medication treatments for dementia stephen thielke · 2017-10-09 · racetams methyleneblue...
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Medication Treatments for Dementia
Stephen Thielke
Treatment is a MORAL decision.
Facts can help you determine HOW to accomplish something.
Facts cannot tell you WHAT YOU WANT to accomplish.
Dementia Meds (Thielke), NWGEC WInter 2015 1
IS
Factual
Scientific
SHOULD
OUGHT
Moral
Values-Based
X
The GoodDiminished symptoms?
Cure?
Years of life?
Quality-adjusted years of life?
Patient autonomy?
Public safety?
“They would thank me later”?
“I wouldn’t want to live like that”?
Long-term ends or the means?
Intentions or results?
Dementia Meds (Thielke), NWGEC WInter 2015 2
“Medications for dementia do not fix the problem. They are unlikely to help you and are expensive and dangerous. You should not take one.”
“We have FDA-approved treatments for dementia. They treat the disease. You should use one.”
“FDA-approved treatments exist. They improve symptoms, but produce no difference in caregiver burden or nursing home … Do you want to use one?”
“Treatments exist, but they do not modify the disease course, and provide only symptomatic benefit in about 1/3 of patients. Do you want to use one?”
Possible Treatment Advice
Official and Unofficial Indications
FDA-approved does not mean “should be prescribed for everyone”.
Medication giving and taking are complex behaviors.
Your reasons for prescribing a medication are less important than the patient’s or family’s reasons for using it.
Why might families want to give medications, regardless of their direct effects?
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One of the first duties of the physician is to educate the masses not to take medicine.
Far too large a section of the treatment of disease is today controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudo-science.
Evidence-Based Outcomes
• The outcome is supposed to be what matters to people who would use the treatment.
• What outcomes were chosen? Were they chosen before or after the study? Did all outcomes improve?
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OVERVIEW:Alzheimer’s Dementia
Cholinesterase InhibitorsMemantine
Other Dementias
Behavioral Symptoms
Definition of Dementia
A significant
chronic
loss
in memory and/or mental functions,
involving structural damage to the brain.
DEMENTIA IS NOT CURABLE.
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THE NEURONS HAVE DIED
Why would you want to give a medication for an incurable disease?
How much risk would you undertake in order to accomplish certain benefits?
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Cognitive Symptoms• Memory problem plus one of:
–Aphasia
–Apraxia
–Agnosia
–Executive dysfunction
• Causes significant functional impairments
Problematic Behaviors• Wandering
• Agitation– Verbal or motor
– Inappropriate or repetitive
• Poorly timed bodily needs
• Unsafe tasks– Driving
– Cooking
AggressionScreamingSexualityRepetitionFollowingDestructionStereotypy
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Neuropsychiatric Symptoms
• Hallucinations
• Delusions
• Paranoia
• Depression
• Apathy
• Emotional incontinence
• Restlessness
Frequency and Course of Symptoms
Cache County Study: 20% of community-dwelling patients with Alzheimer’s dementia have behavioral symptoms.
Lyketsos et al, Am J Psy 2000
Cognitive decline is steady during the course of dementia, but behavioral symptoms fluctuate.
Psychomotor agitation is the most persistent.Devanand et al, Arch Gen Psy 1997
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Categories of Medication with an FDA Indication to Treat Cognitive Symptoms of
Dementia:
2
Medications with an FDA Indication to Treat Behavioral
Symptoms of Dementia:
0
Dementia Meds (Thielke), NWGEC WInter 2015 9
Medications with an FDA Indication to Prevent Dementia:
0
Medications used in at least one trial to prevent or treat dementia
or its symptoms:
>50
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Tricyclics
SSRIs
SNRIs
Bupropion
Mirtazapine
Trazodone
Typical antipsychotics
Atypical antipsychotics
Buspirone
Alpha blockers
Beta blockers
Antihistamines
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Cannabinoids
Opioids
Methylphenidate
Lamotrigine
Antiepileptic drugs
Lithium
Estrogen
Vitamin E
Homocysteine
B Vitamins
Resveratrol
Ginseng
Dementia Meds (Thielke), NWGEC WInter 2015 12
Acetylcholinesterase inhibitors
Nicotine
NMDA antagonists
Lisuride
Racetams
Methylene blue
Intranasal insulin
Cyproterone
NSAIDs
COX2 Inhibitors
H2 blockers
Thiazide diuretics
Calcium channel blockers
ACE inhibitors
Statins
Dementia Meds (Thielke), NWGEC WInter 2015 13
CONCLUSION: Acupuncture at Baihui (GV 20), Shenshu (BL 23), Geshu (BL 17), and the points selected according to the midnight-noon, ebb-flow eight methods of the intelligent turtle combined with the drug nimodipine can yield definite therapeutic effects in vascular dementia.
Zhong 2009
Cholinesterase Inhibitors
Galantamine (Razadyne, Reminyl)Donepezil (Aricept)Rivastigmine (Exelon)Tacrine (Cognex)
Increase levels of acetylcholine more acetylcholine in brain, more parasympathetic activity in periphery
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Cholinesterase Inhibitors
Cholinesterase Inhibitors
Side effects: usually transitory
GI upset, diarrhea
Reduced heart rate
Interactions
Effects are BLOCKED by anticholinergic drugs
No significant drug-drug interactions
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Winblad, 2001
MM
SE
Sco
re
Corey-Bloom, 2000
AD
AS
-Cog
Sco
re
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Tariot, 2000
MM
SE
Sco
re
But…
Courtney, 2004
Over 2 years, patients on donepezil showed 0.8 points improvement in MMSE and a one-point improvement in ADLs
n=565
Dementia Meds (Thielke), NWGEC WInter 2015 17
Cholinesterase Inhibitors
Courtney, 2004
“no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths”
Dementia Meds (Thielke), NWGEC WInter 2015 18
Cost Effectiveness:Cost of cholinesterase inhibitor is
roughly $5 per day
Cost-effectiveness ratio of the most cost-effective medication:
$400 per unit decline in the ADAS-cog subscale over 6 months
The ADAS-cog has 70 points
Perras C, Shukla VK, Lessard C, Skidmore B, Bergman H, Gauthier S. Cholinesterase inhibitors for Alzheimer’s disease: a systematic review of randomized controlled trials [Technology report no 58]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2005.
“Although statistical improvements were noted in the analyses, they do not necessarily translate into clinically relevant benefits for the patients receiving these drugs or for their caregivers.”
Dementia Meds (Thielke), NWGEC WInter 2015 19
MemantinePartially reversible NMDA antagonistApproved for moderate to severe dementiaMost studies evaluated combination of memantine with cholinesterase inhibitors
Few side effects: headache, constipation, confusion
FDA Indications
Generic Trade
FDA Indication (Alzheimer’s Stage)
donepezil Aricept All stages
galantamine Razadyne Mild to moderate
rivastigmine Exelon Mild to moderate
tacrine Cognex Mild to moderate
memantine Namenda Moderate tosevere
This does NOT mean that everyone with a certain stage of dementia should or must be taking the corresponding medication!
Dementia Meds (Thielke), NWGEC WInter 2015 20
“Pharmacologic therapeutic interventions of the 5
FDA-approved drugs discussed in the review have shown statistically significant improvement in scores on various instruments to evaluate changes in patients with dementia. Most of these outcomes are not used in routine clinical practice, and interpretation of the clinical importance of improvements is challenging. Many of the improvements demonstrated in the trials, although statistically significant, were not clinically important or their relative importance cannot be determined at this time.”
Qaseem et al, Current Pharmacologic Treatment of Dementia: A Clinical Practice Guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378
Vascular Dementia
No FDA-indicated treatments
No consistent results from treatment trials of cholinesterase inhibitors
Dementia Meds (Thielke), NWGEC WInter 2015 21
Lewy Body Dementia
AVOID ANTIPSYCHOTICS
No FDA-indicated treatments for LewyBody dementia
Rivastigmine has an indication for treating dementia associated with Parkinson’s disease
AVOID ANTIPSYCHOTICS
Frontotemporal Dementia
No FDA-approved treatments
Many small trials, many of them negative
Difficult to conduct good trials
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Stopping Medications
Patients often seem worse after they have stopped a medication.
This may have nothing to do with the medication.
– Other medical events
– Other changes in treatment
– Changes in caregiving and environment
– Cause and effect
What are the effects of stopping a medication that can be attributed to the medication? Double-blind, placebo-controlled discontinuation trial
Dementia Meds (Thielke), NWGEC WInter 2015 23
Agitation
CONSIDER
Unmet needs
Conditioning
Natural response to environmental cues
BEFORE turning to medications
Common TriggersChange in caregiver
Change in living arrangements
Travel
Hospitalization
Houseguests
Bathing / toileting
Dressing / undressing
Dementia Meds (Thielke), NWGEC WInter 2015 24
High-Yield Behavioral Strategies
Distraction
Empathetic attention
Comforting stimuli
“Return” home
AntipsychoticsIn small studies, typical and atypical agents show modest aggregate improvements in behavioral symptoms compared to placebo on clinician-defined rating scales. Devenand et al, Am J Psy 1998
Street et al, Arch Gen Psy 2000
BLACK BOX WARNING
Elderly patents with dementia-related psychosis treated with atypical or typical antipsychotic drugs are at an increased risk of death compared to placebo.
All-cause mortality is increased by 1.6x
Dementia Meds (Thielke), NWGEC WInter 2015 25
Prescribing an Antipsychotic
Have an informed consent discussion
whenever possible.
Monitor the response
Use the lowest dose possible to achieve the
response.
Stop the drug if there is no positive response.
Continue to consider the causes of agitation.
Continue to apply behavioral approaches.
PrazosinAlpha-1 adrenergic antagonist (opposes adrenaline): counters “fight or flight”
Not a very effective antihypertensive (needs doses of about 20mg per day).
Generally very safe.Used for PTSD symptoms, especially nightmares.
Off-label for dementia-related agitation.The one published trial (Wang 2009) suggested effectiveness and safety.
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Prazosin – rough dosing guidelines
Start at 1mg at bedtime.Increase to 1mg twice a day in 3-4 days.Increase in 1mg increments until agitation improves.
Maximum target dose about 5mg twice a day (10mg total).
Dosing recommendations being developed.
Other possible treatments
Trazodone
SSRIs
Antiepileptic medications
Benzodiazepines (be careful)
Dementia Meds (Thielke), NWGEC WInter 2015 27
AVOID ANTICHOLINERGICS
SOME of the most powerful:-Oxybutynin (Ditropan)-Diphenhydramine (Benadryl)-Doxylamine (Unisom)-Hydroxyzine (Vistaril)-Dimenhydrinate (Dramamine)
Caregiver Interventions vs Pills
Mittelman 2004
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“Medications for dementia do not fix the problem. They are unlikely to help you and are expensive and dangerous. You should not take one.”
“We have FDA-approved treatments for dementia. They treat the disease. You should use one.”
“FDA-approved treatments exist. They improve symptoms, but produce no difference in caregiver burden or nursing home … Do you want to use one?”
“Treatments exist, but they do not modify the disease course, and provide only symptomatic benefit in about 1/3 of patients. Do you want to use one?”
What is the right advice?
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