Lecture 45 - Pharmacotherapy of Neurocognitive Disorders: Dementia Flashcards
DSM-5: Neurocognitive Disorders
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
Neurocognitive domains
The basis for diagnostic criteria; each domain defines expectations for major and mild NCDs
Complex attention
Sustained/divided attention, processing speed
focused on delirium, short term and reversible
Learning and memory
Immediate/recent memory, very-long-term memory
Perceptual/motor
Visual perception/praxis
Executive function
Planning, decision-making, working memory, flexibility
Language
Expressive and receptive language (naming, word finding)
Social Cognition
Recognition of emotions, range of behavior
DSM-5 – Mild Neurocognitive Disorders
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
DSM-5 –
Major Neurocognitive disorder
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
Etiological subtypes
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
Evaluation
◦ Family history of dementia ◦ Head injuries/falls
◦ Alcohol/substance use
◦ Depression
◦ Acute illness
◦ Medication review
◦ Language impairment
◦ Extrapyramidal symptoms ◦ Focal weakness, gait
Differential diagnosis
◦ CV disease/vascular dementia
◦ Lewy body dementia
◦ Parkinson’s disease
◦ Normal pressure hydrocephalus
◦ Mixed dementia
◦ Pick’s disease (frontotemporal)
◦ Huntington’s disease
◦ Reversible causes
Reversible cognitive decline
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
Drug-induced cognitive impairment
- Skeletal Muscle Relaxants
- Tricyclic Antidepressants
- Bladder antispasmodics
- Antihistamines
- OTC allergy/cough cold
- Rx anti-emetics
Rating scales
MMSE
Alzheimer’s Disease Assessment Scale (ADAS)
Montreal Cognitive Assessment (MoCA)
Saint Louis University Mental Status (SLUMS) Exam
MMSE
◦ 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
ADAS
◦ 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
MoCA
◦ 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
SLUMS
◦ 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
Treatment Goals
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
Options for treatment
cholinesterase inhibitors
NMDA receptor antagonist
Cholinesterase inhibitors
◦ 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)
NMDA Receptor Antagonist
◦ 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)
Donepezil
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
Galantamine
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
Rivastigmine
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
Memantine
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
Memantine HCL ER and donepezil capsules (namzaric)
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
Combination Treament
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
Key concepts: Oral Agents
. 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)
Aducanumab targets
the N-terminus of Abeta
Aducanumab
ARIA: up to 40%; requires MRI of brain within one year of starting treatment, then before 7th & 12th doses.
Lecanemab
ARIA: Up to 30%; requires MRI of brain within one year of starting treatment, then before 5th, 7th & 14th doses.
Aducanumab and Lecanemab require
presence of amyloid beta pathology prior to initiating treatment
Non-pharmacological interventions
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)
Behavioral Interventions
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
Agitation Interventions
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
Treatment of psychosis and behavioral disturbances
antipsychotics
antidepressants
Antipsychotics
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
Antidepressants
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
Wandering interventions
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
Sleep Disturbance interventions
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
Other dementia subtypes
vascular dementia
lewy body dementia
Vascular dementia
◦ 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
Lew Body dementia
◦ 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
