Module 4.4.2 (Management of Dementia)

Question 1

What is dementia defined as?

Answer 1

Distinguished from lifelong intellectual disability and single learning disorders as dementia develops during life, and involves alteration in two or more cognitive functions

> The aims of treatment are to promote independence, maintain function and treat symptoms.

Question 2

What is used to treat primary symptoms such as memory loss in alzheimers?

Answer 2

Anticholinesterases

NMDA antagonists

Question 3

What is used to treat seconday symptoms such as depression and hallucinations in alzheimers?

Answer 3

Antipsychotics and Sedatives

Question 4

Summary of different types of dementia?

Answer 4

Question 5

What is the amyloid hypothesis?

Answer 5

• Imbalanced production or removal of beta amyloid causes accumulation and clumping of this peptide in the brain

> reduce amount of amyloid to improve symptoms

• Beta amyloid is both toxic itself and stimulates neurodegeneration and loss of brain tissue

> Treatments targeting amyloid have been found to confer virtually no clinical benefit

Question 6

Any success with verubecestat?

Answer 6

BACE-1 (beta site amyloid precursor protein cleaving enzyme 1) inhibitor

• BACE-1cleaves amyloid precursor protein to produce amyloid-beta peptides
• BACE-1 levels often elevated in late-onset Alzheimer’s

> Ceased in February 2017 as “virtually no chance of finding a positive clinical effect”

Question 7

Why are some theories as to why anti-beta amyloid therapies have failed?

Answer 7

• Administered too late in the disease to be effective
• Inaccurate diagnoses meant they have been trialled in unresponsive patients
• Inadequate penetration into the brain
• Up to half of people with positive Aβ PET scans will not develop dementia

Question 8

How do anticholinesterases work?

Donepezil (AriceptTM), galantamine (ReminylTM) and rivastigmine (ExelonTM)

Answer 8

Accumulation of AB (beta amyoloid) peptide results in destruction of cholinergic neurones and a fall in ACh concentration

> neurotransmitter essential for learning and memory

• Cholinesterase inhibitors (CIs) inhibit breakdown of ACh to increase concentrations in synaptic cleft

> enhances cholinergic function and reduces loss of cholinergic neurotransmitter activity

> As the dementia progresses, fewer cholinergic neurons remain functionally intact, and the effects of CI may be lessened.

• Deterioration of cognition is delayed by 6 months in 25–50% of patients, and by 1 year in 12–20% of patients with mild-to-moderate Alzheimer’s disease
• carefully assess benefit after 3 months of treatment at full or highest tolerated dose.
• Treatment should be stopped if there are significant adverse effects, poor compliance or lack of stabilisation or improvement of symptoms

Question 9

All three CIs seem to have similar efficacy, they dont alter pathology of AD, so how do they work?

> donepezil may be slightly more effective

Answer 9

temporarily delay progression and improve symptoms according to subjective measurements or cognitive assessment tools (e.g. MMSE)

> not everyone responds to treatment

Question 10

What are the adverse effects (CIR) associated with CI? Which one has most GI adverse effects?

Answer 10

Adverse effects occur frequently with all three agents

Better tolerated if slowly titrated to target dose –> increase every four to six weeks

> full dose oral rivastigmine may have more GI adverse effects than donepezil or galantamine

Common​

• nausea, vomiting, diarrhoea, anorexia, abdominal pain, dyspepsia, headache, insomnia, vivid dreams, depression, fatigue, drowsiness, dizziness, tremor, weight loss, muscle cramps, urinary incontinence, increased sweating, hypertension, syncope

Infrequent or rare

• bradycardia, heart block, seizure, agitation, hallucination, confusion, GI haemorrhage

Question 11

Which non-alzheimer dementia should CI be used in?

Answer 11

There is good evidence to support treatment with rivastigmine and donepezil in in dementia with Lewy bodies and Parkinson’s disease dementia

Question 12

Properties of memantine? MOA, is it effective? Who is it used for?

Answer 12

Thought to protect against elevated levels of glutamate

• NMDA antagonist
• but memantine does not stop AD progression

Marginally less deterioration compared to placebo over 6-months in moderate to severe AD

Generally reserved for severe dementia or those intolerant to CIs

Question 13

Factors to consider in relation to continuing CI/ memantine use is? How is this demonstrated?

Answer 13

clinically meaningful response achieved and any adverse effects that may be present

Clinically meaningful response to treatment may be demonstrated by the person’s:

• quality of life
• cognitive function
• behavioural symptoms

> The presence of adverse effects that impact on quality of life and clinical symptoms should prompt a review of the ongoing need for the agent

> People who demonstrate ongoing, meaningful clinical benefit (functionally and/ or cognitively stable) should continue on the medication with ongoing monitoring for continued benefit or the development of any adverse effects

Question 14

Guidelines for deprescribing summary

Answer 14

Question 15

What are behavioural symptoms associated with dementia?

Answer 15

physical aggression, screaming, restlessness, agitation, wandering, culturally inappropriate behaviours, sexual disinhibition, hoarding, cursing and shadowing.

Question 16

What are psychological symptoms associated with dementia?

Answer 16

anxiety, depressive mood, hallucinations and delusions

Question 17

1st line treatment for psychological and behavioural symptoms?

Answer 17

Non-pharmacological approaches first line for responsive behaviours because of a favourable balance of benefits and harms

> Drug therapy should not be first-line for patients with responsive behaviours

Question 18

Who are antipsychotics reserved for? What symptoms are they ineffective for? Why risk of AE so high?

Answer 18

Reserve for residents with distressing agitation, aggression, delusions or psychoses

• Ineffective in treating wandering or disinhibition

AE: increased risk of mortality, stroke and extrapyramidal symptoms

Question 19

what antipsychotics to use for hallucinations, delusions or seriously disturbed behaviour?

Answer 19

Risperidone or olanzapine

Question 20

AE of antipsychotics?

Answer 20

AEs frequent as antipsychotics affect multiple neurotransmitter receptor types and subtypes

• Common: sedation, anxiety, agitation, EPSE, orthostatic hypotension, tachycardia, sexual adverse effects, weight gain, hyperprolactinaemia (may result in galactorrhoea and/ or gynaecomastia)

> EPSE and orthostatic HTN with risperidone

> Olanzapine and some older agents: blurred vision, mydriasis, constipation, nausea, dry mouth, urinary retention

> Avoid typical antipsychotics in residents with Lewy bodies dementia or Parkinson’s disease –> worsen movement disorders

Question 21

When is extrapyramidal side effects highest? What drugs to avoid?

Answer 21

Incidence dose-related

> highest with haloperidol, lowest with some of the newer agents

• Reduce antipsychotic dose to avoid recurrent EPSE when possible
• Avoid anticholinergic drugs (e.g. benztropine)

> may add to anticholinergic effects and worsen tardive dyskinesia and cognition

Question 22

What are some extrapyramidal side effects that may be mistaken for responsive behaviours when using antipsychotics?

Answer 22

Dystonias

• Torticollis, carpopedal spasm, trismus, perioral spasm, oculogyric crisis, laryngeal spasm and opisthotonos

Akathisia

• Feeling of motor restlessness; usually occurs 2–3 days (up to several weeks) after starting treatment and may subside spontaneously
• May present as agitation secondary to psychosis

Parkinsonism

• Tremor, rigidity or bradykinesia; usually develops after weeks or months

Tardive dyskinesia

• Involuntary movements of the face, mouth or tongue, and sometimes head and neck, trunk or limbs

Question 23

Clozapine, olanzapine and quetiapine, associated with?

Answer 23

increased blood glucose, weight gain and dyslipidaemia

• clozapine and olanzapine associated with increased risk of type 2 diabetes

Question 24

Increased death rate in which antipsychotics?

Increased risk of fatal and non-fatal strokes and TIAs in which antispychotics?

Answer 24

Increased death rate noted in placebo-controlled trials of aripiprazole, olanzapine, quetiapine and risperidone in dementia patients (due to CVD events or infections)

Olanzapine and risperidone associated with increased risk of fatal and non-fatal strokes and TIAs

use for lowest possible dose and shortest amount of time

Question 25

Risk of CVA increased for patients being treated with _________ for vascular or mixed dementia, compared with those taking it for Alzheimer’s dementia

Answer 25

Risperidone

> TGA approval for use in responsive behaviour is limited to treatment (up to 12 weeks) of moderate to severe dementia only of the Alzheimer type

Question 26

What are other indications for risperidone?

Answer 26

• treatment of schizophrenia and related psychoses •
• short-term treatment of acute mania associated with bipolar 1 disorder •
• treatment of conduct and other disruptive behaviour disorders in children (>5y.o.), adolescents and adults with sub-average intellectual functioning or mental retardation in whom destructive behaviours are prominent •
• treatment of behavioural disorders associated with autism in children and adolescents

Question 27

Points for withdrawal of antipsychotics?

Answer 27

• • Most responsive behaviours tend to be transient exacerbations
• Many will resolve naturally as dementia progresses •
• Regular monitoring and dose reduction/ withdrawal attempts should be undertaken to minimise exposure to antipsychotic use
• E.g. halve the dose every two weeks until the lowest possible dose is achieved, treat for a further two weeks then cease
• Antipsychotic treatment can always be reintroduced if required

Question 28

How do BZDs work? what ar they used for? Which one to use?

Answer 28

Potentiate inhibitory effects of GABA throughout CNS –> results in anxiolytic, sedative, hypnotic, muscle relaxant and antiepileptic effects

• Short term use may assist some behavioural and psychological symptoms of dementia (BPSD), especially insomnia, anxiety, irritability and tension
• also use as premedication for anxiety-inducing events

> To relieve symptoms of severe anxiety and agitation, use: oxazepam 7.5 mg orally, 1 to 3 times daily

Question 29

AE of BZD? What happens if used for more than 2 weeks?

Answer 29

Worsen cognitive impairment, impair gait and increase the risk of falls

• Particularly long-acting agents, such as nitrazepam and diazepam
• Associated with increased risk of hip fracture among older people by >50%

Use >2 weeks associated with tolerance to sedative effect

• Longer term use results in dependence
• Cognition and gait effects maintained

Question 30

_____ ______ are often amongst the most difficult symptoms of dementia to adequately support. What medications have been used to try to alleviate these symptoms?

Answer 30

Responsive behaviouurs

• anticonvusaltant mood stabilisers, antidepressants, clonidine, cannabis, dextropropoxyphene

> citalopram for agitation has been shown to be effective

Question 31

What is the most effective strategy for this: responsive behaviours are often amongst the most difficult symptoms of dementia to adequately support

Answer 31

Identifying and addressing the unmet need/ sources of responsive behaviour is typically the most effective strategy

> Specialist services are available for these situations –> DBMAS, SBRT, OAMHS

Question 32

Comment on if the following CAM are useful in dementia:

A) Antioxidants

B) vitamins

C) gingko biloba

D) fish oil

Coconut oil • Tumeric • CoEnzyme Q10 • Phosphatidylserine = benefits are minimal, and not recommended

Answer 32

A)

• No convincing data to suggest that antioxidants can prevent AD
• Potential risks of premature death with high dose vitamin E supplementation

B)

• Low levels of folate, vitamin B6, and vitamin B12 associated with risk of dementia…
• .but supplementation does not seem to prevent or slow progression of dementia

C)

Ineffective in preventing progression to dementia in healthy people or those with mild cognitive impairment

• May increase bleeding risk in people taking antithrombotics (e.g. aspirin, warfarin)

D)

• Some observational evidence of minor benefit in preventing dementia, but this has not been replicated in prospective studies
• Clinical trials have found fish oil to be ineffective in treating dementia

Question 33

What is Souvenaid? What may it do?

Answer 33

A nutritional drink containing a combination of fatty acids, vitamins and other nutrients

• Developed with the aim of preventing the loss of important connections between brain cells that occurs in Alzheimer’s disease.
• May slightly improve some kinds of memory in people in the early stages of Alzheimer’s disease or mild cognitive impairment

> No evidence that people who take Souvenaid are less likely to develop alzheimers.

> Expensive ($170/month)

Question 34

Summary

Answer 34

• Development of disease- modifying treatments has been unsuccessful
• Current pharmacological treatments for dementia are generally of limited effectiveness

> This includes medications for both the cognitive and behavioural/ psychological aspects of the condition

• Any medication used in managing dementia symptoms requires regular review for ongoing effectiveness and adverse effects

> Particularly antipsychotics and other sedatives

Question 35

Outline possible treatable causes of dementia, medical causes of memory impairment?

Answer 35

Depressive pseudodementia •

Insomnia •

Hypothyroidism, •

B group vitamin deficiencies, •

Sleep apnoea, •

Neurosyphilis, •

Cerebral space occupying lesions •

Normal pressure hydrocephalus. •

Drugs that may adversely affect cognitive function (notably the benzodiazepines, other sedative hypnotics and drugs with anticholinergic properties)

Question 36

What to do for insomnia in dementia?

Answer 36

People with Alzheimer’s disease and other dementias can suffer from reversal of normal diurnal rhythms, sleep fragmentation, poor sleep quality and shallow sleep. Insomnia can exacerbate symptoms of dementia by decreasing cognitive abilities.

• For people living with dementia who have sleep problems the approach should be a personalised multicomponent sleep management plan that includes sleep hygiene education, exposure to daylight, exercise and personalised activities.

> Melatonin is not appropriate to manage insomnia in people living with Alzheimer’s disease.

> Benzodiazepines and antihistamines with anticholinergic effects such as doxylamine (restavit) are also not appropriate.

Question 37

Importance of managing incontinence in dementia as dementia can cause it?

Answer 37

Importance of management: •

• Loss of bladder control may be humiliating and embarrassing for Mavis. •
• If she is getting up in the night, she may be prone to falls and becoming disorientated. •
• Patients with dementia are vulnerable to superimposed delirium, often due to acute infections such as UTIs. Incontinence may predispose Mavis to UTI’s and therefore mood and behavioural disturbances

Question 38

How to treat vitamin B12 deficinecy?

Answer 38

Initiate hydroxocobalamin 1000mcg IM injection on alternate days for 1-2 weeks or until improvement occurs, then every 3 months

Question 39

What may be used for urge incontinence as anticholinergics are contraindicated?

Answer 39

Mirabegron (non-PBS) is a beta3 agonist which may be considered for urge incontinence if anticholinergics are ineffective, not tolerated (eg due to dry mouth) or contraindicated.

> Mirabegron can increase BP

> It is a moderate inhibitor of CYP2D6 - may increase the concentration of metoprolol which is metabolised by CYP2D6

> monitor BP, HR and cardiac function