ICL 8.4: Psychopharmacology of Neurocognitive Disorders

Question 1

why is there an emergence and growth of geriatric neuropscyhiatry?

Answer 1

1. growth of the size of the elderly population
   Increased prevalence of brain disease amongst the elderly
2. high frequency of psychiatric symptoms
3. recognition that behavioral disturbances are manifestations of brain dysfunction, (i.e. dementia)

Question 2

what is the #1 type of dementia?

Answer 2

alzheimer’s

then cerebrovascular, frontotemporal and diffuse lewy body dementia

Question 3

what are the characteristics of alzheimers?

Answer 3

1. cognitive decline

memory loss; inability to perform daily activities, decline in speech, inability to do ADLs

2. neuropsychiatric symptoms

prevalence of 60-80% with a lifetime risk of 100%

these are the ones that are the reason that the cost of taking care of a dementia patient is so high however the FDA doesn’t recognize them as targets for medications so there’s no medicines or funding for this

Question 4

what are the neuropsychiatric symptoms associated with dementia?

Answer 4

these affect 90% of patients with dementia

1. agitation
2. aggression
3. delusion
4. hallucinations
5. repetitive vocalization
6. wondering
7. depression
8. anxiety

Question 5

what is the significance of the neuropsychiatric symptoms associated with dementia?

Answer 5

1. they are associated with increased hospital stay
2. early nursing home placement
3. caregiver distress/depression

the detection and management of non-cognitive neuropsychiatric symptoms is key in the treatment and care of Alzheimer’s patients and other dementias

Question 6

what are the unmet needs of people who have neuropsychiatric symptoms?

Answer 6

they have unmet physiological needs because sometimes they can’t express their need of:

1. hunger
2. thirst
3. lack of physical activity
4. boredom
5. caregiver ignorance

handle all of these before you put someone on meds for neuropsychiatric symptoms!

Question 7

what are the 2 approaches to choosing a medication for neuropsychiatric symptoms?

Answer 7

1. identify target symptoms and choose the medication that is known to be effective with the most closely related symptom

there are no randomized trials confirming this approach

2. identify target symptoms and choose the medication using an empirically-based approach:
   - antipsychotic medication
   - antidepressants
   - mood stabilizers
   - beta adrenergic receptor blockers

a lot of the stuff we use to address the neuropsychiatric symptoms is off-label and isn’t FDA approved!

Question 8

what are the current challenges with current alzheimer’s medications?

Answer 8

1. limited evidence regarding the use of an individual class of medication
2. reports that new atypical antipsychotic medications might be associated with infrequent but at times serious side effects
3. typical neuroleptics such as Haloperidol may show efficacy but may be associated with a small increase in risk of death

Question 9

what is the CATIE alzheimer’s trial?

Answer 9

a five year trial where 421 people who lived in a home or nursing home were randomized to:
Olanzapine
Quetiapine
Risperidone
Placebo

the conclusions drawn from the CATIE trials were:
1. some patients may benefit greatly from the medications; there was an improvement of 32% versus 21% on placebo

2. there are fewer side effects than thought

no other recommendations made from this trial

further emphasized the management of behavioral problems

other medications for neuropsychiatric symptoms have limitations and risks like the antidepressant medication, sedative-hypnotic medication, and mood stabilizers

Question 10

what is the principle behind the symptomatic treatment for cognitive symptoms of alzheimers?

Answer 10

it’s based on the theory that AD is due to the loss of neurons in the nucleus basalis which is the origin of cholinergic neurotransmission in the brain

so the most successful approach for medications would be to reduce the natural occurring degradation of ACh

Question 11

what are the primary scales used to measure the cognitive domains for Alzheimer’s patients?

Answer 11

1. ADAS: Alzheimer’s Disease Assessment Scale (cognitive, non-cognitive and total scales)
2. MMSE- Mini Mental Status Examinations
3. SIB: Severe impairment battery
4. CIBIC: Clinician-based Impression of change*
5. CIBIC-Plus: Caregiver input*

very important for determining if the medication is working and how much –> clinically important scores were thought to be 4+ points on ADAS and 3+ points on the MMSE and any change on the CIBIC

Question 12

what is the most commonly used alzheimer’s medication?

Answer 12

donepezil aka aricept

Question 13

what were the results from the donepezil study?

Answer 13

the study was donepezil vs. vitamin E placebo for patients with mixed diagnosis of AD, vascular dementia, and Parkinson’s and DS dementia and the results were:

1. the changes in the cognitive scores (ADAS-cog, MMSE, and SIB) were statistically significant but not clinically important
2. one study did show clinically important changes but not statistically significant
3. some but not all found improvement in activities of daily living
4. the evidence is insufficient to determine that a subgroup of patients had clinically important changes

we still use this medication though because we have nothing else to treat the cognitive aspects of dementia

Question 14

what were the results from the galantamine study?

Answer 14

Razadyne study was 10 studies that compared galantamine to placebo in patients with mild to moderate stages of dementia –> 7 studies were AD patients and 2 studies with patients who had both AD and VD

the study showed statistically significant changes in the cognitive scales
but did not reach clinically important changes

Question 15

what were the results from the rivastigmine study?

Answer 15

the exelon study was 9 studies compared with Rivastigmine to placebo

1 study included Parkinson’s Disease, 1 study included Lewy Body Dementia

the results concluded that Rivastigmine did not improve cognition scales (ADAS-cog) but it did show clinically important improvement (CIBIC-plus) –> this is the most important kind of change!

Question 16

what were the results from the tacrine study?

Answer 16

the cognex study was 7 studies that compared tacrine to placebo in patients with mild to moderate dementia

the study concluded that there was insufficient data to determine benefits of the treatment with Tacrine on various cognitive scales

it also, showed serious side effects including liver damage so this medication is no longer on the market

Question 17

what were the results from the memantine study?

Answer 17

the Namenda study was 5 studies that compared Memantine to placebo

they evaluated AD, VD and mixed dementia with moderate to severe dementia

the study concluded that memantine showed statistically significant changes but not clinically important improvement – CIBIC plus was also statistically significant

so memantine does have some role; it’s thought to be a secondary addition to the cholinesterase inhibitor therapy or if someone can’t tolerate the side effects of the cholinesterase inhibitors they can be started on memantine as 1st line treatment

Question 18

what were the results of the donepezil vs. galantamine study?

Answer 18

they were 2 studies with patients who had mild to moderate dementia

the results from the longer study showed no statistical significant differences in the primary outcome measure (Bristow activity of daily living)

however, changes in Cognitive Scales (ADAS-cog and MMSE) favored Galantamine

Question 19

what are the recommendations on initiating cholinesterase inhibitors for dementia?

Answer 19

the decision to initiate treatment should be based on individual needs, evaluating risks versus benefits

in advanced dementia, family or other caregivers might see the slowing of the disease process as a negative effect on the quality of life

we do not have a way to predict which patient might have clinically important improvement

we also have no evidence for how long a dementia patient should be kept on medications

however, we can sometimes see a sharp decline in behavior and cognitive performance when medications are stopped

Question 20

what is the MOA, benefits, and side effects of donepezil?

Answer 20

MOA = acetylcholinesterase inhibitor

benefits = delayed symptom progression in mild, moderate, and advanced Alzheimer disease

side effects = nausea, vomiting , diarrhea, anorexia

notes = routine liver function testing is unnecessary

the higher end of the dosing range may be harder for patients to tolerate

Question 21

what is the MOA, benefits, and side effects of galantamine?

Answer 21

MOA = acetylcholinesterase inhibitor

benefits = delayed symptom progression in mild, moderate, and advanced Alzheimer disease

improvement in caregiver-rated quality of life was observed

side effects = NVD and anorexia

notes = routine liver function testing is unnecessary

the higher end of the dosing range may be harder for patients to tolerate

Question 22

what is the MOA, benefits, and side effects of rivastigmine?

Answer 22

MOA = acetylcholinesterase inhibitor

benefits = delayed symptom progression in mild, moderate, and advanced Alzheimer disease

side effects = NVD and anorexia

notes = routine liver function testing is unnecessary

the higher end of the dosing range may be harder for patients to tolerate

available in a transdermal patch

Question 23

what is the MOA, benefits, and side effects of memantine?

Answer 23

MOA = NMDA-receptor antagonist

benefits = less functional decline, improved cognition, and reduced demands on caregivers in moderate-to-advanced Alzheimer disease

side effects = dizziness, confusion, headache, constipation

notes = available in tablets or solution

avoid concomitant use with amantadine.

Question 24

what are modifying therapies for dementia?

Answer 24

they are therapies that are expected to stop or slow the disease progression by targeting the process that underlies the course of the disease

we don’t have any modifying therapies available now though

would be great if we did because it costs $36,000/year to treat a severe AD patient and it would also help decrease the prevalence of AD

Question 25

what is the amyloid hypothesis?

Answer 25

this is what the modifying therapies are based on!

with AD, there is extracellular amyloid plaque formation which is the pathological hallmark of AD

this cascade of events results in neuronal toxicity and death –> the deficits are in the cholinergic serotonergic, noradrenergic and dopaminergic activities

so the misprocessing Amyloid Percursor Proteins (APP) is the key initial event of AD so the goal of modifying therapies is the prevention of deposits of β-amyloid which would prevent the synaptic and neuronal degeneration caused by the plaques

Question 26

how does amyloid precursor protein eventually cause dementia?

Answer 26

APP is turned into amyloid beta which then creates neurofibrillary tangles which cause neuron death in the basal forebrain and brainstem nuclei which causes NT deficits and leads to dementia syndrome

Question 27

how can immunotherapy help treat AD?

Answer 27

the goal of this treatment is the reduction in amyloid pathology

what they did was overproduce APP in mice and then looked to see if the anti-amyloid mechanism of active and passive immunization could help reduce amyloid-beta levels and increase its clearance from the brain while also inhibiting fibriallogenesis

active immobilization was stopped at phase 2 due to development of meningoencephalitis but passive immunization is under investigation

with passive immunization, administration of Aβ antibodies appears to shift Aβ equilibrium from the brain to the peripheral

also, administration of IV immunoglobulin’s also show some hopeful results with reduced CSF Aβ concentration with a transient increase in Aβ concentration

none of these are used clinically yet but people are working on it!

Question 28

what are secretase inhibitors?

Answer 28

secretase inhibitors block gamma and Beta secretase activity with the result of reducing plaque formation

both gamma and beta secretase raise concerns of severe toxicity

selective Aβ42 lowering agents –> the goal of this therapy is to decrease Aβ42 production and delay disease progression by selectively modulating gamma secretase activity

not yet on the market!

Question 29

what is R-flurbiprofen?

Answer 29

a selective Aβ42 lowering agent

not yet on the market

Question 30

what are anti-Aβ aggregation agents?

Answer 30

they are thought to modify the course of AD by preventing fibrilization and amyloid plaque formation or by increasing the clearance of soluble Aβ

the 2 medications are colostrinin and clioquinol

Question 31

what are the 2 anti-Aβ aggregation agents that are being looked into now? what’s their MOA?

Answer 31

1. colostrinin = naturally occurring prolene rich polypeptide (PRP) inhibitor of Aβ Aggregation and neurotoxicity
2. clioquinol = quinolone antibacterial and anti-fungal agent interfering with copper homeostasis process involved in senile plaque formation

anti-Aβ aggregation agents are thought to modify the course of AD by preventing fibrilization and amyloid plaque formation or by increasing the clearance of soluble Aβ

Question 32

what medical condition can be controlled to try and prevent AD?

Answer 32

hypertension!

untreated hypertension in midlife increase risk for AD and VD

treatment systolic hypertension in 60 and over reduced the incidence of dementia by 50%

treatment of hypertension with angiotensin converting enzyme with or without indapamide reduced the incidence of recurrent strokes with dementia by 45%

Question 33

what preventative measures should not be taken to prevent AD?

Answer 33

anti-inflammatory treatments and estrogen therapy

studies with NSAIDs and estrogen showed no protective effects so they should not be recommended for the prevention of dementia!

Question 34

how do cholesterol and DM2 play into alzheimer’s?

Answer 34

both hypercholesterolemia and DM2 have a high association with increased risk of AD and vascular dementia

Diabetes Mellitus is an independent risk factor for VD

Question 35

what lifestyle modifications can be done to try and prevent dementia?

Answer 35

1. cigarette smoking

increases risk of stroke; evidence of association with AD is mixed

2. head injury

increased risk of dementia later in life

physical inactivity in mid or late life associated with an increase in risk of dementia

3. medications

minimize medication that can cause cognitive impairment like benzodiazepines, anti-cholinergic and sedative hypnotics