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

WHAT IS DEMENTIA?

CLASSIFICATION OF ABNORMAL CLASSIFICATION OF ABNORMAL COGNITIVE STATES COGNITIVE STATES SUBJECTIVE Memory Complaints No Cognitive or Functional deficits MILD Cognitive Impairment (MCI) Memory complaints, some cognitive deficits but No functional Deficits. DEMENTIA Cognitive + Functional Deficits

Concept of Dementia NORMAL SUBJECTIVE IMPAIRMENT MILD COGNITIVE IMPAIRMENT DEMENTIA DECLINE 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 GOALS TARGETS

MEDICATIONS IN DEMENTIA SYMPTOMS - COGNITION - Memory, language, orientation, judgment, planning. - BEHAVIOR - Depression, anxiety, agitation, hallucinations, paranoia, aggressiveness. - OTHER - Weight loss, incontinence, gait disturbances, sleep disturbances

Treatment NORMAL SUBJECTIVE IMPAIRMENT MILD COGNITIVE IMPAIRMENT DEMENTIA DECLINE TIME NATURAL COURSE WITH CURRENT TREATMENTS IDEAL

COGNITION Cholinesterase inhibitors - Aricept – Donepezil - Razadyne – Galantamine - Exelon – Rivastigmine Antagonist of the NMDA glutamate receptor - Namenda – Memantina MEDICATIONS IN DEMENTIA

Cholinesterase Inhibitors MEDICATIONS IN DEMENTIA

ARICEPT – Donepezil Rogers SL, et al. Neurology 1998 MEDICATIONS IN DEMENTIA

ARICEPT – Donepezil Dose: 5mg daily for 4 weeks and then increases to 10mg. There is a 23mg formulation. Interactions: - Metabolized in the liver

RAZADYNE – Galantamine Raskind et al MEDICATIONS IN DEMENTIA

RAZADYNE – Galantamine Dose: 4mg every 12h x 4 weeks 8mg q12h x 4w 8mg q12h x 4w 12mg every12h 12mg every12h Galantamine ER once a day 8, 12, 24mg Interactions: - Metabolized in the liver MEDICATIONS IN DEMENTIA

EXELON – Rivastigmine Farlow et al MEDICATIONS IN DEMENTIA

EXELON – Rivastigmine Oral 1.5mg twice a day x 4 weeks 3mg twice a day x 4 weeks 4.5 mg twice a day x 4 weeks 6mg twice a day Patch 4.6mg o 9.5mg Not metabolized in the liver EXELON – Rivastigmine Oral 1.5mg twice a day x 4 weeks 3mg twice a day x 4 weeks 4.5 mg twice a day x 4 weeks 6mg twice a day Patch 4.6mg o 9.5mg Not metabolized in the liver MEDICATIONS IN DEMENTIA

Cholinesterase inhibitors - Aricept – Donepezil - Razadyne – Galantamine - Exelon – Rivastigmine Side effects: - Nausea, vomiting - Diarrhea - Anorexia - Slow heart rate MEDICATIONS IN DEMENTIA

NAMENDA – Memantina NAMENDA – Memantina Reisberg B, et al. NEJM 2003 MEDICATIONS IN DEMENTIA

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 ( %) 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 ( %) MEDICATIONS IN DEMENTIA

NAMENDA – Memantine NAMENDA – Memantine MEDICATIONS IN DEMENTIA

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? Example Patient 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? Example Patient who can’t verbally communicate her dislike of milk Throws milk carton across the room

How does impaired recognition (agnosia) lead to behavioral problems? Example Patient 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? Example Patient 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?  Example Patient 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  Recognize areas of impaired function and areas of preserved function  Help compensate for impairment  Support residual abilities

WHAT OTHER FACTORS MAY CONTRIBUTE TO BEHAVIORAL CHANGES IN PATIENTS WITH 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 SYMPTOMS MEDICATIONS IN DEMENTIA

DEPRESSION SSRI’s - sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro). Other antidepressants - WELLBUTRIN – Bupropion - EFFEXOR – Venlafaxine - CYMBALTA – Duloxetine - REMERON – Mirtazapina MEDICATIONS IN DEMENTIA

DEPRESSIONAntidepressants: - SSRIs: Zoloft – Sertraline Few interactions Celexa – Citalopram Easy to tolerate Lexapro – Escitalopram Celexa – Citalopram Easy to tolerate Lexapro – Escitalopram Paxil – Paroxetine More interactions More anticholinergic Prozac – Fluoxetine Long half life More interactions More interactions MEDICATIONS IN DEMENTIA

Antidepressants: - SSRIs: Selective Serotonin Reuptake Inhibitors Serotonin - Side effects: - Changes in appetite - Nausea - Dizziness - Somnolence Low sodium (less common) - Antidepressants: - SSRIs: Selective Serotonin Reuptake Inhibitors Serotonin - Side effects: - Changes in appetite - Nausea - Dizziness - Somnolence Low sodium (less common) - MEDICATIONS IN DEMENTIA

Other antidepressants: - WELLBUTRIN – Bupropion Not used in patients with epilepsy - EFFEXOR – Venlafaxine Can increase BP transiently - CYMBALTA – Duloxetine Can cause changes in hepatic function Can help with chronic pain - REMERON – Mirtazapine Increases sleep and appetite MEDICATIONS IN DEMENTIA

PSYCHOSIS - HALLUCINATIONS Visual (Common in Lewy Body Disease ) AuditorySensory - DELUSIONS(More common than hallucinations) ParanoiaConfabulationJealousy MEDICATIONS IN DEMENTIA

PSYCHOSIS ATYPICAL (2nd generation) - RISPERDAL – Risperidone - ZYPREXA – Olanzapine - SEROQUEL – Quetiapine - GEODON – Ziprasidone - ABILIFY – Aripiprazole - (Fanapt, Invega, Latuda, Saphris) TYPICAL (1st generation) - HALDOL – Haloperidol ALL ANTIPSYCHOTICS HAVE A BLACK BOX WARNING MEDICATIONS IN DEMENTIA

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) MEDICATIONS IN DEMENTIA

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 MEDICATIONS IN DEMENTIA

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