Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology
Summary (8 min read)
Introduction
- The British Association for Psychopharmacology (BAP) produced a first edition of clinical practice guidelines for antidementia drugs in 2006 (Burns and O'Brien, 2006) , which were subsequently revised (O'Brien and Burns, 2011) .
- The focus was on new evidence which had become available since the first guidelines were published.
- There is general agreement that anticholinergic burden should be minimised in those with dementia, especially before prescribing cholinergic medication.
- Concerns over cerebrovascular adverse events and increased mortality has forced consideration of alternative approaches to the treatment of BPSD, including ChEIs, memantine and increased the emphasis on non-pharmacological therapies including activity, music therapy and aromatherapy.
Methodology
- The participants were selected for their clinical and research experience in the field of dementia care, and also included a person with dementia.
- The group arrived at its decisions after expert papers were written independently and then presented and discussed at the meeting.
- All relevant papers published up to and including December 2015 were considered.
- Particular emphasis was placed on reviewing the previous recommendations in the light of new evidence published since the last guidelines.
- Assess the evidence for the efficacy of currently available anti-dementia drugs in all common types of dementia and, based on that, make clear recommendations for clinical practice.
Diagnosis and investigations
- The criteria used to define dementia and cognitive disorders continue to cause controversy.
- Two key changes from the fourth edition (DSM-IV; American Psychiatric Association, 2000) of relevance here are (a) a move away from the terms of dementia and mild cognitive impairment to major and mild neurocognitive disorder respectively and (b) the inclusion of Lewy body disorder (major or mild neurocognitive disorder with Lewy bodies).
- The National Institute on Aging-Alzheimer's Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011) , mild cognitive impairment due to AD (Albert et al., 2011) and preclinical AD (Sperling et al., 2011) .
- The main purpose of many of these changes has been to allow internationally agreed criteria to be used for subject selection and stratification for ongoing natural history and therapeutic studies, though the validation and clinical usefulness of these criteria remains to be fully determined.
- Clinical criteria for frontotemporal dementia (FTD) have been updated (Rascovsky et al., 2011) .
Neuroimaging and cerebrospinal fluid (CSF) biomarkers
- There is increasing interest in the use of brain imaging and CSF biomarkers, both to assist with early and accurate differential diagnosis, and as potential markers of disease progression which may be used as surrogate outcome measures for clinical trials.
- AD is associated with medial temporal lobe atrophy, particularly of the entorhinal cortex and hippocampus, and temporoparietal hypoperfusion on SPECT and hypometabolism on FDG PET.
- Decreased cardiac sympathetic uptake, as indicated by decreased metaiodobenzylguanidine (MIBG) SPECT binding has been found in Parkinson's disease and DLB.
- Raised levels of CSF tau (both total and phosphorylated tau) and reduced levels of Aβ1-42 have proved, when combined in a ratio, to have reasonable diagnostic accuracy for separating AD from other dementias (mean sensitivity 72%, mean specificity 78% when comparing AD to other dementias) (Mitchell, 2009) .
- Table 2 provides a summary of assessment and diagnosis recommendation strengths.
Drug treatments for Alzheimer's disease
- Since the previous revision of the guidelines no new drugs have been licensed for AD.
- Donepezil, rivastigmine and galantamine are licensed for mild to moderate AD, memantine for moderate to severe AD, and several randomised controlled trials (RCTs) demonstrate their efficacy in these situations.
- The basic evidence to support the use of these drugs remains unchanged and, in general, the costs of the drugs are now significantly lower, particularly for donepezil.
- Combination therapy using a ChEI initially with the later addition of memantine is now considered optimal treatment in many countries particularly as the dementia advances.
- No new comparative trials between the three ChEIs, or of trials switching between the ChEIs, have been published in the last.
A
- There is type II evidence that medial temporal atrophy can be helpful in the diagnosis of Alzheimer's disease, and for distinguishing Alzheimer's disease from dementia with Lewy bodies in some cases.
- There is type I evidence that amyloid PET imaging can identify patients with elevated amyloid burden in the brain, and so be a useful diagnostic marker for Alzheimer's disease.
- There is type I evidence that MIBG can differentiate dementia with Lewy bodies from Alzheimer's disease.
- There is type I evidence that cholinesterase inhibitors should not be stopped just because the point of severe dementia has been reached.
- HRT should not be prescribed either as a prevention or treatment for dementia, including Alzheimer's disease.
B
- There is type I evidence that dopaminergic SPECT or PET imaging can help differentiate dementia with Lewy bodies from Alzheimer's disease.
- It is widely recognised that a good number of people diagnosed with dementia have mixed brain pathology which is predominantly due to Alzheimer's and cerebrovascular changes.
- Were no different between the intervention and control group.
- Finally, trials themselves need to be conducted in a limited number of centres with access to the target populations to run at scale and maintain data quality and reduce sample heterogeneity.
- The EPAD programme concurrently addresses all these elements.
CSF biomarkers
- There is type II evidence that CSF markers of amyloid and tau may be useful diagnostic markers for Alzheimer's disease, but further standardisation and validation is required before they can be more widely used clinically.
- Previous comparative trials failed to consistently demonstrate any significant differences in efficacy between the three ChEIs, the main differences found being in frequency and type of adverse events (O'Brien and Burns, 2011) .
- Similarly, their previous recommendation that a significant proportion (up to 50%) appear to both tolerate and benefit from switching between ChEIs if they cannot tolerate one, remains valid.
Treatment with cholinesterase inhibitors and memantine
- There is type I evidence showing small cognitive improvements with both cholinesterase inhibitors and memantine in vascular dementia.
- Benefits in terms of global outcome are not seen and adverse events for cholinesterase inhibitors (but not memantine) are significantly greater than placebo.
- Evidence indicates that neither cholinesterase inhibitors nor memantine should be prescribed to people with vascular dementia, though those with mixed vascular dementia and Alzheimer's disease may benefit.
Combination therapy
- B VaD are heterogeneous, ranging from large multiple infarcts caused by emboli to diffuse white matter changes associated with chronic hypoperfusion (O'Brien and Thomas, 2015; O'Brien et al., 2003) .
- Specific pharmacological interventions have involved donepezil, galantamine, rivastigmine and memantine.
- The authors commented that the clinical heterogeneity of VaD patients limited generalisability of the trials' outcomes because the effect of treatment on specific patients or subgroups could not be defined.
- In the SIVD group rivastigmine did not improve MMSE but had beneficial effects upon measures of executive function, neuropsychiatric features, depression and Clinical Dementia Rating.
Cholinesterase inhibitors
- There is type I evidence to support treatment with rivastigmine and donepezil in Lewy body dementias, both in dementia with Lewy bodies and Parkinson's disease dementia.
- There is type I evidence that cholinesterase inhibitors are not recommended for the treatment of frontotemporal dementia.
Other dementias
- This group of disorders is used here to include FTD, the primary progressive aphasias, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and prion dementias amongst others, and the overlap between some of these conditions is illustrated in Figure 4 .
- The existing evidence does not support the use of these drugs in FTD although rates of off-label use remain high, despite increased agitation having been reported with their use in FTD (O'Brien et al., 2011) .
- A small trial of Souvenaid reported beneficial effects in behaviour and social cognition measures over a short time period (Pardini et al., 2015) , but more studies are needed.
- Since the last BAP statement there has been no new trial evidence for ChEIs or coenzyme Q10 in treating PSP.
- There are no adequately powered studies of ChEIs to support the use of these drugs for cognitive impairment in Huntington's disease.
Mild cognitive impairment (MCI) due to AD and prodromal AD
- There have been no new positive studies to inform prescribing in prodromal conditions such as MCI.
- Cochrane and other reviews show lack of efficacy of ChEIs (Birks and Flicker, 2006; Loy and Schneider, 2006) , equivocal findings with piracetam (Flicker and Grimley Evans, 2001) and there is no other evidence to support nootropics.
- Other studies including RCTs of vitamin E and anti-inflammatory drugs have been negative.
- There have been numerous trials conducted and ongoing in MCI due to AD or prodromal AD though none have been successful and progressed beyond Phase 3.
Other relevant issues in management
- The National Institute for Health and Clinical Excellence (NICE) process.
- There is also a NICE dementia guideline, GD42 (NICE, 2006), which was in the process of being fully revised at the time of the publication of this BAP guideline.
- The current guideline recommends the use of ChEIs for Lewy body dementia, but not for FTD, VaD or MCI.
Perspective from a person with dementia
- Many people with dementia and their carers have been important advocates for the clinical use of anti-dementia drugs and this should be an essential part of any decision making process.
- His insights were invaluable and very much accorded with experience of the clinicians on the panel.
- Peter reflected on the wider contexts in which the first prescription can be considered.
- These range from the patient's initial interpretation of the significance of medication to the ethical imperative for professionals to strike a balance between the global quest for cure and the fundamental human rights of people with dementia for care and support.
- This is consistent with the bio-psychosocial model of impairment which includes quality of life indicators.
SSRIs
- There is type II evidence that SSRIs may help some behavioural aspects of frontotemporal dementia, but do not improve cognition.
- Studies are mixed and further evidence is needed.
Treatment with cholinesterase inhibitors and vitamin E
- There is type I evidence that cholinesterase inhibitors are not effective in reducing the risk of developing Alzheimer's disease and type I evidence that vitamin E is not effective in reducing the risk of Alzheimer's disease.
- There is type 1 evidence that cholinesterase inhibitors are not effective in those with mild cognitive impairment A A profession carries the main responsibility for timely diagnosis and for maintaining the health and well-being of each person in their own homes for as long as possible.
- It could also influence public opinion, politicians and the media by avoiding the use of degrading language involving time-bombs and tsunamis.
- In their quest for prevention and cure, the authors have lost sight of the uniqueness of the individual highlighted by Tom Kitwood and more recently by Steven Sabat who focuses on the maintenance of a sense of self and personal identity from first diagnosis to the end of life (Schalock et al., 2016) .
The role of primary care in the management of dementia
- Primary care general practitioners (GPs) increasingly work in larger multidisciplinary teams.
- The contract links achievements in care quality, with a major focus on chronic illness care, properly funded through an evidence-based Quality and Outcomes Framework (QOF).
- A UK pilot trial of a GP educational prescription to support dementia diagnosis and improve quality of care found that GPs had little knowledge of shared care protocols for anti-dementia drugs, with specialists still largely responsible for monitoring (Wilcock et al., 2013) .
- New alternative primary care models with GP-led memory clinics and attached nurse facilitators have been established in some areas.
- With regard to GP-led prescribing, this will be influenced by the revised NICE guidelines (due 2017); such a change in practice would however require upskilling of GPs, prescribing protocols and the development of a shared care, integrated system co-ordinated by possibly specialist nurses.
End of life care
- One-third of older people will die with some form of cognitive impairment or dementia (Brayne et al., 2006) .
- They may experience poor end of life care because they are often not perceived to have a terminal illness and health and social care services may not be optimally configured to meet their complex needs (Sampson et al., 2011) .
- There is little evidence available on how best to prescribe for people with severe dementia, particularly when to stop drugs which are no longer necessary or beneficial.
- In patients with moderate or severe AD, continued treatment with donepezil is associated with significant functional benefits over 12 months; thus continuing a ChEI may be in keeping with a palliative approach (level I evidence) (Howard et al., 2012) .
- Covert medication may be in the person's best interests if conducted within the correct ethical and legal frameworks.
Other putative therapies for dementia
- At the time of the previous guideline, a single randomised placebo-controlled trial (RPCT) of 183 people in Russia showed benefits of dimebon treatment over placebo (Doody et al., 2008) .
- Unfortunately other studies have not been able to replicate these findings and a recent Cochrane review (Chau et al., 2015) concluded there was no beneficial effect of dimebon on cognition in AD, though did not rule out a possible benefit on behaviour.
Hormone replacement therapy (HRT)
- A large primary prevention trial, the Women's Health Initiative Memory Study trial examined the possible benefit of HRT or estrogen replacement therapy (ERT) in reducing dementia in post-menopausal women (participants were 65-79 years at entry).
- Adverse outcomes led to both arms being terminated early.
- Following WHIMS the critical window hypothesis emerged claiming use of ERT in younger women might be beneficial but a recent review has questioned this and there is no good quality data to support this (Maki and Henderson, 2012) .
Withdrawal of anti-dementia drugs
- There is type I evidence that continuing donepezil may decrease the rate of functional decline in moderate/severe dementia.
- There is type III evidence that it may be inappropriate to prescribe memantine and cholinesterase inhibitors in advanced dementia towards the end of life.
- C been proposed for preventing and treating dementia.
- Whilst cross-sectional studies have generally supported this view (Ho et al., 2011) , prospective studies have not found a relationship between dementia and high homocysteine (Ho et al., 2011) and a systematic review of RCTs of B vitamin and folate supplementation found no beneficial effects on cognition in people with or without cognitive impairment (Ford and Almeida, 2012) .
Statins and dementia
- No new RPCTs in relation to dementia prevention have been published since the last guideline.
- Neither of the previous two large studies (heart protection study and PROSPER) found an effect of statins on ameliorating cognitive decline or dementia.
Therapeutic non-invasive brain stimulation
- Interest in the use of non-invasive stimulation approaches such as transcranial direct current stimulation (tDCS) and rapid rate transcranial magnetic stimulation (rTMS) has gained significant traction over the past number of years.
- Mechanistically both tDCS and rTMS modulate cortical activity non-invasively.
- There was very little data to indicate whether any cognitive benefits are sustained.
- In addition, it was noted in the meta-analysis by Hsu et al. (2015) that individual trial sizes were small and protocol designs heterogeneous; furthermore in the studies examined there was also evidence of positive publication although notably across the dementia studies which examined rTMS or tDCS there was a lack of any serious adverse events.
Disease-modifying therapies
- There are several strategies currently being investigated for possible disease-modifying effects in people at high risk of progression to dementia, though most studies focus on AD and include subjects with prodromal AD or preclinical AD.
- These include the use of drugs that may modulate amyloid and/or tau processing, e.g. to decrease production of beta amyloid or to increase its breakdown or removal, and other approaches which try to reduce the likelihood of amyloid monomers binding to produce oligomers and insoluble sheets.
- There have also been anti-inflammatory and neurotrophic strategies.
Immunisation
- The success of mouse vaccine studies led to the first human trials of an active Aβ 1-42 vaccine (AN1792) in people with AD.
- Neuropathological examination of subjects from a phase I RPCT of AN1792 showed variable removal of amyloid plaques and no impact on long term clinical outcomes.
- Aβ, failed to show overall clinical benefit in two large phase III studies of AD.
- Unfortunately, this two-year RPCT study showed no efficacy on primary or secondary outcomes.
- A number of these active or passive immunisation approaches are now being tested in long-term preventative RPCT studies of APOE e4 positive, cognitively normal subjects (CAD106) or presymptomatic carriers of early onset AD mutations (solanezumab, crenezumab and gantenerumab).
Folate and vitamin B12 for dementia
- There is type I evidence that supplementation with folic acid with or without vitamin B12 does not benefit cognition in people with dementia.
- On current evidence, neither vitamin B12 nor folate, either singly or in combination, can be recommended as treatments for dementia, or for dementia prevention.
Statins for the treatment or prevention of dementia
- There is type I evidence that statins do not prevent dementia.
- There is type II evidence that statins do not produce cognitive benefits in Alzheimer's disease.
B rTMS and tDCS
- There is type II evidence indicating benefit of rTMS and tDCS on cognition but effects may not be sustained.
- These treatments are not recommended until further evidence becomes available.
- Epidemiological studies of the protective effects of NSAIDs are generally more positive.
- Likewise a large randomised study of the NSAIDs naproxen and celecoxib in asymptomatic individuals with a family history of AD initially an increased risk of increased cognitive decline for both drugs.
- Table 12 summarises recommendation strengths for disease-modifying therapies.
Optimising outcome measures for trials
- Following the expansion of NHS Memory Services, the number of people diagnosed with dementia in the UK has increased hugely (Mukadam et al., 2014) , so that around 100,000 people per year receive a diagnosis of AD within the NHS.
- These include early diagnosis, information, advance decision making, cognitive stimulation therapy, management of neuropsychiatric symptoms, strategies for family carers, ChEIs in AD, and changes in attitudes, including highlighting personhood and living well with dementia, but there is no cure or disease-modifying treatment for the common dementias (Prince et al., 2011) .
- Currently trials of drugs for disease modification in AD use different outcomes e.g. magnetic resonance imaging (MRI) brain volume change or change in cognition or function.
- They also use differing measures of the same outcome.
- Use of an agreed set of the most valid trials' outcome measures for disease modification studies would improve efficiency and enhance interpretation of data across studies (Ghezzi et al., 2013) .
Prospects for prevention
- Prevention is typically considered in three main subdivisions.
- Secondary prevention is where clinical symptoms are prevented in people with evidence of disease, and tertiary prevention is where a later stage of clinical progression is prevented in people with both disease and symptoms.
- As can be seen from this general description, the terms are dependent upon the definitions of 'disease' and 'symptoms'.
- There are no drugs available that achieve secondary prevention of dementia (Schneider et al., 2014) .
- Non-pharmacological, multi-modal interventions have shown better evidence of success than any drug to date e.g. the FINGER study (Ngandu et al., 2015) .
A Vaccination and immunisation studies
- There is preliminary type II evidence of their effect in Alzheimer's disease on some endpoints, but also type II evidence that amyloid lowering does not affect clinical course.
- Amyloid-lowering agents should not be prescribed until the optimal disease stage, safety and efficacy data are available.
Intervention Level of evidence Recommendation
- Matthew Norton -declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- George McNamara -declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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"Clinical practice with anti-dementi..." refers background in this paper
...The National Institute on Aging-Alzheimer’s Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011), mild cognitive impairment due to AD (Albert et al....
[...]
...The National Institute on Aging-Alzheimer’s Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011), mild cognitive impairment due to AD (Albert et al., 2011) and preclinical AD (Sperling et al., 2011)....
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