Medication Treatments for Dementia Stephen Thielke · 2017-10-09 · Racetams Methyleneblue...

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?


“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?


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?


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.


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?


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


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


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


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


Tricyclics

SSRIs

SNRIs

Bupropion

Mirtazapine

Trazodone

Typical antipsychotics

Atypical antipsychotics

Buspirone

Alpha blockers

Beta blockers

Antihistamines


Cannabinoids

Opioids

Methylphenidate

Lamotrigine

Antiepileptic drugs

Lithium

Estrogen

Vitamin E

Homocysteine

B Vitamins

Resveratrol

Ginseng


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


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




Side effects: usually transitory

GI upset, diarrhea

Reduced heart rate

Interactions

Effects are BLOCKED by anticholinergic drugs

No significant drug-drug interactions


Winblad, 2001

MM

SE

Sco

re

Corey-Bloom, 2000

AD

AS

-Cog

Sco

re


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



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”


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.”


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!


“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


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


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


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


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


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.


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)


AVOID ANTICHOLINERGICS

SOME of the most powerful:-Oxybutynin (Ditropan)-Diphenhydramine (Benadryl)-Doxylamine (Unisom)-Hydroxyzine (Vistaril)-Dimenhydrinate (Dramamine)

Caregiver Interventions vs Pills

Mittelman 2004


“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?


Medication Treatments for Dementia Stephen Thielke · 2017-10-09 · Racetams Methyleneblue...

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Transcript of Medication Treatments for Dementia Stephen Thielke · 2017-10-09 · Racetams Methyleneblue...