Cholinesterase inhibitors in dementia

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INTRODUCTION — Patients with Alzheimer's disease (AD) have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. This early discovery of a marked cholinergic deficit in the brains of patients with AD led to the study of therapeutically augmenting cholinergic activity [1]. However, acetylcholine precursors were found to be ineffective [2,3], while postsynaptic cholinergic receptor agonists had unacceptable side effects [4]. By contrast, the results of studies with cholinesterase inhibitors, which increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft, have been more encouraging, and these drugs may even have some utility in the non-AD dementias.

This topic will discuss the use of cholinesterase inhibitors in the treatment of dementia.

Daniel Press, MD
Michael Alexander, MD

UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.2 is current through April 2007; this topic was last changed on January 5, 2007.

ALZHEIMER'S DISEASE — Four cholinesterase inhibitors, tacrine, donepezil, rivastigmine, and galantamine are currently approved for use in Alzheimer's disease (AD) by the US Food and Drug Administration (FDA). Tacrine was the first agent approved for use in AD, but it can cause hepatotoxicity and is rarely used [5]. The choice between the other three agents is largely based upon cost, individual patient tolerability, and physician experience, as efficacy appears to be similar [6]. (Show table 1).

Donepezil — Donepezil has relatively little peripheral anticholinesterase activity and is generally well tolerated. This combined with its once-daily dosing has made it a popular drug in patients with AD. The recommended dose for donepezil is 5 mg per day for 4 weeks, then increasing to 10 mg per day.

The efficacy of donepezil was demonstrated in a 24-week double-blind study in which patients with mild to moderate AD were randomly assigned to donepezil (5 or 10 mg/day) or placebo [7]. Cognition, as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) [8], and the Clinician's global ratings were significantly improved in both treatment groups compared with placebo. There was no consistent effect noted on patient-related quality of life measures.

A second placebo-controlled trial of donepezil (AD2000) enrolled 566 patients referred to memory clinics with mild to moderate AD, with or without cerebrovascular disease [9]. There was a small but significant beneficial effect of donepezil for cognition compared with placebo, with a 0.8 point difference in the Mini Mental Status Exam (MMSE) score (95% CI 0.5-1.2) [9]. This size effect of cognitive improvement was similar to that seen in other randomized trials of donepezil [10]. Although donepezil slowed the decline in activities of daily living in patients with moderate to severe AD in an earlier study [11], it did not delay entry to institutional care in the AD2000 study [9].

A six-week placebo washout was performed after 24 weeks of the study cited above to examine whether donepezil had any disease-modifying activity [7]. The improvements on cognitive measures were erased, strongly suggesting that the drug does not effect the underlying course of disease.

Donepezil may also have benefit for patients who have crossed the threshold from mild cognitive impairment (MCI) to early stage AD, but the data are limited. One trial enrolled 153 patients with early-stage AD (MMSE scores of 21 to 26 and only mild impairment on activities of normal living) [12]. Donepezil treatment was associated with a significant, but clinically modest, 2.3 point improvement on the ADAS-cog at 24 weeks compared with placebo.

Prolonged treatment with donepezil appears to be safe and effective [13-15]. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) are transient and generally mild, occurring in about 20 percent of patients [7].

Donepezil and other cholinesterase inhibitors appear to modestly improve neuropsychiatric symptoms as well. (See "Treatment of behavioral symptoms related to dementia", section on Cholinesterase inhibitors).

Rivastigmine — Rivastigmine appears to be beneficial in patients with mild to moderate AD [16] and has been approved for use by the FDA. Its side-effect profile is related to cholinergic effects, with significant nausea, vomiting, anorexia, and headaches. It should be given with food to minimize nausea. One case of esophageal rupture due to severe vomiting has been reported; the manufacturer advises slow titration of the drug (eg, initiating therapy at 1.5 mg twice daily with titration every two weeks up to 6 mg twice daily) and, if treatment is interrupted for longer than several days, it should be restarted at the lowest daily dose and then titrated again [17]. While not compared head-to-head with donepezil, its efficacy appears similar, although it may have more gastrointestinal side effects [18].

Galantamine — Galantamine (Razadyne; previously marketed as Reminyl) appears to be effective in patients with mild to moderate AD [19]. Randomized controlled trials have found that treatment with galantamine (maintenance dose 24 or 32 mg/day) slowed the decline in both cognition and activities of daily living compared with placebo in patients with early AD [20-23]. Cognitive benefits of galantamine have been sustained for up to 36 months [24]. A secondary analysis [25] of a randomized controlled trial [21] reported that galantamine-treated AD patients had significantly better overall ADL scores than the placebo group at five months regardless of dementia severity.

Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the most common adverse effects of galantamine. Like rivastigmine, galantamine appears to have similar efficacy to donepezil in patients with AD but may have more gastrointestinal side effects.

The use of galantamine has been associated with increased mortality in patients with MCI [26]. (See "Mild cognitive impairment", section on Cholinesterase inhibitors). Increased mortality has not been observed in patients treated for AD, mixed dementia, or vascular dementia.

Advanced disease — Although efficacy of cholinesterase inhibitors for cognitive effects has been established in patients with mild to moderate AD, it is not clear if patients with advanced AD, including patients in nursing homes, will benefit from therapy. One study has investigated the use of donepezil in patients with moderate to severe AD (defined as MMSE score of 5 to 17), including both community-dwelling individuals and those in assisted living settings who still had measurable functional ability [27]. Donepezil therapy was well tolerated and was associated with significant improvements in global function, cognition, behavior, and activities of daily living compared with placebo.

Similar results were reported in a randomized, double-blind, placebo-controlled study of 208 nursing home residents, 70 percent of whom had a MMSE score <20 at baseline [28].

In another nursing home-based study, 216 patients with severe AD (defined as MMSE score of 1 to 10) were randomly assigned to treatment with donepezil or placebo [29]. At six months, donepezil-treated patients showed improved cognitive ability on a Severe Impairment Battery, while placebo-treated patients worsened. While the incidence of adverse events was similar in both treatment groups, more patients discontinued therapy because of adverse events in the donepezil group.

These data are encouraging but require further confirmation before recommendations can be made for patients with advanced AD.

OTHER DEMENTIAS — Some controversy exists over who should be treated with cholinesterase inhibitors [30,31]. Nonetheless, these medications appear to offer similar or greater benefits for certain non-Alzheimer dementias such as vascular dementia (VaD) and dementia with Lewy bodies (DLB), and perhaps for dementia or cognitive impairment associated with Parkinson's disease (PD).

Vascular dementia — Patients with VaD have shown improvement in cognition, behavior, and activities of daily living with cholinesterase inhibitors [32]. (See "Treatment and prevention of vascular dementia").

Mixed dementia — Mixed dementia denotes a condition with clinical and pathological features of both Alzheimer's disease (AD) and VaD. A systematic review of the literature published in 2004 concluded that cholinesterase inhibitors provide modest clinical benefits for patients with mixed dementia; the benefit is similar in magnitude to that found for cholinesterase inhibitor treatment of AD [33]. Only two trials, one of galantamine [34] and the other of rivastigmine [35], evaluated patients with mixed dementia.

Dementia with Lewy bodies — Patients who have dementia with DLB can have marked improvements in cognition as well as improvements in behavioral symptoms and hallucinations, warranting a trial of cholinesterase inhibitors whenever this diagnosis is suspected [36]. (See "Prognosis and treatment of dementia with Lewy bodies").

Parkinson's disease — In patients with PD, the prevalence of dementia is quite high. Studies suggest that cholinesterase inhibitors have modest benefits in patients who have dementia associated with PD [37-40]. In our experience, a subset of patients show marked improvement with these medications. Because of this and the fact that cholinesterase inhibitors can alleviate visual hallucinations, we suggest a treatment trial in this patient population. (See "Parkinson's disease dementia").

Mild cognitive impairment — The data regarding cholinesterase inhibitors in patients with MCI are discussed separately. (See "Mild cognitive impairment", section on Cholinesterase inhibitors).

Huntington disease — There is currently no evidence that supports the use of cholinesterase inhibitors in patients with Huntington disease. A double-blind, randomized trial of donepezil 10 mg daily in 24 patients with Huntington disease demonstrated no difference between treatment and placebo on measures of cognition, chorea, or quality of life after 12 weeks of therapy [41].

Traumatic brain injury — Animal studies have suggested potential efficacy for cholinesterase inhibitors in patients with cognitive impairment resulting from traumatic brain injury (TBI). However, in a 12-week trial of 157 patients one year after TBI, measures of cognitive improvement were no different in the patients randomly assigned to rivastigmine versus those receiving placebo [42]. Subgroup analysis in this small trial suggested significant benefit for rivastigmine in patients with moderate to severe memory impairment. This finding requires independent confirmation before cholinesterase inhibitors can be recommended for these patients.

PRACTICE ISSUES

Degree of benefit — The average benefit of cholinesterase inhibitors in patients with dementia is a small improvement in cognition and activities of daily living [32,37,43-46]. Whether these drugs significantly improve long-term outcomes, such as the need for nursing home admission or maintaining critical activities of daily living (ADLs), remains in doubt, and the evidence is conflicting [6,9,31,47].

* In a meta-analysis of 29 randomized, placebo-controlled trials completed through December 2001, patients on cholinesterase inhibitors improved 0.1 SDs on ADL scales and 0.09 SDs on instrumental ADL (IADL) scales compared with placebo, an effect that would be similar to preventing a two months per year decline in a typical patient with Alzheimer's disease (AD) [6].
* A second meta-analysis concluded that 12 patients would need to be treated for one to benefit by achieving minimal improvement or better [48]. Treating 12 patients would also result in one additional patient having a treatment-related adverse event (mostly gastrointestinal side effects). Similar benefits are seen with cholinesterase inhibitors in patients with vascular dementia (VaD) [32,43,44], and cholinesterase inhibitors appear to show greater efficacy in patients with diffuse Lewy body dementia [37].
* The AD2000 study, the only nonpharmaceutical industry sponsored trial of cholinesterase inhibitors, found no significant benefit of donepezil compared with placebo for the two primary endpoints: entry to institutional care and progression of disability [9].

Additional evidence suggests that the response to cholinesterase inhibitors may be quite variable, with as many as 30 to 50 percent of patients showing no benefit [49,50], while a smaller proportion (up to 20 percent) may show a greater than average response (7 point ADAS-cog improvement) [33,51].

Duration of therapy — Since cholinesterase inhibitors are a symptomatic treatment and not disease-modifying, we generally administer them for eight weeks and then review the patient's response with the family. Treatment is continued if improvement is noted either on bedside testing or by the family. We stop treatment at this point if there has been no improvement. The Mini Mental Status Exam (MMSE) is not specific enough for following response; we generally use a combination of naming, recall at 30 seconds and five minutes of a four-word list, and semantic fluency (eg, naming as many animals as possible in one minute).

Occasionally patients will worsen after stopping therapy [52,53]. 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.

Cholinesterase inhibitors can be continued indefinitely. However, while there may be a clinical benefit in patients with moderately advanced disease [27,28], we generally discontinue the medication when a patient progresses to advanced dementia, and only reintroduce it if there is any deterioration.

Cost-effectiveness — Early analyses suggested that the cost of cholinesterase inhibitors might be partially or even completely offset by lower home care costs and delayed nursing home placement [54-57]. However, these findings were based upon a number of favorable assumptions, including factors such as the duration of drug effect and delayed nursing home placement, for which controlled data were lacking. Furthermore, the AD2000 study discussed above found no benefit for donepezil compared with placebo for entry to institutional care or formal care costs [9].

RECOMMENDATIONS — The following recommendations are based upon our clinical practice given the existing evidence on therapies for dementia:

* We suggest a treatment trial with a cholinesterase inhibitor for patients with mild to moderate dementia (Grade 2A). The choice between donepezil, rivastigmine, and galantamine can be based upon cost, individual patient tolerance, and physician experience, as efficacy appears to be similar (show table 1). Because of associated hepatotoxicity, we do not routinely use tacrine (Grade 1A).
* Cholinesterase inhibitors in patients with dementia produce, on average, small improvements in measures of cognition and activities of daily living (ADL). Not all patients benefit. Their impact on long-term outcomes, disability and institutionalization, is not clear. (See "Degree of benefit" above).
* Although most studies of cholinesterase inhibitors have been in patients with Alzheimer's disease (AD), there is some evidence of benefit for patients with vascular dementia (VaD), mixed dementia, dementia with Lewy bodies (DLB), and dementia in Parkinson's disease (PD). We suggest a treatment trial of a cholinesterase inhibitor in these patients as well. (Grade 2B). (See "Other dementias" above).
* Patients with dementia may also benefit from memantine and other therapies. (See "Treatment of dementia").
* In patients with severe dementia, cholinesterase inhibitors can be discontinued, but they should be restarted if the patient worsens without the medication (Grade 2C). (See "Duration of therapy" above).
* We do not routinely recommend cholinesterase inhibitors for patients with mild cognitive impairment (MCI), but if memory problems are particularly troubling to the patient, then a trial for symptomatic benefit may be warranted (Grade 2C). (See "Mild cognitive impairment", section on Cholinesterase inhibitors).



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GRAPHICS


Cholinesterase inhibitors

Cholinesterase inhibitors used for treatment of dementia: dose and administration

Donepezil
- Starting dose: 5 mg once daily
- Maintenance dose: 10 mg per day (increased after 4 to 6 weeks)
Galantamine
- Starting dose: 4 mg twice daily
- Maintenance dose: 12 mg twice daily (increased in monthly, 4 mg twice daily increments)
- Comments: Give with meals
Rivastigmine
- Starting dose: 1.5 mg twice daily
- Maintenance dose: 6 mg twice daily (increased in 2 week, 1.5 mg twice daily increments)
- Comments: Give with meals



Recommendation grades

1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other form
C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws

Grade 1A

Grade 1A recommendation
A Grade 1A recommendation is a strong recommendation, and applies to most patients in most circumstances without reservation. Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present.
Explanation:
A Grade 1 recommendation is a strong recommendation. It means that we believe that if you follow the recommendation, you will be doing more good than harm for most, if not all of your patients.
Grade A means that the best estimates of the critical benefits and risks come from consistent data from well-performed, randomized, controlled trials or overwhelming data of some other form (eg, well-executed observational studies with very large treatment effects). Further research is unlikely to have an impact on our confidence in the estimates of benefit and risk.




Grade 2A

Grade 2A recommendation
A Grade 2A recommendation is a weak recommendation, and the best action may differ depending on circumstances or patient or societal values.
Explanation:
A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but you may want to think about it." It is unlikely that you should follow the suggested approach in all your patients, and you might reasonably choose an alternative approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the benefits and risks may be uncertain. In deciding whether to follow a Grade 2 recommendation in an individual patient, you may want to think about your patient's values and preferences or about your patient's risk aversion.
Grade A means that the best estimates of the critical benefits and risks come from consistent data from well-performed, randomized, controlled trials or overwhelming data of some other form (eg, well-executed observational studies with very large treatment effects). Further research is unlikely to have an impact on our confidence in the estimates of benefit and risk.



Grade 2B

Grade 2B recommendation
A Grade 2B recommendation is a weak recommendation; alternative approaches may be better for some patients under some circumstances.
Explanation:
A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but you may want to think about it." It is unlikely that you should follow the suggested approach in all your patients, and you might reasonably choose an alternative approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the benefits and risks may be uncertain. In deciding whether to follow a Grade 2 recommendation in an individual patient, you may want to think about your patient's values and preferences or about your patient's risk aversion.
Grade B means that the best estimates of the critical benefits and risks come from randomized, controlled trials with important limitations (eg, inconsistent results, methodologic flaws, imprecise results, extrapolation from a different population or setting) or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimates of benefit and risk, and may change the estimates.



Grade 2C

Grade 2C recommendation
A Grade 2C recommendation is a very weak recommendation; other alternatives may be equally reasonable.
Explanation:
A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but you may want to think about it." It is unlikely that you should follow the suggested approach in all your patients, and you might reasonably choose an alternative approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the benefits and risks may be uncertain. In deciding whether to follow a Grade 2 recommendation in an individual patient, you may want to think about your patient's values and preferences or about your patient's risk aversion.
Grade C means the evidence comes from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.