Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
cholinesterase inhibitor
Treatment recommended for ALL patients in selected patient group
Treatment should be started when the diagnosis of mild AD is made.
Oral rivastigmine and oral galantamine are approved by the US Food and Drug Administration (FDA) for mild to moderate AD.
Oral donepezil and transdermal rivastigmine are FDA-approved for mild to severe AD.[119]
A once-daily extended-release formulation of galantamine is also available and should be considered when compliance or dosing rationalisation is an issue.[118]
Donepezil has been shown to be beneficial at all stages of the disease.[120] Adverse effects, particularly gastrointestinal, are significantly more common with the higher-dose formulation approved for moderate to severe disease.[121] Increasing the dose to the high end of the dose range may confer only modest benefit.
The rivastigmine transdermal patch may increase compliance and reduce cholinergic adverse effects, and is preferred by carers to oral formulations.[122][123][124][125][126]
[ 
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Patients experiencing adverse effects with oral cholinesterase inhibitors may be transitioned to transdermal rivastigmine therapy without significant complications.[127]
The clinical benefit of cholinesterase inhibitors is modest.[112] Open-label extensions suggest that benefits may continue beyond 1 year with ongoing treatment.[115][116] However, retrospective data from the UK indicate that cholinesterase inhibitors are associated with a period of cognitive stabilisation (2 to 5 months) before a continued decline in cognitive function at the pre-treatment rate.[130]
Cholinesterase inhibitors should be started at the lowest possible dose and titrated gradually. This is particularly relevant in older patients, who are more sensitive to cholinergic adverse effects, and in those in whom comorbidity may be exacerbated by altered acetylcholine metabolism. Renal impairment and hepatic dysfunction can also affect dosing.
Cholinesterase inhibitors should not be stopped abruptly, as patients may experience rebound worsening of cognition. There is little consensus about when to consider discontinuation of these treatments, and what criteria to use.[117]
Primary options
donepezil: mild to moderate disease: 5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day; moderate to severe disease: 5 mg orally once daily initially, increase gradually according to response, maximum 23 mg/day
MoreOR
rivastigmine: 1.5 mg orally twice daily initially, increase gradually according to response, maximum 12 mg/day
OR
rivastigmine transdermal: 4.6 mg/24 hour patch once daily initially, increase gradually according to response, maximum 13.3 mg/24 hour patch once daily
MoreOR
galantamine: 4 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 24 mg/day; 8 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 24 mg/day
Moremanagement of depression
Additional treatment recommended for SOME patients in selected patient group
Depression is very common in people with AD and significantly impacts cognitive function, as well as increasing carer stress.
Non-pharmacological strategies have some evidence of benefit for patients with dementia: some functional benefits of an exercise and educational programme in depression management have been reported.[161] Psychological interventions (e.g., cognitive behavioural therapy, interpersonal therapies) and music therapy may reduce symptoms of anxiety in people with mild dementia.[146][163]
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[Evidence B]
Clinical practice includes a trial of an antidepressant, particularly a selective serotonin-reuptake inhibitor (SSRI) (alongside consideration of non-pharmacological interventions), and monitoring closely for efficacy, as it is not clear who will benefit.[169] Time-limited trials (i.e., 3-6 months) and careful monitoring of adverse effects and efficacy (e.g., using the Geriatric Depression Scale or the Cornell Scale for Depression in Dementia) are recommended.
SSRIs are considered the preferred pharmacological treatment for depression in people with AD, but evidence suggests their clinical effectiveness may be very limited in these patients.[170][171][172][173]
[ ]
[Evidence A]
Sertraline, citalopram, and escitalopram are preferred; SSRIs with a longer half-life (i.e., fluoxetine), those with increased potential for drug-drug interactions mediated by cytochrome P450 (fluoxetine, paroxetine, fluvoxamine), or those known to be more activating (e.g., paroxetine) should be used with caution.
Mirtazapine, an atypical antidepressant, is an appropriate treatment when poor appetite and insomnia are present.
Use of serotonin-noradrenaline reuptake inhibitors may be considered depending on patient preference, comorbidity, and clinician experience.
Doses should be started low and increased gradually according to response. Medications should be titrated to effect over 1-2 months until target dose is reached.
Primary options
sertraline: 50-200 mg orally once daily
OR
citalopram: <60 years of age: 20-40 mg orally once daily; ≥60 years of age: 10-20mg orally once daily
OR
escitalopram: 10-20 mg orally once daily
Secondary options
mirtazapine: 15-45 mg orally once daily
management of dementia-related psychosis
Additional treatment recommended for SOME patients in selected patient group
Antipsychotic use in people with AD is controversial.[182][183][192]
[ ]
The US Food and Drug Administration has issued black box warnings for all atypical and typical antipsychotics in relation to dementia-related psychosis, as they have been shown to increase mortality.[182][183][193] However, in cases of severe agitation or danger to self or others, antipsychotics have shown some benefit in management.
Risperidone, an atypical antipsychotic, may reduce behavioural symptoms of dementia.[184][185]
All antipsychotics have the potential to cause extrapyramidal symptoms, but these adverse effects are less common with atypical antipsychotics than with conventional (typical) antipsychotics.[186] One systematic review and meta-analysis concluded that atypical antipsychotics (and cholinesterase inhibitors) may improve neuropsychiatric symptoms in patients with AD, but should be used with caution.[187][Evidence A]
If there is evidence of vascular dementia, antipsychotics should be used with extra caution and monitoring for cardiovascular adverse effects, because of the reported association with an increased incidence of stroke and cardiovascular events.
The American Psychiatric Association guidelines recommend reserving antipsychotic medication for symptoms that are considered severe, dangerous, and/or cause significant distress, and assessing efficacy and side effects to continuously balance the risk/benefit ratio in each individual patient.[188] Modifiable factors, such as pain, should be addressed prior to instituting therapy.
Low doses of antipsychotics may be prescribed cautiously in patients with neuropsychiatric symptoms.
Primary options
risperidone: 0.25 mg orally once or twice daily initially, increase gradually according to response, maximum 2 mg/day
OR
olanzapine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 5 mg/day
OR
quetiapine: 25 mg orally (immediate-release) once or twice daily initially, increase gradually according to response, maximum 150 mg/day
OR
aripiprazole: 2-5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day
Secondary options
haloperidol: 0.25 to 0.5 mg orally once or twice daily initially, increase gradually according to response, maximum 2 mg/day
OR
ziprasidone: consult specialist for guidance on dose
management of other behavioural and psychological symptoms
Additional treatment recommended for SOME patients in selected patient group
Aggression and agitation have multiple causes in people with AD. Symptoms may stem from comorbid depression, adverse effects of medication, worsening medical conditions, pain, or delirium confusion with complex tasks. The first task of the clinician is to rule out an underlying medical cause for the symptoms.
Non-pharmacological strategies may help to lessen anxiety and agitation, as well as improving carer confidence and reducing carer distress.[164][165] Simple measures such as providing a comfortable environment and encouraging social gatherings help patients adjust to their surroundings and lessen anxiety and agitation. Activities such as gardening, vacuuming, and setting the table provide routine and foster a sense of utility.
Psychological interventions (e.g., cognitive behavioural therapy, interpersonal therapies) and music therapy may reduce symptoms of anxiety in people with dementia.[146][163]
[ ]
[Evidence B]
Selective serotonin-reuptake inhibitors (SSRIs) reduce symptoms of agitation compared with placebo in people with dementia.[175] Data from one randomised controlled trial suggest that citalopram reduces agitation, irritability, anxiety, delusions, and carer distress.[176][177] Patients with milder cognitive impairment and moderate agitation were more likely to respond to citalopram.[178] Monitoring for cardiac side effects, such as prolonged QT interval, is important. Patients who are already taking an SSRI for depression should not be started on citalopram for behavioural or psychological symptoms because of the risk of serotonin syndrome.
There is some evidence that carbamazepine is effective for the management of agitation and aggression in dementia, although tolerability may be an issue.[179]
Trazodone may be considered when agitated behaviours associated with dementia are prevalent.[180][181]
Existing medications such as benzodiazepines or antipsychotics can cause paradoxical agitation or akathisia and may need to be reduced or stopped altogether.
Primary options
citalopram: 10 mg orally once daily initially, increase gradually according to response, maximum 30 mg/day
OR
carbamazepine: 50 mg orally (regular-release tablets) twice daily initially, increase gradually according to response, maximum 200-400 mg/day
OR
trazodone: 50 mg orally two to three times daily initially, increase gradually according to response, maximum 400 mg/day (outpatient) or 600 mg/day (inpatient)
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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer
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