Lecture 45 - Pharmacotherapy of Neurocognitive Disorders: Dementia

Question 1

DSM-5: Neurocognitive Disorders

Answer 1

The DSM-5 changed the nomenclature for the diagnostic criteria of what has previously been known as “dementia”.
New diagnostic criteria have defined dementia, delirium, amnestic, and other cognitive disorders under “Neurocognitive Disorders” (NCDs)
These can be “major” or “mild” and include etiological subtypes
NCDs describe disorders in which the primary deficit is in cognitive
function and are acquired rather than developmental
Must represent a decline from previously attained level of functioning

Question 2

Neurocognitive domains

Answer 2

The basis for diagnostic criteria; each domain defines expectations for major and mild NCDs

Question 3

Complex attention

Answer 3

Sustained/divided attention, processing speed
focused on delirium, short term and reversible

Question 4

Learning and memory

Answer 4

Immediate/recent memory, very-long-term memory

Question 5

Perceptual/motor

Answer 5

Visual perception/praxis

Question 6

Executive function

Answer 6

Planning, decision-making, working memory, flexibility

Question 7

Language

Answer 7

Expressive and receptive language (naming, word finding)

Question 8

Social Cognition

Answer 8

Recognition of emotions, range of behavior

Question 9

DSM-5 – Mild Neurocognitive Disorders

Answer 9

Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains
o Concern of the individual, informant, or clinician that there is a mild decline in cognitive function
o Modest impairment in documented cognitive performance
Does NOT interfere with independence
Not attributed to a delirium episode (acute, temporary, cognitive decline)
Not better explained by another mental or medical disorder

Question 10

DSM-5 –
Major Neurocognitive disorder

Answer 10

Evidence of significant cognitive decline from a previous level of performance in one or more domains
o Concern of the individual, informant, or clinician of significant decline
o Substantial impairment in documented cognitive performance
Cognitive deficits interfere with independence
Not attributed to a delirium episode (acute, temporary, cognitive decline)
Not better explained by another mental or medical disorder

Question 11

Etiological subtypes

Answer 11

May be used in either major or mild NCDs
Alzheimer’s disease
Vascular dementia
Lewy body disease
*May be considered unspecified if doesn’t fit any of the above
*Can specify with or without behavioral disturbances

Question 12

Evaluation

Answer 12

◦ Family history of dementia ◦ Head injuries/falls
◦ Alcohol/substance use
◦ Depression
◦ Acute illness
◦ Medication review
◦ Language impairment
◦ Extrapyramidal symptoms ◦ Focal weakness, gait

Question 13

Differential diagnosis

Answer 13

◦ CV disease/vascular dementia
◦ Lewy body dementia
◦ Parkinson’s disease
◦ Normal pressure hydrocephalus
◦ Mixed dementia
◦ Pick’s disease (frontotemporal)
◦ Huntington’s disease
◦ Reversible causes

Question 14

Reversible cognitive decline

Answer 14

Also known as “reversible labs”
◦ B12 or folate deficiency
◦ Hypothyroidism
◦ CBC
◦ Electrolytes
◦ Liver function tests
◦ Infection (especially UTI)
◦ Depression – pseudodementia
◦ RPR/VDRL – syphilis
some or all of these labs should be evaluated
Rarely explains symptoms
Infection may cause delirium presentation with or without underlying dementia

Question 15

Drug-induced cognitive impairment

Answer 15

• Skeletal Muscle Relaxants
• Tricyclic Antidepressants
• Bladder antispasmodics
• Antihistamines
• OTC allergy/cough cold
• Rx anti-emetics

Question 16

Rating scales

Answer 16

MMSE
Alzheimer’s Disease Assessment Scale (ADAS)
Montreal Cognitive Assessment (MoCA)
Saint Louis University Mental Status (SLUMS) Exam

Question 17

MMSE

Answer 17

◦ Used to assess cognitive functioning
◦ Evaluates orientation, memory, attention, naming, comprehension, spatial orientation
◦ Change in 3-4 points over a 1 year period indicates significant decline
◦ Maximum score = 30 points
◦ Mild: 26 – 18; Moderate: 17 – 10; Severe: 9 – 0
◦ Test performance is influenced by age and educational level
◦ Clinically used to follow scores over time, but large clinical variation

Question 18

ADAS

Answer 18

◦ Evaluates severity of dysfunction in cognitive and non-cognitive behaviors over time
◦ 11 cognitive items, 10 non-cognitive behavioral items
◦ Cognitive subscale used by FDA in evaluating clinical trials as a primary outcome measure (ADAS-cog)
◦ Range of scores 0-70, higher scores indicate worse cognitive performance
◦ Average cognitive decline in an untreated person with severe Alzheimer’s disease is a 6 – 11 point decrease per year

Question 19

MoCA

Answer 19

◦ Better differentiates mild cognitive impairment
◦ Visuospatial/executive, naming (animals), memory (remember 3 objects)
◦ Attention – repeating numbers forward/backward
◦ Language/fluency
◦ Abstraction – how do 3 objects relate to
each other
◦ Orientation
◦ 30 point total score

Question 20

SLUMS

Answer 20

◦ Orientation – day/year/state
◦ Remember 5 objects
◦ Making change
◦ Naming animals in one minute
◦ Numbers forward/backward
◦ Clock face drawing
◦ Spatial orientation
◦ Listening to a story and relating details back
◦ 30 point total scale

Question 21

Treatment Goals

Answer 21

Currently, the goal of treatment is to slow the symptoms of cognitive decline and preserve functioning for as long as possible
Newest remove pathology, but impact on long-term progression, disease course continues to be studied
Treatment of psychiatric and behavioral problems may maintain ability to live in one’s own home as long as possible.
no disease modifying agent

Question 22

Options for treatment

Answer 22

cholinesterase inhibitors
NMDA receptor antagonist

Question 23

Cholinesterase inhibitors

Answer 23

◦ Recommended as first-line treatment with no preference as to agent
◦ All are FDA-approved for mild to moderate dementia
◦ Donepezil is FDA-approved for severe dementia
◦ Donepezil usually chosen first due to ease of dose titration and once-daily dosing
◦ Donepezil (Aricept)
◦ Rivastigmine (Exelon)
◦ Galantamine (Razadyne)

Question 24

NMDA Receptor Antagonist

Answer 24

◦ Does not slow or prevent neurodegeneration
◦ FDA-approved in moderate to severe dementia only
◦ NOT useful in mild cognitive impairments
◦ Marginal benefit usually realized in Alzheimer’s disease
◦ Memantine (Namenda)
◦ Donepezil/Memantine (Namzaric)

Question 25

Donepezil

Answer 25

efficacy at 5 mg
Dosing: Initiate 5mg once daily at bedtime, increase to 10mg once daily at bedtime after 4 – 6 weeks
Side Effects: GI bleeding (caution if used with NSAIDs), N/V/D, bradycardia, syncope, insomnia, weight loss
P450 2D6 and 3A3/4 substrate

Question 26

Galantamine

Answer 26

cannot prove efficacy at a starting dose
Dosing: IR = Initiate 4mg twice daily for 4 weeks with breakfast and dinner; Doses > 16 mg/day are not recommended for moderate renal/hepatic impairment
Side effects: GI bleeding, weight loss (warnings)
N/V/D, bradycardia, syncope, insomnia
P450 2D6 and 3A4 substrate

Question 27

Rivastigmine

Answer 27

cannot prove efficacy at a starting dose
Dosing: Oral: Initiate 1.5mg twice daily for at least 2 weeks; Take with meals to minimize GI effects
SE: Toxicity due to not removing previous patch every day N/V/D (SIGNIFICANT)
Esophageal rupture in one case (reason for need to restart lower dose if therapy interrupted); No P450 interactions

Question 28

Memantine

Answer 28

IR tablets only available as generic
Dosing: Dose adjustment required in severe renal impairment (CrCl
= 5 – 29 ml/min) = Initiate 5mg once daily x 1 week, if tolerated, target dose = 5mg twice daily (IR). LA dose max
= 14 mg/day
IR: Initiate 5mg once daily x 1 week, LA: Initiate 7mg once daily x 1 week
SE: Use with caution in patients with seizure disorder, hallucinations, insomnia, confusion, Use with caution with carbonic anhydrase inhibitors and sodium bicarbonate – clearance of memantine is reduced by 80% if urine is alkalinized
No P450 interactions

Question 29

Memantine HCL ER and donepezil capsules (namzaric)

Answer 29

On donepezil 10 mg only: start Namzaric 7/10 daily and increase by 7 mg increments as tolerated to 28/10 target dose once daily
If on memantine 10 mg twice daily or ER 28 mg once daily, switch to Namzaric 28/10 with evening meal once daily
Warning for vagotonic effects like bradycardia and heart block; increased risk of GI ulceration; diarrhea, nausea, vomiting; bladder outflow obstructions

Question 30

Combination Treament

Answer 30

Cholinesterase inhibitor + NMDA receptor antagonist
Initial treatment is generally a cholinesterase inhibitor
If decline noted despite treatment at maximum tolerated dose, consider use of NMDA receptor antagonist in combination if patient is in moderate to severe stage
Unfortunately, decline is very common, drug therapy may maintain current cognitive functioning for a matter of months
more efficacious than either treatment alone

Question 31

Key concepts: Oral Agents

Answer 31

. Target dose is highest tolerated
. Many adverse effects of treatment are possible (and likely); early
recognition may aid benefits/risk discussions
. Sudden stop/start of therapies should be avoided
. Withdrawal of therapy (among persistent users) should be considered with progressed symptoms
. Management of behavioral symptoms of dementia poorly responsive to drug (and possibly worse)

Question 32

Aducanumab targets

Answer 32

the N-terminus of Abeta

Question 33

Aducanumab

Answer 33

ARIA: up to 40%; requires MRI of brain within one year of starting treatment, then before 7th & 12th doses.

Question 34

Lecanemab

Answer 34

ARIA: Up to 30%; requires MRI of brain within one year of starting treatment, then before 5th, 7th & 14th doses.

Question 35

Aducanumab and Lecanemab require

Answer 35

presence of amyloid beta pathology prior to initiating treatment

Question 36

Non-pharmacological interventions

Answer 36

Consider vision, hearing, and other sensory impairments
Cognitive stimulation (puzzles, problem solving, Sudoku) can have short-term benefits on cognition an QOL
Maintain a consistent, structured environment with appropriate stimulation Provide frequent reminders and orientation cues
Reduce choices, keep requests simple, avoid complex tasks that lead to frustration Monitor for sudden changes in cognition and functioning
◦ Could be delirium due to reversible cause (dehydration or urinary tract infection/pneumonia)

Question 37

Behavioral Interventions

Answer 37

Increase enjoyable activities – listen to music, light exercise, pet therapy
Redirect and refocus – reminiscence therapy
Increase social activities – keep them busy
Encourage activities that are appropriate to the individual patient’s functional level
Establish regular sleep habits
Make sure the environment is safe, calm, and predictable
Watch caregiver for signs/symptoms of depression

Question 38

Agitation Interventions

Answer 38

Recognize triggers – pain, fecal impaction, medical illness, boredom, depression, stressors
Intervene early, recognize behavior
Outdoor activities more efficacious than antipsychotics for managing
agitation and aggression
Maintain calmness in interactions, avoid arguing or trying to reason. Avoid confrontation – meet the patient where they are and avoid forcing them into your reality – live in theirs unless is causes distress to them or others
Introduce distraction techniques, turn attention to something pleasant Minimize audio and visual stressors from the environment

Question 39

Treatment of psychosis and behavioral disturbances

Answer 39

antipsychotics
antidepressants

Question 40

Antipsychotics

Answer 40

PSYCHOSIS or severe behavioral problems (psychomotor agitation, combativeness)
NOT USEFUL for repetitive behaviors (yelling, wandering)
Atypical antipsychotics – quetiapine, risperidone
Boxed warning for increased risk of death or stroke in older adults with dementia

Question 41

Antidepressants

Answer 41

Depression is a common co-morbid condition in dementia
If unaddressed, could worsen cognitive symptoms
Antidepressant efficacy is controversial, but sometimes warranted given tolerability of antidepressants
SSRIs usually first-line – avoid paroxetine
Mirtazapine, venlafaxine, bupropion may also be considered

Question 42

Wandering interventions

Answer 42

Environmental Modifications – Put coat/hat away to reduce visual cues to leave
Activities – keep patient busy with activities that they enjoy, participate with them (escort)
Electronic alarm system – likely available in residential facility
Secure environment with complex door handles, safety locks
Safety plan – ID bracelet, name in clothing
“Silver Alert” and Alzheimer’s Association Safe Return Program Wearable technologies or inserts

Question 43

Sleep Disturbance interventions

Answer 43

Consistent bedtime
Minimize daytime napping
Restrict alcohol and caffeine intake
Avoid changes in daily routine that could disrupt sleep at night
Keep nighttime noise, light level, and change in temperature to a minimum
Avoid television
If listening to music, be sure it’s the patient’s preferred music or music with slower rate – heart rate can slow to match rhythm

Question 44

Other dementia subtypes

Answer 44

vascular dementia
lewy body dementia

Question 45

Vascular dementia

Answer 45

◦ Cognitive decline usually a result of vascular insult (stroke)
◦ Treat vascular condition, ie, hypertension
◦ Cholinesterase inhibitors are recommended
◦ Especially useful if “mixed dementia” – vascular + Alzheimer’s - common

Question 46

Lew Body dementia

Answer 46

◦ Fluctuating cognition with variations in attention and alertness
◦ Visual hallucinations common
◦ Cholinesterase inhibitors and memantine
may be helpful
◦ VERY sensitive to side effects of antipsychotics, may have to use, but low doses – quetiapine usual choice