PHARMACOLOGICAL STRATEGIES IN THE MANAGEMENT OF ALZHEIMER’S DISEASE Daniel Varon, MD Wien Center for Alzheimer’s Disease and Memory Disorders.

PHARMACOLOGICAL STRATEGIES IN PHARMACOLOGICAL STRATEGIES IN THE MANAGEMENT OF ALZHEIMER’S THE MANAGEMENT OF ALZHEIMER’S DISEASEDISEASE

Daniel Varon, MDWien Center for Alzheimer’s Disease

and Memory Disorders

WHAT IS DEMENTIA?WHAT IS DEMENTIA?

CLASSIFICATION OF ABNORMALCLASSIFICATION OF ABNORMAL COGNITIVE STATESCOGNITIVE STATES

SUBJECTIVE Memory Complaints SUBJECTIVE Memory Complaints

No No Cognitive or Functional deficitsCognitive or Functional deficits

MILD Cognitive Impairment (MCI) MILD Cognitive Impairment (MCI)

Memory complaints, some cognitive deficits butMemory complaints, some cognitive deficits but

NoNo functional Deficits. functional Deficits.

DEMENTIADEMENTIA

Cognitive + Functional DeficitsCognitive + Functional Deficits

Concept of Dementia

NORMAL

SUBJECTIVE IMPAIRMENT

MILD COGNITIVE IMPAIRMENT

DEMENTIA

DEC

LINE

TIME

Types of dementia

Goals of Treatment in Dementia

Improve or preserve ADL function Reduce caregiver burden Enhance quality of life

Improve or preserve cognitive function Improve or preserve behavioral

function Slow deterioration Manage psychiatric and behavioral

symptoms

GOALSGOALS

TARGETSTARGETS

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SYMPTOMSSYMPTOMS

- COGNITION- COGNITION- Memory, language, orientation, - Memory, language, orientation,

judgment, planning. judgment, planning.

- BEHAVIOR- BEHAVIOR-- Depression, anxiety, agitation, Depression, anxiety, agitation,

hallucinations, paranoia, hallucinations, paranoia, aggressiveness. aggressiveness.

- OTHER- OTHER- Weight loss, incontinence, - Weight loss, incontinence,

gait disturbances, sleep gait disturbances, sleep disturbances disturbances

Treatment

NORMAL

SUBJECTIVE IMPAIRMENT

MILD COGNITIVE IMPAIRMENT

DEMENTIA

DEC

LINE

TIME

NATURAL COURSENATURAL COURSE

WITH CURRENTWITH CURRENTTREATMENTSTREATMENTS

IDEALIDEAL

COGNITIONCOGNITION

Cholinesterase inhibitors

- Aricept – Donepezil - Razadyne – Galantamine- Exelon – Rivastigmine

Antagonist of the NMDA glutamate receptor

- Namenda – Memantina

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Cholinesterase Inhibitors

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ARICEPT – Donepezil

Rogers SL, et al. Neurology 1998

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ARICEPT – DonepezilARICEPT – Donepezil

Dose: 5mg daily for 4 weeks and then increases to Dose: 5mg daily for 4 weeks and then increases to 10mg. There is a 23mg formulation.10mg. There is a 23mg formulation.

Interactions: Interactions: - Metabolized in the liver- Metabolized in the liver

RAZADYNE – Galantamine

Raskind et al. 2000

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RAZADYNE – GalantamineRAZADYNE – Galantamine

Dose: 4mg every 12h x 4 weeks Dose: 4mg every 12h x 4 weeks 8mg q12h x 4w8mg q12h x 4w 12mg every12h12mg every12h

Galantamine ER once a day 8, 12, 24mgGalantamine ER once a day 8, 12, 24mg

Interactions: Interactions: - Metabolized in the liver- Metabolized in the liver

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EXELON – Rivastigmine

Farlow et al. 2000

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EXELON – Rivastigmine

Oral 1.5mg twice a day x 4 weeks3mg twice a day x 4 weeks4.5 mg twice a day x 4 weeks6mg twice a day

Patch4.6mg o 9.5mg

Not metabolized in the liver

EXELON – Rivastigmine

Oral 1.5mg twice a day x 4 weeks3mg twice a day x 4 weeks4.5 mg twice a day x 4 weeks6mg twice a day

Patch4.6mg o 9.5mg

Not metabolized in the liver

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Cholinesterase inhibitorsCholinesterase inhibitors

- Aricept – Donepezil - Aricept – Donepezil - Razadyne – Galantamine- Razadyne – Galantamine- Exelon – Rivastigmine- Exelon – Rivastigmine

Side effects:Side effects:- Nausea, vomiting- Nausea, vomiting- Diarrhea- Diarrhea- Anorexia- Anorexia- Slow heart rate- Slow heart rate

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NAMENDA – Memantina

NAMENDA – Memantina

Reisberg B, et al. NEJM 2003

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NAMENDA – Memantina

Dosis: 5mg every 7 days 5mg q12h x 7 days 5mg QAM y 10mg QPM x 7 days 10mg q/12h

Interactions:- Not metabolized in the liver- Excreted through the kidney mostly unchanged (50 - 80%)

NAMENDA – Memantina

Dosis: 5mg every 7 days 5mg q12h x 7 days 5mg QAM y 10mg QPM x 7 days 10mg q/12h

Interactions:- Not metabolized in the liver- Excreted through the kidney mostly unchanged (50 - 80%)

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NAMENDA – Memantine

NAMENDA – Memantine

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Behavioral and Psychological Symptoms of Dementia (BPSD)

Symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia.

BPSD leads to increased suffering, early institutionalization, increased cost of care, and causes significant loss in the quality of life for the patient’s caregivers and family.

About two-thirds of people with dementia experience some BPSD at some point during the course of their illness.

The figure may rise to 70-80% among patients with dementia who reside in nursing homes.

Common Psychological Changes:Early and Middle Stages of Dementia

Depression Anxiety

Fear of being alone Paranoia

Delusions about “imposters” Accusations of infidelity

Personality changes

Behavioral Disturbances:Middles Stages

Wandering Restlessness

Fidgeting Pacing

Inappropriate handling of objects Rummaging Hoarding

Verbal agitation Repetitious speech Verbal aggression

Physical combativeness

Appropriate treatment of behavioral symptoms in patients with dementia

Many factors can cause or contribute to behavioral disturbances

Causal and contributing factors must be identified and should inform treatment

Combination of treatment modalities is often necessary to ensure optimal care

How does memory impairment lead to behavioral problems?

ExamplePatient is able to dress himself, but can’t remember where his clothes are kept

Walks around naked

How does language impairment (aphasia) lead to behavioral problems?

ExamplePatient who can’t verbally communicate her dislike of milk

Throws milk carton across the room

How does impaired recognition (agnosia) lead to behavioral problems?

ExamplePatient can maneuver to pull down his pants, but can’t recognize that a toilet is a receptacle for urination

Urinates on floor

How does impairment in performance of motor tasks (apraxia) lead to behavioral problems?

ExamplePatient is continent of bladder, but cannot unzip or unbutton to pull down her pants

Wets her clothing

How does impaired executive functioning lead to behavioral problems?

ExamplePatient lacks understanding of socially appropriate behavior and is unable to restrain impulses (disinhibition)

Talks or behaves in a sexually inappropriate manner in public.

Initial approach to assessment, management, and prevention

Recognizeareas of impaired function

andareas of preserved function

Help compensate for impairment Support residual abilities

WHAT OTHER FACTORS MAY CONTRIBUTE TO BEHAVIORAL CHANGES IN PATIENTSWITH DEMENTIA?

Management of Behavioral Disturbances in Dementia

Address unmet physical and psychological needs

Environmental modifications Treat medical conditions Treat psychiatric symptoms

Non-pharmacologic interventions Pharmacologic treatment

Interpersonal strategies / caregiver education

Medical conditions and somatic discomfort that can lead to behavioral disturbances

Somatic discomfort Pain Constipation Urinary urgency Shortness of breath Dizziness Fatigue Heartburn Headache

Medical condition– Arthritis– Dehydration– Prostatic hypertrophy– COPD– Cerebrovascular disease– CHF– Impaired vision– Impaired hearing– Urinary infection

Nonpharmacologic Strategies

Arrange regular exercise Try to maintain social/family activities

Review photos and souvenirs Reminisce and tell old stories Senior centers and day centers Engaging in tasks and familiar activities within their capacities

Limit expectations

Communication Techniques

Use short sentences Use simple sentence structure, and frequent

reminders about content of conversation Keep concepts focused Use repetition Be patient Be prepared to have the same conversation

multiple times Do not use leading questions if you want to find

out information (“You’re hungry, aren’t you?”) Don’t argue. Don’t expect logic.

BEHAVIORAL SYMPTOMSBEHAVIORAL SYMPTOMS

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0 5 10 15 20 25 30

Delusions

Hallucinations

Agitation

Depression

Anxiety

Apathy

Sleep disturbance

DEPRESSIONSSRI’s - sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro).

Other antidepressants

- WELLBUTRIN – Bupropion

- EFFEXOR – Venlafaxine

- CYMBALTA – Duloxetine

- REMERON – Mirtazapina

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DEPRESSIONDEPRESSION

Antidepressants:Antidepressants:

- SSRIs: Zoloft – SertralineSSRIs: Zoloft – Sertraline Few interactionsFew interactions Celexa – CitalopramCelexa – Citalopram Easy to tolerateEasy to tolerate

Lexapro – Escitalopram Lexapro – Escitalopram

Paxil – ParoxetinePaxil – Paroxetine More interactions More interactions More anticholinergic More anticholinergic

Prozac – FluoxetineProzac – Fluoxetine Long half lifeLong half life More interactionsMore interactions

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Antidepressants:

- SSRIs: Selective Serotonin Reuptake Inhibitors

Serotonin

- Side effects:- Changes in appetite- Nausea - Dizziness- SomnolenceLow sodium (less common)-

Antidepressants:

- SSRIs: Selective Serotonin Reuptake Inhibitors

Serotonin

- Side effects:- Changes in appetite- Nausea - Dizziness- SomnolenceLow sodium (less common)-

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Other antidepressants:Other antidepressants:

- WELLBUTRIN – Bupropion - WELLBUTRIN – Bupropion Not used in patients with epilepsyNot used in patients with epilepsy

- EFFEXOR – Venlafaxine- EFFEXOR – VenlafaxineCan increase BP Can increase BP transiently transiently

- CYMBALTA – Duloxetine- CYMBALTA – DuloxetineCan cause changes in hepatic functionCan cause changes in hepatic functionCan help with chronic painCan help with chronic pain

- REMERON – Mirtazapine- REMERON – MirtazapineIncreases sleep and appetiteIncreases sleep and appetite

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PSYCHOSISPSYCHOSIS

- - HALLUCINATIONSHALLUCINATIONSVisual Visual (Common in Lewy Body Disease )(Common in Lewy Body Disease )AuditoryAuditorySensorySensory

- - DELUSIONSDELUSIONS (More common than hallucinations)(More common than hallucinations)ParanoiaParanoiaConfabulationConfabulationJealousy Jealousy

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PSYCHOSISPSYCHOSIS

ATYPICAL (2nd generation)ATYPICAL (2nd generation)- RISPERDAL – Risperidone- RISPERDAL – Risperidone- ZYPREXA – Olanzapine- ZYPREXA – Olanzapine- SEROQUEL – Quetiapine- SEROQUEL – Quetiapine- GEODON – Ziprasidone- GEODON – Ziprasidone- ABILIFY – Aripiprazole- ABILIFY – Aripiprazole- (Fanapt, Invega, Latuda, Saphris)- (Fanapt, Invega, Latuda, Saphris)

TYPICAL (1st generation)TYPICAL (1st generation)- HALDOL – Haloperidol- HALDOL – Haloperidol

ALL ANTIPSYCHOTICS HAVE A ALL ANTIPSYCHOTICS HAVE A BLACK BOX WARNINGBLACK BOX WARNING

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SLEEP ALTERATIONS

- Sleep hygiene (initial option)

- Trazodone (second option)- Ambien (Zolpidem) - Lunesta (Eszopiclone) - Sonata (Zaleplon) - Temazepam and other benzo’s (last option)

SLEEP ALTERATIONS

- Sleep hygiene (initial option)

- Trazodone (second option)- Ambien (Zolpidem) - Lunesta (Eszopiclone) - Sonata (Zaleplon) - Temazepam and other benzo’s (last option)

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Urinary incontinence

- Behavioral adjustments

- Vesicare, Enablex, Detrol, Sanctura less effects on the CNS - anticholinergic

- Ditropan – can interfere with memory

Urinary incontinence

- Behavioral adjustments

- Vesicare, Enablex, Detrol, Sanctura less effects on the CNS - anticholinergic

- Ditropan – can interfere with memory

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Treatment and help are available

Alzheimer’s disease is not yet curable, but effective treatments are available, and symptoms can be managed