Dementia management

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.

Acetylcholinesterase inhibitors

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.

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.

References

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4. Banerjee S. The use of antipsychotic medication for people with dementia: Time for action. Department of Health: London; 2009.
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