Transcript Pharmacological interventions in the treatment of agitated

Pharmacological Interventions for
the Cognitively Impaired
Geriatric Patient
Indiana Osteopathic Association
117th Annual Convention
May 2 – 4, 2014
French Lick Resort
John J. Wernert, M.D., MHA
Professional Development Associates
Faculty Disclosure
John J. Wernert, M.D, MHA
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Consultant:
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Eskenazi Health
Franciscan Alliance
Federally Qualified Health Centers
Archdiocese of Indianapolis
Extended Care Facilities
LEARNING OBJECTIVES
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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
it’s natural course”
Philosopher Arthur Schopenhauer
Most common reasons for
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 Disorders
U.S. Society = $500 Billion annually
 19 % of the average American
income is devoted to treating Brain
diseases
 55 % cost is Dementias
 Psychiatric Illnesses = $170 Billion
 AD alone > $100 billion
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Prevalence of Mental
Disorders Age 65+
 Mental
disorders:
(including dementia)
 Psychiatric disorders
26.3%
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
More time needed to learn new
information
 Working-memory capacity is limited
 Slowed retrieval time
 Too much clutter – hard to prioritize
 Long-term memory becomes less
reliable
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Sensory impairments
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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:
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Caused by metabolic stress
 Cell Level = transcription errors
 Body Level = develop comorbidities
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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:
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Confirmed
– Age
– Family History
– APOE-4 gene (only 50 % of genetic variability)
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Possible
– Other genes
– Head trauma
– Lower educational achievement (use it or
loose it vs healthy lifestyle)
– Chronic stress
– Depression
Protective Factors for Brain
Aging:
Aerobic exercise
 Estrogen
 Anti-inflammatory drugs
 Anti-oxidants
 Low-fat diet
 Wine (Germans say beer)
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Wine and Reduced Incidence of Dementia?
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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)
Neurodegeneration
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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
the “Three D’s”:
 Delirium
↓↓ ↑↑
 Dementia
↕↕
 Depression
Neurodegenerative Conditions
lead to all three “D’s”
High risk of polypharmacy
 Despondency of chronic illness
 Weakened resistance
 Fragile brain = iatrogenic illnesses
 Sensitive to drug side effects
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Delirium vs Dementia
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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;
Under-recognized (missed 50%)
 Reversible (if cause correctible)
 Present in 30 % of hospitalized elderly
 Delays discharge
 Increases need for ECF placement
 Higher mortality (6 mo mortality>50%)
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Depression Associated with
Worse Health Outcomes
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Worse outcomes
– Hip fractures
– Myocardial infarction
– Cancer (Mossey 1990; Penninx et al. 2001; Evans 1999)
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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 in Older Adults and
Health Care Costs
Annual Cost of Healthcare
$7,000
$6,000
$5,000
None CES-D<8
Moderate CES-D=8-15
Severe CES-D>16
$4,000
$3,000
$2,000
$1,000
$0
0 (n=859)
1-2 (n=616)
3-5 (n=659)
6-16 (n=423)
Levels of Chronic Disease Score
Unutzer, et al., 1997; JAMA
Suicide in Older Adults
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65+: highest suicide rate of any age group
85+: 2X the national average (CDC 1999)
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Peak suicide rates:
– Suicide rate goes up continuously for men
– Peaks at midlife for women, then declines
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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 May be aware of
about memory
changes in cognition;
impairment
fluctuates
Likely to hide or be
unaware of cognitive
deficits
Activities of Daily
Living (ADLs)
May neglect basic self- May be intact or
care
impaired
May be intact early,
impaired as disease
progresses
Instrumental Activities May be intact or
of Daily Living (IADLs) impaired
May be intact or
impaired
May be intact early,
impaired before ADLs
as disease progresses
Summary of Findings
Dementia and Delirium strongly linked
 Depression is common in medical
disorders among older patients
 All three “D’s”;
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– 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
Condition prone to the three “D’s”:
Parkinson’s Disease
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Imbalance of ACH – Dopamine
– Not enough Dop = Parkinsons
– Too much Dop = psychosis
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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
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Dementia
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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
in Dementia
C
Age-Associated Memory Impairment
O
G
N
Assymptomatic
I
MCI
T
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AD
O
N
Age
30
40
50
60
70
80
SDAT
39 % go undiagnosed
 Early onset of Memory Deficits
 Absense of Neurologic Deficits
 No CVA or injury on CT
 Makes up 70 % of Dementia Pt’s
 >5.5 million Americans currently Dx
 Already 4th leading cause of death
 Live 7 – 10 years after DX
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International Working Group for New
Research Criteria for the DX of
Alzheimer’s Disease
Current dx dependent upon
documenting mental decline
 New Proposed Diagnostic Criteria for
SDAT
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– MCI and evidence of AD from
biomarkers ( eg, + amyloid scan, CSF
markers of amyloid or tau)
– AD = Dementia + biomarkers
Three of the new guidelines focus
on three stages of Alzheimer's
disease:
(1) dementia due to Alzheimer's
 (2) mild cognitive impairment (MCI)
due to Alzheimer's
 (3) preclinical (presymptomatic)
Alzheimer's.
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“Pre-clinical Alzheimer’s”
5 year study of monoclonal
antibodies + screening tests
 Looking for specific biomarkers
 30% over 65 have amyloid plaques
 Brain changes caused by the disease
may begin decades before symptoms
such as memory loss and confusion
occur.
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“Pre-clinical Alzheimer’s”
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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 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.
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Neuroimaging
Structural
Imaging
• CT
• MRI
Functional
Imaging
• fMRI
• PET
Molecular
Imaging
• SPECT
• Radiotracers
Neuroimaging and Dementia
AAN Guidelines = MRI / CT
 Medicare reimbursement – FDG-PET
to differentiate AD from FTD
 Developing PET technologies –
amyloid plaque and tau tangle
imaging
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Neurology 2004; www.cms.gov
Amyloid Scans
Pre-senile Alzheimer’s Disease
Rare
 Prior to age 60
 Autosomal 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
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SDAT: Making the Diagnosis
Earlier (risk factors)
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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 Considerations
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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)
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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;
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?
Safety Issues (driving, compliance)
 Advanced Planning while Pt
competent (POA, HCR, Guardian)
 Family Stress and Misunderstanding
 Early Education of Caregivers
 Specific, stabilizing Tx Available
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Approved AD/Cognitive Treatments
Aricept (Donepezil)
 Exelon (Rivastigmine) AChE + BuChE
 Reminyl (Galantamine)
 Namenda (Memantine)
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Vitamin E (a-tocopherol) 1200 IU/d
Possibly beneficial:
Estrogen (HRT)
 Selegiline
 Ginko biloba
 Cholesterol lowering agents
 Reality Therapy
 Music Therapy
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…and the Pipeline is dry…
NMDA receptor antagonists. Limits
excitotoxicity caused by excessive presynaptic 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)
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Vascular Dementia
20% of Dementias
 Not always clear findings on CT/MRI
 Early Gait Disturbance
 Frequent falls
 Early incontinence
 Usually prominent personality and
mood changes
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4 Sub-types of Vascular Dementia
Single infarct Dementia (behavior
worse with frontal involvement)
 MID
 Small vessel disease (must be more
than mild)
 Watershed injury (hypoperfusion)
 Males vs Female considerations
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The remaining 10 %
Frontal Lobe Dementias (Picks)
 Lewy Body Dementia
 Parkinson’s Dz
 Other Neurodegenerative conditions
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Bottom Line Diagnose early,
Treat early,
So patients can
Stay Home Longer!
(on average, 18 – 24 months)
Geriatric Brain injuries:
Usually associated with falls
 Acute and Massive CVA’s
 Less favorable outcomes
 Increased mortality
 More likely need ECF
 More likely depressed
 Much more sensitive to medications
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When brain is injured, behaviors
are inevitable
Challenge is to determine which
behaviors are tolerable, and which
require medication or behavioral
treatments.
Medications used too often?
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“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.”
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Am J Psychiatry. 2011;168:831-839, 767-769. Abstract Editorial
What behaviors will respond to
medications?
Agitation – acute and chronic
 Psychosis – especially positive
symptoms
 Depression – situational and major
 Anxiety
 Mood Instability - Bipolar
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Choices for treating Agitated
Behaviors
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Antipsychotics
– Typical
– Atypical (really second generation)
Antidepressants
 Anxiolytics
 Mood Stabilizers
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ANTIPSYCHOTICS CONVENTIONALS
Haldol (haloperidol)
 Prolixin (fluphenazine)
 Navane (thiothixene)
 Loxitane (loxapine)
 Moban (molidone)
 Stelazine (trifluoperazine)
 Mellaril (thioridazine)
 Thorazine (chlorpromazine)
 Trilafon (perphenazine)
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ANTIPSYCHOTICS - ATYPICALS
 Risperdal
(risperidone)
 Zyprexa (olanzapine)
 Seroquel (quetiapine)
 Clozaril (clozapine)
 Geodon (ziprasidone)
 Abilify (aripiprazole) - ?3rd generation
New
nd
2
Generation have no role
Fanapt (iloperidone)
 Saphris (asenapine)
 Invega (paliperidone)
 Latuda (lurasidone)
 Solian (amisulpride)
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Safety vs Effectiveness
Atypicals clearly safer, but don’t
always work
 If they do work, can be given longer
 Conventionals often work faster and
are more effective.
 Must be used with more caution, and
for shorter periods of time
 Monitoring is the key
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FDA Advisory for Antipsychotic Drugs
Used for TX of Behavioral Disorders in
Elderly PT’s [Black Box] (April 11, 2005)
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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
Guidelines 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 longterm-care setting. "That is the most important way the
guidelines will change practice.“
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“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
Antidepressants
Work best when agitation clearly
related to mood
 Premorbid HX of Depression
 Don’t expect quick results – may take
6 – 12 weeks.
 Can safely give long term
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If you must use atypicals:
Be prepared to do Gradual Dose
Reductions (GDR’s) – even if patient
is doing well
 Start low
 Write for automatic stop dates
 Don’t assume the patient is better
solely because of medication
 Continue to trial behavioral
interventions
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Anti-Anxiety medications
Benzodiazepines – Ativan most
common
 Benefits:
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– IM / PO / IV
– Relatively fast acting
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Risks
– Falls, Falls, Falls (hypotension)
– Respiratory Depression
– Dependence and Withdrawal
Other Anxiolytics
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Buspar (Buspirone)
– Not much bang for the buck
– Slow onset
– Good data in MR/DD
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Sedative Hypnotics
– Watch for cumulative effect
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Neurontin (Gabapentin)
– Expensive, but works
Sedative/Hypnotics
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Can be helpful for sleep regulation
 Low dose Trazodone
– 25 – 50 mg q 8 pm
– Give at 5 pm if sundowning an issue
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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
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Mood Stabilizers
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Lithium
– Oldest
– Riskiest, especially in elderly
– Requires much monitoring
Depakote (Divalproex)
 Neurontin (Gabapentin)
 Newer Agents (Trileptal, et al)
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My Conclusions on pharmacologic
treatments of agitation
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Vascular Dementia
– Depakote/Neurontin work best
– Get on “plateau”
– Remember Stroke prophylaxis
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SDAT
– Short term – anything that works
– Mid to Late stages need mood stabilizers
– AchI may help over the long term
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Delirium
– Recognize, then fix the cause
– Antipsychotics work best (old>new)
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Depression
– Think long-term
Conclusions: Brain Injury
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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
complicated” dementia:
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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 Control
Control upsetting behaviors
Maintain ADL’s
Improve thinking function
Summary
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Patients with cognitive impairment commonly
become restless and agitated
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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
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Unfortunately, medications have become the
mainstay of treatment. Use short term
What can you do at end stages?
Care for the Caregiver(s) and keep
them functional (respite works)
 Increase frequency of visits
 Palliative Care / HOSPICE
 Home Visits
 Join the Alzheimer’s Association and
be a community resource
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Conclusions
Research Funding has dramatically
increased - biomarkers
 Proper Diagnosis drives treatment –
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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
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QUESTIONS ?
Professional Development Associates
John J. Wernert, MD
[email protected]