Alzheimer's%20disease%20-and-%20dementia Treatment

• Severity of the disease should be assessed prior to medication

Important to explain to patient and family prior to initiating therapy:

• Medications will not cure dementia and may not work for everyone
• Symptomatic treatment, even with improvement of symptoms, will not stop disease progression and cognitive decline will continue even with therapy
• Response to medications should be monitored to assess cognitive, behavioral and functional benefits
• Dose titration and change of medication should be done if necessary

Treatments for Psychosis and Agitation

• Indicated when non-pharmacological options (eg identification and treatment of underlying causes, psychotherapy, education and collaboration among health care providers, patient and family, etc) fail or when the behavior requires urgent attention such as dangerous aggression
• Aim of treatment is to minimize psychotic symptoms (eg paranoia, hallucinations, etc) and the associated or independent symptoms (eg screaming, violence)
  • This will help increase comfort and safety of patients and families
• Intervention used should be directed by the level of agitation experienced by the patient and the risk to caregivers and patient
  • Violent behavior usually needs to be treated by pharmacological therapy
• Agitation needs to be investigated further to reveal underlying causes
  • If agitation continues repeatedly, psychosocial measures should be used as 1st-line therapy
• If psychosocial measures are unsuccessful or if agitation is thought to be dangerous to patient/caregiver then pharmacological therapy is warranted

Pharmacological Therapy for Cognitive Symptoms

Cholinesterase Inhibitors (ChEIs)

• Should be considered in patients in all stages of Alzheimer's disease
• All inhibit cholinesterase in the synaptic cleft, thereby enhancing central cholinergic function
  • Donepezil inhibits acetylcholinesterase
  • Galantamine inhibits acetylcholinesterase and provides allosteric modulation of nicotinic receptors
  • Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase
• Improve cognitive, behavioral and functional measures in Alzheimer's disease
• May also be given in patients with dementia with Lewy bodies
• Donepezil and Galantamine have shown modest efficacy in treating cognitive impairment in patients with vascular dementia or mixed dementia but should be used with caution
• Generally well tolerated, common side effect being GI disturbances (nausea, vomiting, diarrhea) which tend to be mild to moderate in severity
• Not recommended for the treatment of FTD and mild cognitive impairment

• Donepezil

• Showed significant effects in cognitive function as evaluated by cognitive subscale of the Alzheimer's disease Assessment Scale
• Studies have shown efficacy of Donepezil in reducing a number of behavioral problems and psychotic symptoms in patients with mild to moderate dementia
• Used for the treatment of mild to moderate Alzheimer's disease and has been approved for use in more severe forms of Alzheimer's disease and dementia with Lewy bodies

• Galantamine

• Improves functional ability and may also provide significant effects on behavior in patients with Alzheimer's disease
• Used in patients with mild to moderate Alzheimer's disease in maintaining cognition
• Can be considered in patients with mild to moderate dementia with Lewy bodies that cannot tolerate Donepezil and Rivastigmine
• Higher doses are more efficacious than lower doses, but doses >24 mg/day showed no added benefit
• Slow dose escalation appears to improve its tolerability
• There is evidence of some benefit in cognition in patients with mixed Alzheimer's disease and cerebrovascular disease

• Rivastigmine

• Showed significant effects in cognitive and global function in patients with mild to moderately severe Alzheimer's disease
• Meta-analysis results show that Rivastigmine may provide benefit in Alzheimer's disease patients experiencing rapid symptom progression compared to those with slow progression
• Also found to be effective in managing cognitive decline among patients with dementia with Lewy bodies
• Transdermal patch preparation has the advantage of causing less gastrointestinal side effects, better 24 hour drug profile and easier to administer in patients
  • Approved for treatment of all stages of Alzheimer's disease

• Used in patients with mild to moderate dementia associated with Parkinson’s disease and severe dementia with Lewy bodies
*Please see Parkinson’s Disease and Parkinson’s Disease Dementia disease management chart for further information

Aducanumab and Lecanemab

• Amyloid beta-directed antibodies indicated for the treatment of Alzheimer's disease with confirmed amyloid pathology
• Studies have shown significant dose- and time-dependent reduction of amyloid beta plaque compared to placebo
• Approved under accelerated approval by the US Food and Drug Administration (FDA) to be initiated in patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease
  • No safety or effectiveness data on initiating treatment at earlier or later stages of the disease

Memantine

• Noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist given in patients with moderate to severe Alzheimer's disease
• May be given to patients with mild to moderate Alzheimer's disease as monotherapy if cholinesterase inhibitor is contraindicated, not tolerated or in cases of disease progression despite an adequate trial of cholinesterase inhibitors
• Current available data suggest that combination with cholinesterase inhibitor increases likelihood of delaying symptom progression compared to cholinesterase inhibitor alone in moderate to severe cases of established Alzheimer's disease
• Studies suggest improvement of cognition at all levels of Alzheimer's disease severity but effects on behavior, activities of daily living and global outcome were more significant for moderate to severe Alzheimer's disease

Other Agents Used to Treat Cognitive Symptoms

Ginkgo biloba (EGb 761)

• A botanical product derived from maidenhair tree that has clinical trials supporting its efficacy in Alzheimer's disease and vascular dementia
• Potential mechanisms of action include antiplatelet activity, vasoactive effects, increasing neuron tolerance to anoxia and prevention of membrane damage caused by free radicals
• Majority of studies confirm Ginkgo biloba is safe with few side effects

Cerebrolysin

• Nootropic agent composed of 25% low molecular weight peptides and free amino acids produced by the bio-technologically standardized enzymatic breakdown of purified porcine brain proteins
• Studies showed Cerebrolysin preparation is well-tolerated
• Useful addition to current treatment options for dementia based on current available clinical data

Selegiline

• A selective monoamine oxidase-B (MAO-B) inhibitor; postulated to act as an antioxidant or neuroprotective agent in Alzheimer's disease patients
• Evidence for its efficacy in the treatment of Alzheimer's disease symptoms is minimal

Vitamin E

• Generally not recommended for treatment of cognitive symptoms of dementia due to its limited evidence of efficacy and safety concerns
  • After weighing the potential benefits and risks of vitamin E, some physicians may still opt to give it at doses ≤ 400 IU/day
  • Doses >400 IU/day resulted in statistically significant increase in mortality
• New safety concerns include increased dose-dependent mortality, increased heart failure rate in patients with diabetes mellitus and cardiovascular disease
• Associated with worsening of coagulation defects among vitamin K-deficient patients

Pharmacological Therapy for Neuropsychiatric Symptoms

Anti-dementia Agents

• Donepezil may be used to treat negative symptoms such as aberrant motor behavior, apathy, and mood disorder (eg anxiety, depression)
• Memantine is also used to treat positive symptoms such as agitation or aggression irritability, hallucination and delusion
• Rivastigmine may be used to treat behavioral and psychological symptoms of DLB

Antipsychotics¹

• Conduct an assessment exploring possible reasons of distress and check for and address clinical or environmental causes (eg delirium, neglect or pain) of distress before starting patient on antipsychotics
• Primary treatment available for psychotic symptoms of dementia who are at risk of inflicting harm to self and others and severe distress in patients experiencing agitation, delusion or hallucinations
• Dose and the need for medication must be constantly reviewed and the risk of stroke and myocardial infarction should be considered
• Lowest effective dose should be used at the shortest period needed after (American Psychiatric Society recommends tapering dose within 16 weeks of initiation) and side effects should first be treated by decreasing the dose
  • Treatment of elderly patients with dementia-related psychosis with antipsychotics may be associated with increased risk of cerebrovascular and cardiovascular events including fatalities
  • Reassess at least every 6 weeks
• Antipsychotics are considered in severe behavioral and psychological symptoms of dementia unresponsive to other treatment
  • Is not recommended for routine treatment of patients with dementia with aggression and psychosis
• Atypical agents may be better tolerated
• Choice of agent will be based on side effect profile that is most suited to the patient
• Commonly administered in the evening to help sleep and to treat ‘sundowning’
• Oral route is usually preferred
• Medications for Alzheimer's disease and vascular dementia eg cholinesterase inhibitors and/or Memantine should be optimized and given at the appropriate doses since these provide good behavioral control
• Brexpiprazole has been approved by the US FDA for the treatment of agitation symptoms associated with dementia due to Alzheimer's Disease

Benzodiazepines¹

• For agitation, where anxiety is a prominent feature
• Useful as start doses for occasional agitation or when sedation is needed eg dental procedure
• Generally not used in dementia unless in cases that they are necessary
• Risk of disinhibition, over sedation, falls and delirium
• Short-acting agents and agents that do not require metabolism for activation are preferred
• Start with low doses; increase dose carefully and cautiously
  • Elderly are more sensitive to the side effects of benzodiazepines

Treatment for Depression and Apathy

Antidepressants¹

• Tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) may be used to treat depression
  • SSRIs are the preferred agents
• Occasionally, cognitive deficits may partially improve with treatment of depression
• Choice of agent depends on drug interactions, side effects and desired action
  • Tricyclic antidepressants have significant cardiovascular effects and anticholinergic properties
  • SSRI have better side effect profile
  • Dietary restrictions (high tyramine food), drug interactions and side effects tend to limit the usefulness of MAOIs
• Start with low doses; increase dose carefully and cautiously
  • Elderly are more sensitive to the side effects of antidepressants
• Not effective for behavioral and psychological symptoms of dementia in patients with FTD

¹Various antipsychotics, benzodiazepines and antidepressants are available. Specific prescribing information may be found in the latest MIMS.

Supportive Measures

• Psychosocial intervention is tailored to individual’s needs with goals of maintaining cognitive function and doing activities that promotes independence
  • It consists of supportive measures and psychotherapy

Psychotherapy/Functional Training

• May be beneficial to some patients 
• Aims to improve quality of life and maximize function in view of existing deficits
  • Promote cognition, independence and wellbeing
• Choice of therapy should be based on patient characteristics and preference, availability and cost
• Treatment must be tailored to the cognitive abilities and tolerance of each patient as adverse emotional effects have been reported
• Therapy must be offered regularly as most do not have a lasting effect

Cognitive-Behavioral Therapy

• Shown in one clinical trial to have favorable results in the early stages of Alzheimer’s disease
• Aims to address disabilities resulting from impact of cognitive impairment on activities of daily living
• Emphasis on improving or maintaining functions of daily living, strength building and compensating impairments, and promote independence
  
• Cognitive stimulation let the patient engage in a range of activities and discussions
• Cognitive training are tailored for each patient’s level of ability to reflect particular cognitive functions
  

Behavioral Therapy

• Based on the principles of conditioning and learning theory
• Objective is aimed at eliminating or suppressing behavioral and psychological symptoms
• Efficacy in dementia has been shown in few studies only

Interpersonal Therapy

• Focuses on either interpersonal disputes, interpersonal/personality difficulties, bereavement and life events/ transitions
• Aims to help patients interact more efficiently with others
• Mild to moderate depressed patients may undergo brief structured attachment-focused therapies

Reality Orientation

• One of the most commonly used strategies
• Helps patients with memory loss and disorientation to recall facts about themselves and their surroundings
• Reorients patients by continuous stimulation and repetitive orientation to the environment (eg time, place and person)
• Deals with regular use of orientation devices (eg signposts, notices, memory aids)
• May slow decline in cognition and may help delay placement in nursing homes

Validation Therapy

• Involves acknowledging, supporting the feelings and meanings hidden behind the patient’s behavior and speech
• Promotes contentment resulting in less negative affect and behavioral disturbances

Reminiscence Therapy

• Helps the patient by reliving the past positive and personally important experiences
• Promotes restoration of self-worth, improvement in motivation, well-being, self-care, behavior and social interaction

Verbal Episodic Memory Therapy

• Episodic memory are recent or distant past events and experiences are tested using either verbal or visual materials
  
• Verbal episodic memory tests let the patient reads lists of words or a short story to be recalled immediately and after a delay
  

Functional Training

• Focuses on optimization of function and activities of daily living
• Includes activities such as skill training or activity planning, exercise, assistive technology and rehabilitation programs (eg occupational therapy, physiotherapy) which promote independence

Alternative Therapies

• Involve aromatherapy, massage and touch therapy, art, activity (eg sport, drama, dance), light and music therapies