INTRODUCTION — Cholinesterase inhibitors and memantine are the only currently available symptomatic medications for cognition and global functioning in patients with dementia. Cholinesterase inhibitors target the acetylcholine deficit arising from loss of neurons in the nucleus basalis of Meynert and its projections in patients with dementia. They are considered symptomatic therapies and are not believed to be neuroprotective or to alter the underlying disease trajectory.
This topic will discuss the use of cholinesterase inhibitors in the treatment of dementia. Topics on other aspects of the treatment of dementia include:
●(See "Treatment of Alzheimer disease".)
●(See "Management of neuropsychiatric symptoms of dementia".)
●(See "Management of the patient with dementia".)
●(See "Care of patients with advanced dementia".)
INDICATIONS
Alzheimer disease — The majority of patients with newly diagnosed Alzheimer disease (AD) should be offered a trial of a cholinesterase inhibitor for symptomatic treatment of cognition and global functioning. The degree of expected benefit is modest, and therapy should not be continued indefinitely in patients who do not appear to be benefiting or who have significant side effects. There is no convincing evidence that cholinesterase inhibitors are neuroprotective or have the ability to alter the underlying disease trajectory. Specific recommendations for patients with AD are discussed separately. (See "Treatment of Alzheimer disease", section on 'Cholinesterase inhibitors'.)
Non-Alzheimer dementia syndromes — Cholinesterase inhibitors are also suggested in most patients with dementia with Lewy bodies (DLB) and may have comparatively greater symptomatic benefits than are observed in patients with AD. (See "Prognosis and treatment of dementia with Lewy bodies", section on 'Cholinesterase inhibitors'.)
There is less consensus on the role of cholinesterase inhibitors in patients with other forms of dementia, and regulatory approval is more variable for non-AD diagnoses. Most of the studies of cholinesterase inhibitors have been performed in patients with a clinical diagnosis of AD, and data are more limited and less consistent for other forms of dementia. Although AD is by far the most common cause of dementia in older adults, evidence of mixed pathology at the time of autopsy is common, especially the combination of Alzheimer and vascular pathology [1-3]. Many experts therefore find it reasonable to offer a trial of a cholinesterase inhibitor in patients with a clinical diagnosis of other types of dementia, including:
●Vascular dementia (see "Treatment of vascular cognitive impairment and dementia", section on 'Cholinesterase inhibitors')
●Parkinson disease dementia (see "Cognitive impairment and dementia in Parkinson disease", section on 'Cholinesterase inhibitors')
In the aggregate, trials have not provided support for the use of cholinesterase inhibitors for these indications:
●Preventing progression of mild cognitive impairment to dementia (see "Mild cognitive impairment: Prognosis and treatment", section on 'Acetylcholinesterase inhibitors')
●Frontotemporal dementia (see "Frontotemporal dementia: Treatment", section on 'Cognitive dysfunction')
●Dementia in patients with Huntington disease (see "Huntington disease: Management", section on 'Cognitive impairment and dementia')
●Cognitive impairment in patients with multiple sclerosis (see "Symptom management of multiple sclerosis in adults", section on 'Cognitive impairment')
This approach is generally consistent with guidelines from multiple societies including the American Academy of Neurology [4], American Psychiatric Association [5], Canadian Consensus Conference [6], National Institute for Health and Care Excellence (NICE) [7], British Association for Psychopharmacology [8], and European Federation of Neurological Societies (EFNS) [9,10].
CHOICE OF DRUG — Three cholinesterase inhibitors are available for use in a variety of formulations:
●Donepezil, available as a once-daily tablet and a once-daily disintegrating sublingual tablet
●Galantamine, available as a twice-daily tablet or solution and an extended-release once-daily capsule
●Rivastigmine, available as a twice-daily capsule, a twice-daily solution (in some regions), and a 24-hour transdermal patch
All have demonstrated efficacy compared with placebo, and a limited number of direct comparisons do not suggest major differences in efficacy or tolerability among the three drugs [11-16]. Selection of an agent is therefore based largely upon ease of use, individual patient tolerability, cost, and clinician and patient preference (table 1).
In a pragmatic, open-label trial of 196 older adults with possible or probable AD who were initiating treatment with a cholinesterase inhibitor at one of four memory care practices in the United States, patients were randomly assigned to donepezil, galantamine, or rivastigmine using dosing and formulations at the discretion of the treating clinician [15]. At 18 weeks, rates of discontinuation for any reason (including study withdrawal/loss to follow-up) were similar for the three drugs (39, 53, and 59 percent, respectively; p = 0.06). The most common reasons for discontinuation were adverse events (56 percent) and cost (29 percent). Among the three drugs, donepezil was the most likely to be titrated to the maximum dose (53, 5, and 29 percent) and the least likely to be discontinued for cost-related reasons (0, 26, and 30 percent). Side-effect rates and profiles were largely similar among groups. Other studies have also found higher discontinuation rates for rivastigmine and similar rates for donepezil and galantamine [11,17].
ADMINISTRATION
Contraindications and precautions — Cholinesterase inhibitors enhance vagal tone and are contraindicated in patients with baseline bradycardia or known cardiac conduction system disease (eg, sick sinus syndrome, incomplete heart block) due to risk of syncope, falls, and fractures.
Caution should be used when any of the three drugs are used in combination with drugs that induce bradycardia or alter atrioventricular (AV) nodal conduction (eg, beta blockers, calcium channel blockers, lacosamide). Specific drug interactions may be determined by use of the Lexicomp drug interactions tool (Lexi-Interact) included with UpToDate.
Galantamine should not be used in patients with end-stage kidney disease or severe hepatic impairment, and the rivastigmine patch requires dose adjustments for hepatic impairment and low body weight.
Specific drugs — Although side effects are largely similar across drugs, dose and formulation vary among the three cholinesterase inhibitors.
Donepezil — Donepezil is the oldest cholinesterase inhibitor still in use and remains a preferred and widely prescribed drug in this class due to its once-daily dosing and ease of use.
The recommended starting dose of donepezil is 5 mg per day, increasing to 10 mg per day after four to six weeks. Donepezil is available in pill form and also as an oral disintegrating tablet for those unable or unwilling to swallow a pill. Because nightly dosing can be associated with vivid dreaming or nightmares, we typically start with morning dosing to avoid sleep disturbances and then switch to nightly dosing if daytime nausea occurs.
A 23 mg noncrushable tablet of donepezil is available, but evidence does not support a clinically important advantage to the higher dose and it is associated with increased side effects [18].
Gastrointestinal symptoms (upset stomach, nausea, diarrhea, anorexia) are the most common side effects with prolonged use of donepezil, occurring in approximately 20 to 30 percent of patients [15,19-22]. Symptomatic bradycardia can occur and is also related to cholinergic toxicity [23,24]. Rare cases of rhabdomyolysis and/or neuroleptic malignant syndrome have been reported in postmarketing surveillance [25].
No dose adjustments are needed for renal or hepatic impairment.
Galantamine — Galantamine is available as a twice-daily tablet or solution and as a once-daily extended-release capsule. The latter is preferred unless patients cannot swallow capsules.
The recommended starting dose is 8 mg once daily (4 mg twice daily for immediate release), increasing to 16 mg once daily (8 mg twice daily for immediate release) after four weeks and then to a target maintenance dose of 24 mg once daily (12 mg twice daily for immediate release) after four more weeks.
Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the most common adverse effects and may be more likely with galantamine than with donepezil. Galantamine should be given with meals to decrease the risk of nausea.
Galantamine should not be used in patients with end-stage kidney disease or severe hepatic impairment. A maximum dose of 12 mg is advised in patients with moderate renal (creatinine clearance 9 to 59 mL/minute) or hepatic impairment.
The use of galantamine has been associated with increased mortality in patients with mild cognitive impairment [26] (see "Mild cognitive impairment: Prognosis and treatment", section on 'Acetylcholinesterase inhibitors'). Increased mortality has not been observed in patients treated for AD, mixed dementia, or vascular dementia.
Rivastigmine — Rivastigmine is available in oral and transdermal formulations. The transdermal patch is preferred over the oral formulation because it has better tolerability and similar efficacy [27].
Three dose levels of the transdermal patch are available: 4.6, 9.5, and 13.3 mg/24 hours. The recommended starting dose of 4.6 mg/24 hours can be titrated upwards every four weeks. The patch can cause skin irritation, and application sites should be rotated. Two trials have shown a possible dose effect, with greater cognitive improvement on some but not all outcome measures with higher-dose patches [28,29].
The transdermal patch should be used at the lowest dose only (4.6 mg/24 hours) in patients with mild to moderate hepatic impairment, and the patch has not been studied in patients with severe hepatic impairment. The lowest dose should also be used in patients with low body weight (<50 kg).
If used, oral rivastigmine should be given with food and titrated more slowly than the other drugs due to increased risk of nausea, vomiting, anorexia, and headaches. Rivastigmine pill or solution is started at 1.5 mg twice daily, increasing in two- to four-week intervals by 1.5 mg twice-daily increments. If treatment is interrupted for longer than several days, it should be restarted at the lowest daily dose and then titrated again [30]. One trial found that side effects of oral rivastigmine may be ameliorated and higher daily doses achieved when it is given three times a day, rather than twice daily [31].
Approach to common side effects — An approach to some of the more common or expected side effects of cholinesterase inhibitors is presented below. Because the benefits of cholinesterase inhibitors are modest, clinicians should assess whether the patient is benefiting from the drug before persisting, and use caution to avoid prescribing cascades (ie, prescribing a new drug to treat an unrecognized adverse effect of an existing therapy). (See "Drug prescribing for older adults", section on 'Prescribing cascades'.)
Nausea and diarrhea — The most common side effects of cholinesterase inhibitors are gastrointestinal (primarily diarrhea, nausea, and vomiting). The toxicity is dose related and often resolves with time or dose reduction.
For oral rivastigmine, taking smaller doses more frequently or changing to a patch formulation may help. Both galantamine and oral rivastigmine should be taken with meals [32].
Donepezil seems to be less likely to cause gastrointestinal upset than the other two drugs, so switching to donepezil may be reasonable in patients who do not tolerate galantamine or rivastigmine.
Anorexia and weight loss — Weight loss occurs more commonly with cholinesterase inhibitors than placebo, but the clinical importance of this effect can be difficult to determine in individual patients, as dementia itself is often associated with weight loss.
In a case-control study that included 1188 patients with dementia who were started on a cholinesterase inhibitor (mostly donepezil and galantamine) and 2189 propensity score-matched controls, the mean weight loss over one year was 3.1 pounds in treated patients and 2.5 pounds in controls (p = 0.02) [33]. The proportion of patients who developed significant weight loss (10 pounds or more over one year) was also significantly higher in treated patients (29 versus 23 percent). In a meta-analysis of nine placebo-controlled randomized trials with a median follow-up of five months, the risk of any weight loss was twofold higher in patients randomized to receive a cholinesterase inhibitor (6 versus 3 percent; odds ratio [OR] 2.18, 95% CI 1.50-3.17) [34].
In patients who are noted to be losing weight while on a cholinesterase inhibitor, we typically pursue nutritional counseling before stopping therapy and monitor the trend in weight over time. AD is often associated with anosmia, which detracts from taste. Enhancing the taste of food with spices, sweet and sour flavoring, or soy sauce can help with appetite. For patients with comorbid depression, mirtazapine is a good choice of antidepressant because it can augment appetite.
Bradycardia and hypotension — Bradycardia, heart block, and syncope can arise due to enhanced vagal tone. Cholinergic therapy should be discontinued in patients who develop symptomatic bradycardia and/or hypotension for which no other addressable cause is identified (eg, concomitant antihypertensive therapy). Cholinesterase inhibitors should be avoided in patients with baseline bradycardia or known cardiac conduction system disease. (See 'Contraindications and precautions' above.)
In one population-based cohort, the incidence of hospitalization for syncope was 3.2 events per 100 person-years for individuals taking cholinesterase inhibitors (68 percent were taking donepezil) [24]. This event rate was 1.7 times higher than in a control group. Similarly, a meta-analysis of 54 randomized trials found that cholinesterase inhibitors were associated with 1.5-fold greater risk of syncope than placebo [35].
Sleep disturbances — Insomnia, vivid dreams, and other sleep disturbances may be more common with donepezil than the other two drugs. If vivid dreams or nightmares arise on donepezil, switching to morning dosing or to an alternative drug may help [32].
Additional strategies for the management of sleep disturbances in patients with dementia are reviewed separately. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Management'.)
FOLLOW-UP AND MONITORING — Patients who are started on a cholinesterase inhibitor should be seen for follow-up at three and six months to assess drug tolerance and response. A phone call at two weeks can be useful to troubleshoot early side effects. Patients on a stable dose of drug are then seen every 6 to 12 months thereafter. Routine laboratory monitoring is not required for any of the cholinesterase inhibitors.
Assessment of response — Response to cholinesterase inhibitors can be subtle and gradual. We typically counsel patients and families to anticipate a six-month trial before making a decision about whether the medication is helping or not.
The Mini-Mental State Examination (MMSE) is not specific enough for following response; we generally use a combination of naming, recall of a four-word list or story at 30 seconds and five minutes, and semantic fluency (eg, naming as many animals as possible in one minute). The Montreal Cognitive Assessment (MoCA) can be administered at each visit to track change over time. The MoCA is accessible online and in multiple languages at www.mocatest.org. It is a 30-point test that takes approximately 10 minutes to administer. Other brief cognitive tests are reviewed separately. (See "The mental status examination in adults", section on 'Cognitive screening tests'.)
Caregiver impression of change, behavioral symptoms, sleep, and other neuropsychiatric symptoms should also be assessed at each visit. (See "Management of neuropsychiatric symptoms of dementia", section on 'Symptom assessment'.)
There is conflicting evidence that pharmacogenetics may influence the response to cholinesterase treatment, such that some patients are either hyper- or hypometabolizers of these agents [36-39]. As an example, some studies have suggested that patients with a specific CYP2D6 allele have a poorer response to donepezil treatment, particularly if they also have the apolipoprotein E (APOE) epsilon 4 allele [37,39]. However, these associations do not appear to have a consistent effect on treatment response and have no clear association with adverse effects. Thus, we do not test for these alleles and instead assess and respond to the observed clinical effects and/or side effects.
Duration of therapy — There is no consensus on how long to continue cholinesterase inhibitors in patients who are tolerating therapy, and even patients who respond initially will ultimately progress.
Patients who do not respond initially — Since cholinesterase inhibitors are a symptomatic treatment and not disease modifying, some clinicians, patients, and families choose to stop treatment after a six-month trial if there has been no subjective or objective improvement. Unless the medication is already at the lowest dose, it should be tapered by 50 percent for two to three weeks before stopping to minimize risk of worsening. An alternative cholinesterase inhibitor is not typically used in this setting unless a patient is unable to achieve a target dose on the initial chosen drug due to side effects or formulation. Memantine can be added or substituted in patients with moderate to severe dementia. (See 'Role of memantine' below.)
Others feel that it is not possible to determine which patients are responders based on initial response to medication and therefore suggest continuing medication as long as the patient agrees to it and tolerates it [40]. Support for this approach is also drawn from a clinical trial of 295 patients with moderate to severe AD who were already taking donepezil, which compared the efficacy of four treatment strategies: no therapy (donepezil discontinued), donepezil continued alone, donepezil continued with memantine added, and memantine therapy alone [41,42]. After one year, patients assigned to receive donepezil therapy had, on average, a higher score on the MMSE (1.9 points) and a better score on the Bristol Activities of Daily Living Scale (BADLS; 3.0 points) compared with those not receiving donepezil. The average differences in the MMSE score, but not the BADLS, met the prespecified threshold considered by the investigators to be clinically important. The trial was stopped early due to slow recruitment. A post hoc analysis suggested that discontinuation of donepezil might increase the risk of nursing home placement over the next 12 months, but not over the prespecified four-year follow-up period [42].
Other reasons for discontinuation — Aside from lack of perceived benefit, other reasons for discontinuation of cholinesterase inhibitors include:
●Intolerable side effects despite dose reduction. If the main reason for discontinuation of a drug is gastrointestinal side effects, sometimes switching to a different formulation or drug can help. Memantine is also an option in patients with moderate to severe disease and may be better tolerated. (See 'Approach to common side effects' above and 'Role of memantine' below.)
●Rate of cognitive, functional, or behavioral decline is greater on treatment compared with pretreatment baseline. Of note, fluctuations in cognition and behavior are common in patients with dementia and are often multifactorial. An approach to the evaluation and management of neuropsychiatric symptoms of dementia is presented separately. (See "Management of neuropsychiatric symptoms of dementia".)
●Comorbidities or nonadherence make continued use of the drug unacceptably risky or futile.
●Progression to an advanced stage of dementia (eg, Functional Assessment Stage 7 (table 2)), in which there is little hope for a clinically meaningful benefit to continued therapy. (See "Care of patients with advanced dementia", section on 'Continuation of anti-dementia and other chronic medications'.)
Patients who worsen when drug is stopped — Occasionally patients will worsen after stopping therapy, even when appropriately tapered over a two- to three-week period [43-45]. It is not clear if this is a sign that they benefited from the medication, but we generally reintroduce it when clinical decline is closely temporally linked with medication withdrawal. While data from clinical trials suggested that treatment gaps (periods in which the patient did not take cholinesterase inhibitor) were associated with worse outcomes, a large observational study of older adult patients prescribed cholinesterase inhibitors found that the risk of institutionalization or death did not appear to be increased among those who experienced treatment gaps [46].
Role of memantine — Memantine is commonly added to cholinesterase inhibitor therapy when patients reach a moderate stage of AD (MMSE ≤18), based on moderate-quality data that the combination therapy leads to modest symptomatic benefits on cognition and behavior. Memantine can also be used as a single agent among patients who do not tolerate cholinesterase inhibitors. (See "Treatment of Alzheimer disease", section on 'Memantine'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)" and "Patient education: Tips for caregivers of people with Alzheimer disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Mechanism of action – Cholinesterase inhibitors target the acetylcholine deficit arising from loss of neurons in the brain. These are symptomatic therapies and are not believed to be neuroprotective or to alter the disease trajectory. (See 'Introduction' above.)
●Indications – Cholinesterase inhibitors have been most extensively evaluated in patients with Alzheimer disease (AD) dementia. (See "Treatment of Alzheimer disease", section on 'Cholinesterase inhibitors'.)
Lower-quality data support a trial of a cholinesterase inhibitor in patients with other forms of dementia, including dementia with Lewy bodies (DLB), vascular dementia, and Parkinson disease dementia. Recommendations for treatment of these disorders are discussed separately. (See "Prognosis and treatment of dementia with Lewy bodies", section on 'Cholinesterase inhibitors' and "Treatment of vascular cognitive impairment and dementia", section on 'Cholinesterase inhibitors' and "Cognitive impairment and dementia in Parkinson disease", section on 'Cholinesterase inhibitors'.)
●Contraindications – Cholinesterase inhibitors are contraindicated in patients with baseline bradycardia or known cardiac conduction system disease (eg, sick sinus syndrome, incomplete heart block) due to risk of syncope, falls, and fractures.
They should be used with caution in combination with drugs that induce bradycardia or alter nodal conduction. (See 'Contraindications and precautions' above.)
●Dosing and administration – The choice among donepezil, galantamine, and rivastigmine is based upon ease of use, individual patient tolerance, cost, and clinician and patient preference; efficacy appears to be similar (table 1). (See 'Choice of drug' above.)
•Donepezil is available as a once-daily tablet and a once-daily disintegrating sublingual tablet. The starting dose is 5 mg once daily. No dose adjustments are needed for renal or hepatic impairment. (See 'Donepezil' above.)
•Galantamine is available as a once-daily extended-release capsule and twice-daily tablet or solution. The starting dose is 8 mg once daily for the extended-release capsule (4 mg twice daily for immediate release), with meals. Dose adjustments are required for renal or hepatic impairment. (See 'Galantamine' above.)
•Rivastigmine is available as an oral capsule or solution (starting dose 1.5 mg twice daily) and as a daily transdermal patch (starting dose 4.6 mg/24 hours). The patch is preferred due to superior pharmacokinetics and tolerability; it requires dose adjustments for hepatic impairment and low body weight. (See 'Rivastigmine' above.)
●Adverse effects – The most common side effects of cholinesterase inhibitors are diarrhea, nausea, and vomiting. The toxicity is dose related and often resolves with time or dose reduction. Additional side effects include anorexia and weight loss, bradycardia and hypotension, syncope, and sleep disturbances. (See 'Approach to common side effects' above.)
●Duration of treatment – There is no consensus on how long to continue cholinesterase inhibitors in patients who are tolerating therapy. Even patients who respond initially will ultimately decline. Some clinicians, patients, and families choose to stop treatment after six months if there is no improvement. Others feel that it is not possible to determine which patients are responders based on initial response and continue medication as long as the patient agrees and tolerates it. (See 'Duration of therapy' above.)
Other reasons for discontinuation include poor tolerance despite dose reduction or drug switching, comorbidities or nonadherence that make continued use risky or futile, and progression to an advanced stage of dementia. (See 'Other reasons for discontinuation' above.)
●Approach to discontinuation – Unless the medication is already at the lowest dose, it should be tapered by 50 percent for two to three weeks before stopping to minimize risk of worsening.
We generally reintroduce therapy if a clinical decline occurs shortly after medication withdrawal. (See 'Patients who worsen when drug is stopped' above.)
