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Current pharmacological therapy for dementia aims to improve the symptoms of dementia and delay further decline. The acetylcholinesterase inhibitors donepezil, galantamine and rivastigmine increase levels of the neurotransmitter acetylcholine in neuronal synapses in the brain by preventing its breakdown. The glutamate receptor antagonist memantine blocks the effect of glutamate on N-methyl-D-aspartate receptors, reducing calcium-induced cell death.
Future treatments could target the development of neuritic plaques and neurofibrillary tangles in the brain and may offer a cure for some forms of dementia; however useful therapies are likely to be many years
The management of dementia is multifactorial: there is no single approach that will control the symptoms of dementia completely. Although pharmacological therapy can help, the treatments available are not curative.Other interventions need to be implemented alongside medicines to ensure patients get the most benefit from treatment and clinicians should consider patients’ needs holistically.
People with dementia often lose their most recent memories and may use a time in their past as a reference point. Being aware of an individual’s previous occupation and character can help when formulating strategies for managing his or her condition.
Routine and familiarity go a long way toward retaining function and independence, and aids such as diaries and reminder charts can be useful in prompting memory retrieval. Using colour to make key objects — such as charts, telephones and doorways — stand out can also be helpful.
Current options for pharmacological therapy include the acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine, and the glutamate receptorantagonist memantine. Donepezil, galantamine andrivastigmine are recommended by the National Institute for Health and Care Excellence as options for managing patients with mild or moderate Alzheimer’s disease. Memantine is recommended for patients with moderateAlzheimer’s disease who cannot take AChE inhibitors, and for patients with severe Alzheimer’s disease.1
All the current licensed medicines for dementia are available as generics. However, it should be borne in mind that people with dementia often find it difficult to cope with change and take in new information, and changes in presentation such as tablet size, shape and colour may cause confusion, leading to non-adherence.Considerations for the management of behavioural and psychological symptoms of dementia are described in Box 1.
Box 1: Managing behavioural and psychological symptoms of dementia
In the past, antipsychotic medicines were commonly used to manage behavioural and psychological symptoms of dementia(BPSD). However, this approach carried risks: in 2004 theCommittee on Safety of Medicines reported that there was a threefold increase in risk of cerebrovascular events when olanzapine or risperidone were used for people with dementia.2 Similar findings were later identified with other antipsychotics.3
In 2009, a Department of Health-commissioned report into the use of antipsychotics for BPSD revealed that some 25% of dementia patients had been prescribed an antipsychotic, with an estimated impact of 1,800 deaths and 1,620 cerebrovascular events per year.4The author proposed that antipsychotics could be stopped in two-thirds of cases.
Risperidone is currently the only antipsychotic that has a licencefor BPSD; this use is limited to six weeks and there is a “blacktriangle” for this indication. The maximum dose of risperidone forBPSD is 2mg per day.
Before prescribing an antipsychotic for BPSD clinicians should consider:5
- What might be causing the behaviour and explore non-pharmacological options, taking into account the patient’s likes, dislikes and personality
- Ensuring adequate pain relief — it can be difficult to assess pain levels in a person with dementia
- Other physical causes for distress, such as constipationDelirium — look for markers of infection or side effects of new medicines
- Whether the patient is adequately hydrated
- Mobility, risk of venous thromboembolism and level of sedation
If an antipsychotic is prescribed it should be time-limited, with regular reviews. Behaviour changes should be monitored and the antipsychotic continued only if improvements are observed, with periodic stopping of the medicine to see if BPSD recur.
AChE inhibitors work by boosting the action of the neurotransmitter acetylcholine. In cholinergic synapses, acetylcholine is broken down quickly by the enzymeAChE, the predominant cholinesterase in the brain. To compensate for the loss of cholinergic neurones inAlzheimer’s disease, AChE inhibitors block the action ofAChE and prolong the length of time that acetylcholine is present in the synapse.
However, there will come a point at which the loss of cholinergic neurones is so great that there is simply not enough acetylcholine being released for these medicines to have a benefit.
Although AChE inhibitors do not cure dementia, they can improve symptoms or prolong a patient’s current level of functioning. Around one third of people who are prescribed AChE inhibitors show transient improvements before gradually declining again; another third of patients maintain their current level of functioning for a period of time before deteriorating; and the final third continue to decline despite treatment. Of this final third, around half will benefit from switching to an alternative AChE inhibitor.6
AChE inhibitors, like all cholinergics, are believed to have the potential to cause generalised convulsions(although seizure activity may also be associated withAlzheimer’s disease). Other precautions and side effects that are common to all AChE inhibitors can be found in Box 2.
Box 2: Acetylcholinesterase inhibitors
Acetylcholinesterase inhibitors should be used with caution in the following patient groups:
- Patients with sick sinus syndrome or any other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block
- Patients at increased risk of developing ulcers
- Patients with a history of asthma or obstructive pulmonary disease
The side effects of acetylcholinesterase inhibitors include:
- Nausea, anorexia and vomiting
- Diarrhoea, gastrointestinal upset and ulceration
- Alertness and agitation
- Bradycardia, and sinoatrial and atrioventricular block
- Urinary incontinence
- Pain, headache and muscle cramps
Donepezil Donepezil hydrochloride is a specific and reversible inhibitor of AChE. It was first made available in the UK in 1997, and is licensed for the symptomatic treatment of mild to moderately severe Alzheimer’s disease.
Treatment starts at 5mg daily. Donepezil should betaken orally at bedtime (morning administration may be more suitable if sleep disturbances become a problem).The 5mg dose should be continued for at least one monthto allow the earliest clinical responses to treatment to be assessed and to allow steady state concentrations to be achieved (the half-life of donepezil is 70 hours). After a clinical assessment at one month, the dose can be increased to 10mg daily. The maximum recommended daily dose in the UK is 10mg. However, a 23mg tablet is available in the US.
Donepezil can be used in renal impairment and in mild to moderate hepatic impairment.
Galantamine Galantamine is an alkaloid that occurs naturally in snowdrop and daffodil bulbs. It is a competitive reversible inhibitor of AChE. Galantamine is also an allosteric modulator of nicotinic receptors, meaning it can increase the receptivity of nicotinic receptors to acetylcholine.7
The half-life of galantamine is eight to 10 hours and peak plasma concentration of the prolonged-release capsule occurs around four and a half hours after taking the dose.Treatment starts at 8mg daily, increasing every four weeks as needed to a maximum licensed dose of 24mg daily.
For patients with severe hepatic impairment, the use of galantamine is contraindicated. For those with moderately impaired hepatic function, it is recommended that dosing should begin with one 8mg prolonged-release capsule every other day, preferably taken in the morning, for one week, followed by 8mg once daily for four weeks; the maximum daily dose should not exceed 16mg. No dose adjustment is required for patients with mild hepatic impairment.
For patients with severe renal impairment (creatinine clearance [CrCl] below 9ml/min), the use of galantamine is contraindicated. For those with a CrCl above 9ml/minno dosage adjustment is required.
Rivastigmine Rivastigmine is an AChE and butyrylcholinesterase inhibitor of the carbamate type. It interacts with target enzymes by forming a covalently bound complex that temporarily inactivates them.8
Rivastigmine is licensed for Alzheimer’s disease and is the only AChE inhibitor to be licensed for dementia inParkinson’s disease. It can be administered orally or via a transdermal patch. The oral dose is usually started at1.5mg twice a day and is best taken after food. This can be increased at two-week intervals to a maximum dose of 6mg twice a day.
Transdermal patches are started at a dose of 4.6mg daily, increasing to a maximum dose of 13.3mg daily, if needed. Rivastigmine patches can cause contact rashes; therefore, the site of administration should be changed every day, avoiding previous application sites for at least 14 days. If the rash is severe and troublesome, an alternative medicine should be used.
Plasma levels of rivastigmine peak approximately one hour after oral ingestion, and effects can last around nine hours. The metabolites of rivastigmine are predominantly eliminated by the kidneys; therefore patients who have clinically significant renal or hepatic impairment are at an increased risk of having adverse reactions to rivastigmine and doses should be titrated according to individual tolerability. No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment.
Glutamate receptor antagonists
Memantine Memantine is a moderate-affinity uncompetitive antagonist of N-methyl-D-aspartate(NMDA) receptors. It modulates the effects of glutamate, which at elevated levels can lead to neuronal dysfunction. An increase in glutamate levels can cause an overstimulation of NMDA-receptors, allowing calcium to flow into the cell. Increased calcium levels lead to cell death.
Memantine is licensed for moderate to severeAlzheimer’s disease and can be used alongside treatment with an AChE inhibitor.
Peak plasma concentration is reached four to eight hours after ingestion, and the terminal half-life is 60–100hours. Treatment starts at 5mg daily, increasing by 5mg each week until the maximum licensed daily dose of 20mg is reached.
The side effects of memantine include constipation, hypertension, dizziness, headache and tiredness. Less common side effects include vomiting, hallucinations, confusion and, very rarely, seizures.
For patients with severe renal impairment (CrCl5–29ml/min) the maximum daily dose of memantine should not exceed 10mg. For those with moderate renal impairment (CrCl 30–49ml/min) doses of 10mg daily are also advised, but if memantine is well tolerated after at least seven days of treatment the dose can be titrated to20mg. For patients with mildly impaired renal function (CrCl 50–80ml/min) no dose adjustment is required. Memantine is not recommended for patients with severe hepatic impairment. No dose adjustment is needed for patients with mild or moderate hepatic impairment.
Ongoing dementia research
Research into the development of new treatments for dementia focuses strongly on preventing the formation of beta-amyloid (Ab) neuritic plaques and neurofibrillary tangles — the pathophysiological hallmarks of Alzheimer’s disease.
Immunising the body against Ab could prevent the formation of neuritic plaques and clear the protein from the brain. One Alzheimer’s vaccine that reached clinical trials mobilised the immune system to attack Ab.However, this study was stopped early when some participants developed acute brain inflammation.9
Other investigations involve administering antibodies against Ab. The monoclonal antibody bapineuzumab has been tested in this way.10Studies of both intravenous and subcutaneous use of the drug were discontinued for safety and efficacy reasons.
Another angle for research is the use of intravenous infusions of normal human immunoglobulin, a product derived from donated blood.11 A study of intravenous immunoglobulin in people with mild to moderateAlzheimer’s disease did not meet its primary endpoints of preventing cognitive decline.12 An alternative strategy is to reduce the amount of Ab formed in the brain by targeting the Ab precursor protein(APP). MK-8931, a novel investigational oral APP site-cleaving enzyme (BACE) inhibitor, has shown promise in a phase II/III study in patients with mild to moderateAlzheimer’s disease. Patients are still being recruited to the trial following an interim analysis of safety data from200 patients treated with the drug for at least three months.13 A new phase III study is also being launched to evaluate MK-8931 in patients with amnestic mild cognitive impairment due to Alzheimer’s disease.13
A further area of research is investigating ways that tau protein might be prevented from forming neurofibrillary tangles. Early research in this area examined the use of methylene blue, which affects tau aggregation and also seems to have an effect on mitochondrial biochemical pathways. An enhanced formulation of methylene blue, TRx0237 (also called LMTX), is now undergoing phaseIII investigation.14,15
Alzheimer’s disease causes chronic, low-level brain cell inflammation. Non-steroidal anti-inflammatory drugs have not been shown to prevent or delay Alzheimer’s disease.16Researchers are also looking at the effect of insulin on brain cell function and seeking to identify insulin changes in the brain that might be related to Alzheimer’s disease.17 Findings from a four-month pilot study of intranasal insulin support the carrying out of longer studies inpatients with amnestic mild cognitive impairment orAlzheimer’s disease.18
Despite the range of research being pursued to search for new dementia medicines, useful therapies are likely tobe many years away. There are substantial gaps in knowledge around the roles of inflammation, tauphosphorylation and plaque formation, and whether thesechanges in fact lead to Alzheimer’s disease or aremanifestations of events that have already created thecondition.
- 1National Institute for Health and Care Excellence. Alzheimer’s disease —donepezil, galantamine, rivastigmine and memantine. March 2011.www.nice.org.uk/guidance/ta217 (accessed 1 November 2013).
- Medicines and Healthcare products Regulatory Agency Committee on theSafety of Medicines. Atypical antipsychotics and stroke. March 2004. www.mhra.gov.uk/safetyinformation (accessed 17 February 2014).
- Huybrechts KF, Gerhard T, Crystal S, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs:population based cohort study. BMJ 2012;344:e977.
- Banerjee S. The use of antipsychotic medication for people with dementia: Time for action. Department of Health: London; 2009.
- Alzheimer’s Society. Reducing the use of antipsychotic drugs: A guide to the treatment and care of behavioural and psychological symptoms of dementia. 2011. www.alzheimers.org.uk (accessed 17 February 2014).
- Bullock R, Connolly C. Switching cholinesterase inhibitor therapy inAlzheimer’s disease — donepezil to rivastigmine. Is it worth it?International Journal of Geriatric Psychiatry 2002;17:288–9.
- Shire Pharmaceuticals Ltd. Reminyl XL: Summary of product characteristics. August 2013. www.emc.medicines.org.uk (accessed 1November 2013).
- Novartis Pharmaceuticals UK Ltd. Exelon: Summary of productcharacteristics. April 2013. www.emc.medicines.org.uk (accessed 1November 2013).
- Alzheimer’s Association. The “Alzheimer vaccine”. Fact sheet AN-1792.www.alz.org/dsw/documents/an-1792.pdf (accessed 25 January 2014).
- Clinicaltrials.gov. Bapineuzumab in patients with mild to moderateAlzheimer’s disease (ApoE4 carrier). www.clinicaltrials.gov/ct2/show/record/NCT00575055 (accessed 15 October 2013).
- Baxter. Baxter to initiate second phase III trial studying Gammagard liquid (IGIV) for the treatment of Alzheimer’s disease. January 2012. www.baxter.com/press_room/press_releases/2012/01_23_12_gammagard.html (accessed 2 November 2013).
- Baxter. Baxter announces top line results of phase III study of immunoglobulin for Alzheimer’s disease. May 2013. www.baxter.com/press_room/press_releases/2013/05_07_13_gap_study.html (accessed 2November 2013).
- Merck. Merck advances development program for investigationalAlzheimer’s disease therapy, MK-8931. December 2013.www.mercknewsroom.com/news-release/prescription-medicine-news/merck-advances-development-program-investigational-alzheimer(accessed 17 February 2014).
- Wischik CM, Bentham P, Wischik DJ, et al. Tau aggregation inhibitor therapy with Rember arrests disease progression in mild and moderateAlzheimer’s disease over 50 weeks. Alzheimer’s & Dementia 2008;4:T167.
- National Institute on Aging. TRx0237 for mild to moderate Alzheimer’s disease. www.nia.nih.gov/alzheimers/clinical-trials/trx0237-mild-alzheimers-disease (accessed 17 February 2014).
- Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003;327:128.
- Craft S, Cholerton B, Baker LD. Insulin and Alzheimer’s disease: untangling the web. Journal of Alzheimer’s Disease 2013;33:S263–75.
- Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy forAlzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Archives of Neurology 2012;69:29–38.