Anti-dementia medicines
| Type | Recommendation |
|---|---|
| When to deprescribe | |
| CBR |
We suggest deprescribing be offered to older people taking cholinesterase inhibitors for the cognitive symptoms of dementia:
|
| Ongoing treatment | |
| CBR |
If deprescribing is unsuccessful despite multiple attempts, we suggest maintaining the lowest effective dose; however, we suggest reassessing the need for long-term therapy periodically. |
| How to deprescribe | |
| CBR |
We suggest individualising the tapering schedule and adjusting it according to the individual's response. In general, we suggest halving the daily dose every four weeks, ensuring the absence of withdrawal symptoms or worsening of global, cognitive, functional, or neuropsychiatric outcomes before initiating further tapering. Once half the lowest standard dose formulation is reached, we suggest ceasing completely. |
| CBR | For people on combination therapy of cholinesterase inhibitors and medicines with anticholinergic properties, we suggest first considering the deprescribing of anticholinergics due to the potential adverse effects on cognitive function. Tapering of anticholinergics can generally follow the same approach as cholinesterase inhibitors tapering; however, we suggest individualising the tapering schedule and adjusting it as needed according to the individual's response. The dose for concomitant cholinesterase inhibitors may also need to be adjusted due to the reduction in opposing mechanisms of action following the dose reduction of anticholinergics. |
| GPS |
Healthcare providers should consider and offer adequate non-pharmacological management options to individuals and their families, care providers(e.g. verbal de-escalation, psychological intervention, engaging individuals in meaningful activities, increased staff-to-patient ratio, increased staff training in behaviour management) as appropriate to manage challenging behaviours in dementia (ungraded good practice statement). |
| Monitoring | |
| CBR |
We suggest closely monitoring individuals for withdrawal symptoms or symptoms of disease exacerbation (e.g. worsening neuropsychiatric symptoms including agitation and apathy, cognitive decline, worsening behavioural symptoms, reduced ability in activities of daily living) every one to two weeks following each dose adjustment until at least four weeks after the medicine is fully ceased if practical. After this initial period, we suggest monthly monitoring for at least three months, followed by monitoring every six months thereafter. However, this should be tailored based on individual factors such as their preferences, responses and tolerance to deprescribing. If in-person visits are impractical, we suggest advising people to report symptoms and/or any appearance of new symptoms as needed. |
| GPS | Healthcare providers should provide clear guidance to care providers on recognising withdrawal symptoms and symptoms of disease exacerbation, enabling them to seek timely medical advice (ungraded good practice statement). |
| GPS | Healthcare providers should use validated assessment tools to evaluate changes in cognitive function, neuropsychiatric symptoms, functional status, and quality of life (e.g. Psychogeriatric Assessment Scales for cognitive function, Neuropsychiatric Inventory for neuropsychiatric symptoms, Functional Status Questionnaire for functional status, and EQ-5D for health-related quality of life) (ungraded good practice statement). |
CBR, consensus-based recommendation; GPS, good practice statement
The Australian Institute of Health and Welfare reported a 24% increase in the prescription rates of dementia-specific medications for Australians aged 30 and over from 2013-2014 to 2022-2024, with a greater increase in men than women [710].
Cholinesterase inhibitors and memantine are symptomatic treatments for dementia, with current evidence suggesting their efficacy is modest and unlikely to modify disease progression [711]. The continuation of treatment with these anti-dementia medicines should be based on a demonstrable, clinically meaningful response, such as improvements in quality of life, cognitive function, and/or behavioural symptoms [710].
A systematic review that included two RCTs focusing on cholinesterase inhibitors pharmacotherapy for Alzheimer's disease found modest but significant cognitive improvements in individuals with moderate to severe functional impairments who received cholinesterase inhibitors and these medicines were generally well tolerated [712]. However, the efficacy of long-term cholinesterase inhibitors beyond 12 months remains uncertain. Cholinesterase inhibitors may cause side effects, which older people are particularly susceptible to. Common side effects include dizziness, drowsiness, depression, sleep disturbances (e.g. insomnia, vivid dreams), and gastrointestinal issues (e.g. diarrhoea, anorexia, abdominal pain, dyspepsia) [601]. It is essential to assess these adverse effects carefully and weigh the potential benefits against the risks in the decision about discontinuing or continuing treatment.
The 2019 evidence-based clinical practice guideline for deprescribing cholinesterase inhibitors and memantine recognises the limited availability of high-quality, generalisable studies to inform deprescribing decisions [37]. Similarly, a 2021 Cochrane systematic review of six trials highlighted the lack of evidence to guide decisions about discontinuing or continuing cholinesterase inhibitors and/or memantine, particularly for dementia types other than Alzheimer's disease [713].
The 2025 Korean Dementia Association clinical practice guidelines for dementia provide the following recommendations regarding the use of cholinesterase inhibitors and memantine [714]. The use of cholinesterase inhibitors is strongly recommended for Alzheimer's disease and Lewy body dementia due to their efficacy in improving cognitive function, activities of daily living, and dementia severity (moderate certainty). For vascular dementia and Parkinson's disease dementia, the use of cholinesterase inhibitors is conditionally recommended (moderate certainty). For moderate to severe Alzheimer's disease, the use of memantine is strongly recommended (moderate certainty).
Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).
Given the potential risks associated with long-term use of cholinesterase inhibitors, deprescribing should be considered if side effects are intolerable or if there has been no clinically meaningful improvement. In contrast, for people who continue to receive meaningful therapeutic benefits with tolerable risks, cholinesterase inhibitors may be continued with periodic monitoring for emerging risks and benefits.
Given the lack of evidence for cholinesterase inhibitors in dementias other than Alzheimer's disease, dementia of Parkinson's disease, Lewy body dementia, or vascular dementia, deprescribing may be considered appropriate and should be offered to individuals currently taking cholinesterase inhibitors for indications other than these.
We identified seven studies related to the deprescribing of cholinesterase inhibitors (four RCTs and three before-and-after studies) from the systematic review and meta-analysis [715-720].
Overall, all studies included participants with varying severity of dementia and different types of dementia (Alzheimer's disease, DLB, and/or PDD) in people living in different settings (community or long-term care facilities). None of the reported outcomes reached statistical significance except for a significant worsening in BPSD for PDD in a single-arm study. However, this study is of very low certainty due to a very small sample size, lacking a concurrent control group, a very short follow-up duration after withdrawal (six weeks), and other methodological limitations. In addition, dementia is a progressive disease which makes it challenging to clearly differentiate between natural disease progression and withdrawal effects after stopping cholinesterase inhibitors. The current evidence is insufficient to inform evidence-based recommendations.
If deprescribing cholinesterase inhibitors are considered appropriate, it may be appropriate to closely monitor for withdrawal symptoms or symptoms of disease exacerbation (e.g. worsening neuropsychiatric symptoms including agitation and apathy, cognitive decline, worsening behavioural symptoms, reduced ability in activities of daily living).
Key study characteristics and results
A narrative summary of each study is provided below, highlighting key characteristics and main findings.
Gaudig 2011 reported two different study designs comparing the continuation and discontinuation of galantamine for six weeks in patients with mild to moderate Alzheimer’s disease [716]. Participants were excluded if they had symptoms of other conditions that might contribute to dementia or cognitive impairment resulting from brain injury. In study one, a before-and-after study, participants in the control group who continued with galantamine had a significant improvement in cognition measured using the Alzheimer's Disease Assessment Scale-Cognitive scales (MD 2.50, 95% CI 1.18, 3.82) at the end of six weeks follow-up. There was no significant difference between the two groups in terms of mortality (OR 0.51, 95% CI 0.02, 12.66), adverse drug events (OR 0.99, 95% CI 0.66, 1.47), or serious adverse events (OR 0.82, 95% CI 0.05, 13.58). Similar outcomes were reported in study 2, an RCT, where there was no significant difference in adverse drug events (OR 0.61, 95% 0.24, 1.58), serious adverse events (OR 0.73, 95% CI 0.29, 1.86), or cognition (MD 1.60, 95% CI -1.15, 4.35) at the end of six weeks follow-up.
Scarpini 2011 randomised 139 patients with mild to moderate (MMSE score of 11 to 24) Alzheimer’s disease who had been taking galantamine for 12 months to continuation (n=76) or discontinuation (n=63) [720]. Participants were excluded if they had another neurodegenerative disorder other than Alzheimer's Disease, a history of previous cerebral infarction, or had used acetylcholinesterase inhibitors in the past three months. Other cholinesterase inhibitors (donepezil, tacrine, rivastigmine), nootropics, antidepressants, mood stabilisers, and anticholinergics were not permitted during the trial. At 24 months, there were no significant differences between the two groups in terms of mortality (OR 0.47, 95% CI 0.09, 2.49), adverse drug events (OR 0.71, 95% CI 0.34, 1.48), and serious adverse events (OR 0.40, 95% CI 0.12, 1.33).
Herrmann 2016 randomised 40 residents of long-term care facilities with moderate to severe Alzheimer's disease (MMSE ≤ 15) who had been taking cholinesterase inhibitors for at least two years to continuation (n=21) versus discontinuation (n=19) [717]. Participants were included if there had been no changes to their dose in the past three months and excluded if they had dementia other than Alzheimer's dementia or were using transdermal rivastigmine. Concomitant psychotropics were permitted during the trial as long as they had been taking a stable dose for at least a month. After two months, there were no significant differences between the two groups in clinical exacerbation (OR 3.75, 95% CI 0.36, 39.59), neuropsychiatric symptoms measured using NPI-NH (MD -4.70, 95% CI -11.53, 2.13), global clinical status measured using the Clinical Global Impression Scale (MD 0.20, 95% CI -0.08, 0.48) or agitation measured using the Cohen-Mansfield Agitation Inventory score (MD 2.80, 95% CI -3.01, 8.61). Similarly, there was no difference in activities of daily living measured using the Alzheimer's Disease Cooperative Study-Activities of Daily Living modified for severe Alzheimer's Disease (MD 0.10, 95% CI -2.14, 2.34), Apathy Evaluation Scale score (MD 1.50, 95% CI -2.65, 5.65), cognition measured using standardised MMSE (MD -1.70, 95% CI -3.91, 0.51), or quality of life measured using the Quality of Life in Late Stage Dementia (MD -0.40, 95% CI -3.12, 2.32).
Moo 2021 randomised 62 primary care patients with dementia associated with Parkinson’s disease who had been taking cholinesterase inhibitors for at least 12 months to continuation (n=36) versus discontinuation (n=26) [719]. The severity of dementia at baseline was unclear. At six weeks, there were no significant differences between the two groups in activities of daily living measured using the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (MD 2.02, 95% CI -16.32, 20.36) or cognition measured using the Six-Item Screener (MD 0.28, 95% CI -0.59, 1.15).
Garcia-Garcia 2022 conducted a before-and-after study that included institutionalised patients with severe dementia who had been taking cholinesterase inhibitors for at least 12 months [715]. Cholinesterase was discontinued if 1) cognition and/or function significantly worsened over the past six months, 2) there had been no improvement, stabilisation or reduction in the rate of decline at any time during the treatment, or 3) dementia was severe/end-stage (dependence in most activities of daily living, inability to respond to the environment and/or limited life expectancy). Participants with underlying psychiatric disorders or a disability that could affect cognitive and/or functional assessment were excluded. Cholinesterase inhibitors were deemed suitable to be discontinued in 23 participants. Compared to baseline, after three months of discontinuation, there were no significant differences in cognition measured using MMSE (p = 0.441) and the Reisberg’s Global Deterioration Scale (p = 0.976), BPSD measured using the NPI (p = 0.882), or activities of daily living measured using the Barthel index (p = 0.08).
Minette 2003 evaluated the impact of abrupt discontinuation of donepezil in eight participants with probable dementia with Lewy bodie (DLB) and 11 participants with Parkinson’s disease who subsequently developed dementia (PDD) [718]. Participants were excluded if they had a severe gastrointestinal, renal or liver disease, a history of cardiac bradyarrhythmia, asthma, bladder outflow obstruction, a recent history of cerebrovascular disease, or if they were taking cholinergic, anticholinergic, NSAID or neuroleptics. At baseline, participants with DLB had a mean MMSE score of 15.3 whereas participants with PDD had a mean MMSE score of 18.2, indicating moderate cognitive impairment. All participants received up to 10mg of donepezil daily for 20 weeks prior to a six-week withdrawal period. After withdrawal, both groups of participants had no significant changes in cognition measured using Mini-Mental State Examination or BPSD measured using NPI when compared to baseline. However, when compared to the treatment period at week 20, participants with PDD showed a significant worsening in BPSD measured using NPI after withdrawal (Z = -2.6, p = 0.008) whereas both groups of participants showed a significant worsening in cognition after withdrawal (p not stated).
Various methods were used for deprescribing in the included studies and tapering across several weeks was the most common method. While there was no direct evidence that any particular method was associated with the greatest benefits and harms, dose tapering is likely more acceptable than abrupt cessation and helpful in determining the lowest effective dose for some patients requiring dose reduction rather than complete cessation. The tapering approach should be individualised with the speed adjusted according to the individual's response and preferences.
In people receiving both cholinesterase inhibitors and medicines with anticholinergic properties concurrently, it may be appropriate to first consider withdrawing the anticholinergic medicine, given its potential to impair cognitive function and contribute to a potentially inappropriate prescribing cascade with cholinesterase inhibitors.
In the two RCTs, one RCT tapered cholinesterase inhibitors for two weeks before the complete withdrawal (n=40, moderate certainty) [717] whereas the other RCT halved the dose for three weeks (n=62, very low certainty) [719]. The method of deprescribing was not described in the other two RCTs (n=257, very low certainty) [716, 720].
In the two before-and-after studies, the cholinesterase inhibitors dose was halved every week through available formulations to the lowest available dose before complete withdrawal in one study (n=23, very low certainty) [715], and the method was not described in the other study (n=723, very low certainty) [716].
In the single-arm study, donepezil was discontinued abruptly (n=19, very low certainty) [718].