Pharmacological Interventions for Pharmacological Interventions for the Cognitively Impaired the Cognitively Impaired

Geriatric PatientGeriatric Patient

Indiana Osteopathic Association

117th Annual Convention

May 2 – 4, 2014

French Lick Resort

John J. Wernert, M.D., MHA

Professional Development Associates

Faculty DisclosureFaculty DisclosureJohn J. Wernert, M.D, MHAJohn J. Wernert, M.D, MHA

Consultant:– Eskenazi Health– Franciscan Alliance– Federally Qualified Health Centers– Archdiocese of Indianapolis– Extended Care Facilities

LEARNING OBJECTIVESLEARNING OBJECTIVES Discuss new discoveries and theories about brain

deterioration and memory decline. Explore genetic and environmental risk factors

for development of cognitive disorders.                   

Differentiate Delirium, Depression and Dementia in Geriatric patients.

Review Behavioral manifestations of dementing illnesses. 

Discuss how emerging targets and therapies may impact behavioral and medical recommendations relevant to treating cognitively impaired patients.

““The singular benefit of old age is to see life whole and know The singular benefit of old age is to see life whole and know it’s natural course”it’s natural course”

Philosopher Arthur SchopenhauerPhilosopher Arthur Schopenhauer

Most common reasons for Most common reasons for referral to Geriatric Psychiatrist:referral to Geriatric Psychiatrist:

Memory Impairment– (AACD vs MCI vs Dementia)

Affective Problems

– (Apathy vs Depression)Behavioral Problems

– (wandering vs agitation)

The Cost of Brain DisordersThe Cost of Brain Disorders

U.S. Society = $500 Billion annually19 % of the average American

income is devoted to treating Brain diseases

55 % cost is DementiasPsychiatric Illnesses = $170 BillionAD alone > $100 billion

Prevalence of Mental Prevalence of Mental Disorders Age 65+Disorders Age 65+

Mental disorders: 26.3%(including dementia)

Psychiatric disorders 19.8% based on prevalence of 30-40% of dementia complicated by depression, psychosis, or agitation.

Jeste, et al., 1999

Brain Aging is not a sudden event, but rather a continuous process.

RISK FACTORS:

Decline in 20’s

Medical illness

Genetics

Plasticity

Variability

Crowded desktop

Crowded Mental Desktop Crowded Mental Desktop

More time needed to learn new information

Working-memory capacity is limitedSlowed retrieval time Too much clutter – hard to prioritizeLong-term memory becomes less

reliable

Sensory impairments Sensory impairments

Auditory and visual acuity decline Quality of sensory input blurs the sharpness

of the memory By 40’s, more distractible By 50’s, harder to focus and stay on point. By 60’s, difficult to filter out extraneous noise By 70’s, memory lost due to “missed” input

Brain Aging:Brain Aging:

Caused by metabolic stress Cell Level = transcription errors Body Level = develop comorbidities

MCI - 15% per year convert to AD AD develops slowly over decades Adults who will get AD, already have it!

– 30% over age 65 already have amyloid plaques

Risk Factors for Brain Aging:Risk Factors for Brain Aging: Confirmed

– Age– Family History– APOE-4 gene (only 50 % of genetic variability)

Possible– Other genes– Head trauma– Lower educational achievement (use it or

loose it vs healthy lifestyle)– Chronic stress– Depression

Protective Factors for Brain Protective Factors for Brain Aging:Aging:Aerobic exerciseEstrogenAnti-inflammatory drugsAnti-oxidantsLow-fat dietWine (Germans say beer)

Wine and Reduced Incidence of Dementia?Wine and Reduced Incidence of Dementia?

Copenhagen City study 83 pt’s, 1626 controls over age

65 Studied over 15 years Grouped by intake and dx MMSE scores of 24 or up Monthly and weekly intake of

wine = decreased risk Monthly intake beer = higher

risk Total alcohol intake had no

significant effect on risk• Neurology (2002;59:1313-1319)

NeurodegenerationNeurodegeneration

Usually a NORMAL Brain going through a slow, gradual deterioration– Parkinsons Disease– Dementing Illnesses– Demyelinating Disorders (MS)– Infectious (HIV, Syphilis)– Neoplastic (brain vs paraneoplastic)

Neurodegeneration predisposes to Neurodegeneration predisposes to the “Three D’s”:the “Three D’s”:

Delirium

↓↓ ↑↑Dementia

↕↕Depression

Neurodegenerative Conditions Neurodegenerative Conditions lead to all three “D’s”lead to all three “D’s”High risk of polypharmacyDespondency of chronic illnessWeakened resistance Fragile brain = iatrogenic illnessesSensitive to drug side effects

Delirium vs DementiaDelirium vs Dementia Delirium

– Acute– Fluctuating course

Dementia– Insidious Onset– Chronic memory Disturbances– Persistent Sxs

Dementia pt’s 3x more likely to get delirious Delirious elderly patients are 4X more likely to

have dementia

Delirium; Delirium;

Under-recognized (missed 50%)Reversible (if cause correctible)Present in 30 % of hospitalized

elderlyDelays dischargeIncreases need for ECF placementHigher mortality (6 mo mortality>50%)

Worse outcomes– Hip fractures– Myocardial infarction– Cancer (Mossey 1990; Penninx et al. 2001; Evans 1999)

Increased mortality rates– Myocardial Infarction (Frasure-Smith 1993, 1995)

– Long term Care Residents (Katz 1989, Rovner 1991, Parmelee 1992; Ashby1991; Shah 1993, Samuels 1997)

Depression Associated with Depression Associated with Worse Health OutcomesWorse Health Outcomes

Depression in Older Adults and Depression in Older Adults and Health Care Costs Health Care Costs

$0

$1,000

$2,000

$3,000

$4,000

$5,000

$6,000

$7,000

0 (n=859) 1-2 (n=616) 3-5 (n=659) 6-16 (n=423)

Levels of Chronic Disease Score

An

nu

al C

ost

of H

ealt

hca

re None CES-D<8Moderate CES-D=8-15Severe CES-D>16

Unutzer, et al., 1997; JAMA

Suicide in Older AdultsSuicide in Older Adults

65+: highest suicide rate of any age group85+: 2X the national average (CDC 1999)

Peak suicide rates: – Suicide rate goes up continuously for men – Peaks at midlife for women, then declines

1/3 of older men saw their primary care physician in the week before completing suicide; 70% within the prior month

  Depression Delirium Dementia

Onset Weeks to months Hours to days Months to years

Mood Low/apathetic Fluctuates Fluctuates

Course Chronic; responds to treatment.

Acute; responds to treatment

Chronic, with deterioration over time

Self-Awareness Likely to be concerned about memory impairment

May be aware of changes in cognition; fluctuates

Likely to hide or be unaware of cognitive deficits

Activities of Daily Living (ADLs)

May neglect basic self-care

May be intact or impaired

May be intact early, impaired as disease progresses

Instrumental Activities of Daily Living (IADLs)

May be intact or impaired

May be intact or impaired

May be intact early, impaired before ADLs as disease progresses

Summary of FindingsSummary of Findings

Dementia and Delirium strongly linkedDepression is common in medical

disorders among older patients All three “D’s”;

– Associated with worse health outcomes– Greater use and costs of medications– Greater incidence of iatrogenic illness– ↑ medical outpatient visits, emergency

visits, and hospitalizations

Example of Neurodegenerative Example of Neurodegenerative Condition prone to the three “D’s”:Condition prone to the three “D’s”:

Parkinson’s DiseaseParkinson’s Disease

Imbalance of ACH – Dopamine– Not enough Dop = Parkinsons– Too much Dop = psychosis

20-30 % will develop Dementia Increasing Dop doesn’t prevent dementia 50 % will become depressed sometime during

illness Drug-induced delirium and hallucinations

common cause of psychiatric symptoms

DementiaDementia

Acquired persistent decline in several realms of intellectual ability

Demence described in Paris Assylums (1820’s) Frequent alteration in behavior and mood Alzheimer’s Dz most common, but not all

dementia is AD Constitutes the greatest health challenge for the

Baby Boom generation – will be the #1 reason why you need an ECF

Course of Age-Related Changes Course of Age-Related Changes in Dementiain Dementia

Age-Associated Memory Impairment

Age 30 40 50 60 70 80

MCI

AD

Assymptomatic

C

O

G

N

I

T

I

O

N

SDATSDAT39 % go undiagnosedEarly onset of Memory DeficitsAbsense of Neurologic DeficitsNo CVA or injury on CTMakes up 70 % of Dementia Pt’s>5.5 million Americans currently DxAlready 4th leading cause of deathLive 7 – 10 years after DX

International Working Group for New International Working Group for New Research Criteria for the DX of Research Criteria for the DX of Alzheimer’s DiseaseAlzheimer’s Disease

Current dx dependent upon documenting mental decline

New Proposed Diagnostic Criteria for SDAT– MCI and evidence of AD from biomarkers

( eg, + amyloid scan, CSF markers of amyloid or tau)

– AD = Dementia + biomarkers

Three of the new guidelines Three of the new guidelines focus on three stages of focus on three stages of Alzheimer's disease: Alzheimer's disease:

(1) dementia due to Alzheimer's(2) mild cognitive impairment (MCI)

due to Alzheimer's(3) preclinical (presymptomatic)

Alzheimer's.

““Pre-clinical Alzheimer’s”Pre-clinical Alzheimer’s”

5 year study of monoclonal antibodies + screening tests

Looking for specific biomarkers30% over 65 have amyloid plaquesBrain changes caused by the disease

may begin decades before symptoms such as memory loss and confusion occur.

““Pre-clinical Alzheimer’s”Pre-clinical Alzheimer’s”

The new guidelines are not an immediate call for diagnosis of this preclinical stage and do not include specific diagnostic criteria. They rather propose a research agenda to identify biomarkers that may signal when these presymptomatic brain changes begin.

Reliable predictors don’t existReliable predictors don’t exist

There are currently no validated biomarkers for Alzheimer's disease, but researchers are investigating several promising candidates

We now know that Alzheimer's has already caused severe brain damage in individuals who meet the criteria for mental decline.

NeuroimagingNeuroimaging

Neuroimaging and DementiaNeuroimaging and DementiaAAN Guidelines = MRI / CT Medicare reimbursement – FDG-PET

to differentiate AD from FTDDeveloping PET technologies –

amyloid plaque and tau tangle imaging

Neurology 2004; www.cms.gov

Amyloid ScansAmyloid Scans

Pre-senile Alzheimer’s DiseasePre-senile Alzheimer’s Disease

RarePrior to age 60Autosomal dominant inheritance due to

mutations presenelin I (chrom 14), presenelin II (chrom 1) and APOE (chrom 19).

Earlier symptom onset (personality sx)Abnormal / high amyloid deposition

SDAT: Making the Diagnosis SDAT: Making the Diagnosis Earlier (risk factors)Earlier (risk factors) Early warning signs

– Progressive and insidious– Functional– Behavioral

“Red Flags” (Natural Brain Stress tests)– Delirium (especially recurrent)– Depression (or AD apathy)– Catastophic Rxn (too much input)

Concurrent Medical Illnesses– Why is this pt doing poorly NOW

Listen to the Family (“He’s just not right”)– See them separately– They will tell you the diagnosis

Genetic ConsiderationsGenetic Considerations Should NOT be used solely as predictive test –

helpful in research and validation Rare autosomal dominant families with early

onset (age 50 – 60) dementia– Mutations cause the disease

• Presenilin genes (chromosomes 1 and 14)• APP gene (Chromosome 21)

Apolipoprotein E (APOE)– Gene on chrom 19; 3 alleles, 5 common genotypes (3/3, 3/4, 2/3,

2/4, 4/4)– APOE-4 in 20% US population– APOE-4 increases risk, lowers age onset– APOE alone not considered useful predictive test

Genetic Risk factors;Genetic Risk factors;Early onset of mutations in chromosome 1, 14, and 21

Late onset of mutations in chromosome 19     -apolipoprotein E gen (APOE 2, 3, and 4)     4/4 greatest risk (3% of population)     3/4 next risk (20% of population)     2 may be protective

 APOE 4 neither necessary nor sufficient to cause dementia

Why Diagnose AD Early?Why Diagnose AD Early?

Safety Issues (driving, compliance)Advanced Planning while Pt

competent (POA, HCR, Guardian)Family Stress and MisunderstandingEarly Education of CaregiversSpecific, stabilizing Tx Available

Approved AD/Cognitive TreatmentsApproved AD/Cognitive Treatments

Aricept (Donepezil)Exelon (Rivastigmine) AChE + BuChEReminyl (Galantamine)Namenda (Memantine)

Vitamin E (a-tocopherol) 1200 IU/d

Possibly beneficial:Possibly beneficial:

Estrogen (HRT)SelegilineGinko bilobaCholesterol lowering agentsReality TherapyMusic Therapy

……and the Pipeline is dry…and the Pipeline is dry…NMDA receptor antagonists. Limits

excitotoxicity caused by excessive pre-synaptic glutamate release. Mixed results

Alzhemed – organic molecule to prevent formation & deposition of beta amyloid fibrils in the brain. (withdrawn 2007)

Preventive Therapies – “Alzheimer’s vaccine” (Lilly's Alzheimer's drug solanezumab flunks out 2012)

Vascular DementiaVascular Dementia

20% of DementiasNot always clear findings on CT/MRIEarly Gait DisturbanceFrequent fallsEarly incontinenceUsually prominent personality and

mood changes

4 Sub-types of Vascular Dementia4 Sub-types of Vascular Dementia

Single infarct Dementia (behavior worse with frontal involvement)

MIDSmall vessel disease (must be more

than mild)Watershed injury (hypoperfusion)Males vs Female considerations

The remaining 10 %The remaining 10 %

Frontal Lobe Dementias (Picks)Lewy Body DementiaParkinson’s DzOther Neurodegenerative conditions

Bottom Line -Bottom Line -

Diagnose early,

Treat early,

So patients can

Stay Home Longer!(on average, 18 – 24 months)

Geriatric Brain injuries:Geriatric Brain injuries:

Usually associated with fallsAcute and Massive CVA’sLess favorable outcomesIncreased mortalityMore likely need ECFMore likely depressedMuch more sensitive to medications

When brain is injured, behaviors When brain is injured, behaviors are inevitableare inevitable

Challenge is to determine which behaviors are tolerable, and which require medication or behavioral

treatments.

Medications used too often?Medications used too often?

“Much of medication use is due to the lack of interest, willingness, funding, or ability to provide psychosocial or environmental interventions to patients with agitation, aggression, and psychosis who have dementia.”

“Despite the widespread awareness of adverse consequences, we can only infer that atypical antipsychotics continue to be prescribed for dementia treatment because there is a lack of alternatives and there is a perceived clinical benefit by care providers.”

– Am J Psychiatry. 2011;168:831-839, 767-769. Abstract Editorial

What behaviors will respond to What behaviors will respond to medications?medications?Agitation – acute and chronicPsychosis – especially positive

symptomsDepression – situational and majorAnxietyMood Instability - Bipolar

Choices for treating Agitated Choices for treating Agitated BehaviorsBehaviors

Antipsychotics – Typical– Atypical (really second generation)

AntidepressantsAnxiolyticsMood Stabilizers

ANTIPSYCHOTICS - ANTIPSYCHOTICS - CONVENTIONALSCONVENTIONALS

Haldol (haloperidol)Prolixin (fluphenazine)Navane (thiothixene)Loxitane (loxapine)Moban (molidone)Stelazine (trifluoperazine)Mellaril (thioridazine)Thorazine (chlorpromazine)Trilafon (perphenazine)

ANTIPSYCHOTICS - ATYPICALSANTIPSYCHOTICS - ATYPICALS

Risperdal (risperidone)Zyprexa (olanzapine)Seroquel (quetiapine)Clozaril (clozapine)Geodon (ziprasidone)Abilify (aripiprazole) - ?3rd generation

New 2New 2ndnd Generation have no role Generation have no role

Fanapt (iloperidone)Saphris (asenapine)Invega (paliperidone)Latuda (lurasidone)Solian (amisulpride)

Safety vs EffectivenessSafety vs Effectiveness

Atypicals clearly safer, but don’t always work

If they do work, can be given longerConventionals often work faster and

are more effective.Must be used with more caution, and

for shorter periods of timeMonitoring is the key

FDA Advisory for Antipsychotic Drugs FDA Advisory for Antipsychotic Drugs Used for TX of Behavioral Disorders in Used for TX of Behavioral Disorders in Elderly PT’s [Black Box] Elderly PT’s [Black Box] (April 11, 2005)(April 11, 2005)

Atypicals to treat behavioral DO showed 1.7 times higher death rate vs placebo

Absolute risks: 4.5% drug, 2.6% placebo All antipsychotics may be affected Death causes varied

– Most heart related or infections (pneumonia)

Important Change in Practice Important Change in Practice Guidelines 2007: Limit AntipsychoticsGuidelines 2007: Limit Antipsychotics

For patients who have neuropsychiatric symptoms, such as agitation, delusion, hallucinations, and aggression, there is stronger evidence that nondrug treatment should be tried first and that real efforts should be made to limit the use of antipsychotics in all settings — at home and in the long-term-care setting. "That is the most important way the guidelines will change practice.“

“Real efforts need to be made to make sure that when antipsychotics are prescribed, they are both necessary and effective; when they are not effective, they should be discontinued.“

– 2007 second addition APA Treatment Guidelines Updated Guidelines for Treating Patients With Dementia

– Supplement to American Journal of Psychiatry

AntidepressantsAntidepressants

Work best when agitation clearly related to mood

Premorbid HX of DepressionDon’t expect quick results – may take

6 – 12 weeks.Can safely give long term

If you must use atypicals:If you must use atypicals:

Be prepared to do Gradual Dose Reductions (GDR’s) – even if patient is doing well

Start lowWrite for automatic stop datesDon’t assume the patient is better

solely because of medicationContinue to trial behavioral

interventions

Anti-Anxiety medicationsAnti-Anxiety medications

Benzodiazepines – Ativan most common

Benefits:– IM / PO / IV– Relatively fast acting

Risks– Falls, Falls, Falls (hypotension)– Respiratory Depression– Dependence and Withdrawal

Other AnxiolyticsOther Anxiolytics

Buspar (Buspirone)– Not much bang for the buck– Slow onset– Good data in MR/DD

Sedative Hypnotics– Watch for cumulative effect

Neurontin (Gabapentin)– Expensive, but works

Sedative/HypnoticsSedative/Hypnotics Can be helpful for sleep regulation Low dose Trazodone

– 25 – 50 mg q 8 pm– Give at 5 pm if sundowning an issue

Remeron– 7.5 mg = increase sedation / appetite

Vistaril + Benadryl – avoid Melatonin 3 -6 mg may be helpful Minimize use of Ambien, Lunesta and BZ

hypnotics

Mood StabilizersMood Stabilizers

Lithium– Oldest– Riskiest, especially in elderly– Requires much monitoring

Depakote (Divalproex)Neurontin (Gabapentin)Newer Agents (Trileptal, et al)

My Conclusions on pharmacologic My Conclusions on pharmacologic treatments of agitationtreatments of agitation

Vascular Dementia– Depakote/Neurontin work best– Get on “plateau” – Remember Stroke prophylaxis

SDAT– Short term – anything that works– Mid to Late stages need mood stabilizers– AchI may help over the long term

Delirium– Recognize, then fix the cause– Antipsychotics work best (old>new)

Depression– Think long-term

Conclusions: Brain InjuryConclusions: Brain Injury

Acute agitation responds best to older antipsychotics, but only use short term (very sensitive EPSE)

Many are prone to seizures, so anticonvulsants may be best “first line” choice

Long Acting BZ’s (Klonopin) may raise seizure threshold and help “chronic” anxiety

Conclusions on treating“non Conclusions on treating“non complicated” dementia:complicated” dementia: Achesterase Inhibitors can help decelerate

decline– “Brain Boost” lasts 1 – 2 years– May be helpful in Vascular Dementia– Can delay ECF placement by 22 months

Can also help with Symptom ControlControl upsetting behaviorsMaintain ADL’sImprove thinking function

SummarySummary Patients with cognitive impairment commonly

become restless and agitated

Environmental triggers, medical disorders, and medication side effects need to be ruled out as contributing factors

Treatment approach must include appropriate nondrug interventions, as well as thoughtfully chosen medications

Primary caregiver requires attention, support, and respite

Unfortunately, medications have become the mainstay of treatment. Use short term

What can you do at end stages?What can you do at end stages?

Care for the Caregiver(s) and keep them functional (respite works)

Increase frequency of visitsPalliative Care / HOSPICEHome VisitsJoin the Alzheimer’s Association and

be a community resource

ConclusionsConclusionsResearch Funding has dramatically

increased - biomarkersProper Diagnosis drives treatment –

Depression v Delirim v Dementia

Early diagnosis doesn’t change the outcome, but can bend the curve

Few new treatments available since 2004– still not hopeless

Proper treatment improves Quality of Life and delays ECF placement

QUESTIONS ?QUESTIONS ?

Professional Development Associates

John J. Wernert, MD

dr.john.wernert@gmail.com