting dose 125 mg BIDMaximum dose 625 mg BIDNausea, GI disturbances are most prominent ADRTremor, weight gain, hair loss, drowsiness

Mr. L. is no longer able to care for his wife due to his decline in health. Mrs. L. is placed in the locked dementia section of an assisted living facility. She rarely speaks, gets up frequently during the night and wanders into other residents’ rooms, disrupting their sleep.

During the day, she paces the hall. She battles with staff who attempt to assist her with bathing and hygiene.

Mrs. R. L.

Mrs. R. L.

She has fallen twice, once fracturing her wrist. At her last evaluation, her MMSE score was 7/30 and her CDR was 3/5.Current medications include:

Donepezil 10 mg HSMemantine 10 mg BIDEsomeprazole 20 mg dailyAmlodipine 10 mg dailyHCTZ 12.5 mg daily Zolpidem 10 mg HS PRNQuetiapine 50 mg BID for combativenessVicodin 1 tablet q4h PRN pain

What factors are contributing to her current behaviors?

What changes, if any, do you recommend in her medication regimen?

SummaryEarly diagnosis is essentialThe pharmacist should:

Evaluate ALL medicationsRefer to community resources Work with the patient and caregiversEnsure medication regimens are simpleMinimize medication changes, and avoid changes during transition timesCommunicate with all health care providers

Questions?…

Questions?…