Four drugs are licensed in the UK to treat Alzheimer's disease — donepezil (Aricept^®), rivastigmine (Exelon^®), galantamine (Reminyl^®), and memantine (Ebixa^®). Rivastigmine is also licensed for dementia in Parkinson's Disease.

Donepezil, rivastigmine, and galantamine are acetylcholinesterase inhibitors; they are licensed to treat mild-to-moderate dementia in Alzheimer's disease. They are the only drug treatments recommended by the National Institute for Health and Clinical Excellence (NICE).

They inhibit cholinesterase from breaking down acetylcholine, thus increasing the level and duration of action of acetylcholine in the brain. Decline in cognition is thought to be associated with a decline in cholinergic neurons and decreasing levels of acetylcholine in the brain [Taylor et al, 2009].

Although donepezil, rivastigmine, and galantamine have slightly different pharmacological actions, these differences have not been shown to result in differences in efficacy or tolerability [National Collaborating Centre for Mental Health, 2007].

Donepezil selectively inhibits acetylcholinesterase.

Rivastigmine affects acetylcholinesterase and butyrylcholinesterase.

Galantamine selectively inhibits acetylcholinesterase and also affects nicotinic receptors.

The three drugs are available as oral preparations. Donepezil is also available as an orodispersible preparation, and rivastigmine is also available as a patch.

Memantine is also licensed for the treatment of moderate-to-severe Alzheimer's disease. However, NICE does not recommend it except as part of a clinical study [National Collaborating Centre for Mental Health, 2007].

Memantine is thought to work by acting as a neuroprotective agent, by acting as an antagonist at N-methyl-D-aspartate (NMDA) receptors.

Galantamine is contraindicated in people with severe renal impairment (creatinine clearance less than 9 mL/min or chronic kidney disease stage 5 [estimated glomerular filtration rate < 15 mL/minute/1.73m²]) or severe hepatic impairment (Child–Pugh score greater than 9) [ABPI Medicines Compendium, 2009c].

Acetylcholinesterase inhibitors are aways initiated in secondary care by a specialist. However treatment may be continued and monitored by a general practitioner under a shared care protocol [National Collaborating Centre for Mental Health, 2007].

Donepezil

The usual starting dose is 5 mg once a day. This is usually maintained for at least 1 month [ABPI Medicines Compendium, 2009a; Taylor et al, 2009].

The dose is usually increased to 10 mg each day (usual treatment dose) if the person has tolerated the starting dose [ABPI Medicines Compendium, 2009a; Taylor et al, 2009].

Galantamine

The usual starting dose is 8 mg twice a day (8 mg XL daily). The dose is normally titrated upwards every 4 weeks if the person is able to tolerate the increase in dose. The dose is increased by 8 mg twice a day until a usual treatment dose of 24 mg XL daily.

Rivastigmine (oral)

The usual starting dose is 1.5 mg twice a day for 2 weeks. If this has been well tolerated, the dose is titrated every 2 weeks until a target treatment dose of 6 mg twice a day has been reached [ABPI Medicines Compendium, 2009b; Taylor et al, 2009].

Rivastigmine (patch)

The usual starting dose is to apply one 4.6 mg/24 hours patch daily. If this is well tolerated, the dose is titrated up after 4 weeks to 9.5 mg/24 hours patch daily.

If switching the person from oral to transdermal therapy:

For people taking 3 mg to 6 mg orally each day — prescribe a 4.6 mg/24 hours patch.

If the person is taking 9 mg orally each day and is not tolerating the dose well — prescribed a 4.6 mg/24 hours patch.

If the person is taking 9 mg orally each day and is tolerating this dose well — prescribe a 9.5 mg/24 hours patch.

If the person is taking 12 mg daily — prescribe a 9.5 mg/24 hours patch.

When converting from oral to transdermal therapy, the first patch should be applied on the day following the last oral dose.

Acetylcholinesterase inhibitors are generally well tolerated [Birks, 2006; Burns and Iliffe, 2009b], common adverse effects include diarrhoea, muscle cramps, fatigue, nausea, vomiting, insomnia, and headache. These are caused by cholinergic stimulation. A titration period of about 3 months is needed to develop tolerance and to minimize these adverse effects [Birks, 2006].

Less common adverse effects include symptoms of the common cold, anorexia, psychiatric disorders, syncope and seizures, dizziness, rash, pruritus, fatigue, pain, and urinary incontinence [BNF 58, 2009; Taylor et al, 2009].

Bronchospasm has been associated with acetylcholinesterase inhibitors. If used in people with a history of asthma or obstructive pulmonary disease, they should be advised to report any deterioration in breathing.

Bradycardia has been reported rarely in people taking acetylcholinesterase inhibitors. People with sick sinus syndrome or cardiac conduction conditions, such as sinoatrial or atrioventricular block, should not be given acetylcholinesterase inhibitors.

If acetylcholinesterase inhibitors must be used, review the person regularly to exclude symptomatic bradycardia.

Electrocardiographic (ECG) monitoring is not necessary [Taylor et al, 2009].

Increased risk of gastrointestinal bleeding — monitor people with a history of ulcers and those taking nonsteroidal anti-inflammatory drugs [ABPI Medicines Compendium, 2009a].

Ability to drive

Acetylcholinesterase inhibitors can cause fatigue, dizziness, and muscle cramps, mainly when initiating or increasing the dose. The person's ability to drive should be assessed routinely [ABPI Medicines Compendium, 2009a].

Dementia itself may cause impairment of driving performance or compromise the ability to use machinery.

For more information, see Assessing driving safety.

CKS recommends that people requiring a change in the dose of acetylcholinesterase inhibitor should be referred to specialist mental health services, or that advice should be sought.

Donepezil

Azole antifungals (ketoconazole and itraconazole) and selective serotonin reuptake inhibitors (paroxetine and fluoxetine) increase serum levels of donepezil and may increase adverse effects.

If adverse effects develop or worsen, consider reducing the dose of donepezil or both drugs.

Rifampicin, phenytoin, carbamazepine, phenobarbitone, and dexamethasone decrease the plasma levels of donepezil. Use these drugs only if no alternative is available. If there is no suitable alternative, try to use the lowest possible dose. Regular alcohol intake also reduces plasma levels of donepezil.

Rivastigmine does not undergo hepatic metabolism and appears to be least likely to cause problematic drug interactions [ABPI Medicines Compendium, 2009b; Taylor et al, 2009].

Galantamine

Ketoconazole, erythromycin, ritonavir, quinidine, paroxetine, fluoxetine, fluvoxamine, and amitriptyline all increase the plasma level of galantamine and may increase adverse effects [Taylor et al, 2009].

If adverse effects develop or worsen, consider reducing the dose of galantamine [Baxter, 2008].

Acetylcholinesterase inhibitors are aways initiated in secondary care by a specialist. However treatment may be continued and monitored by a general practitioner under a shared care protocol [National Collaborating Centre for Mental Health, 2007].

Shared care protocols vary from area to area. However, in general, after an acetylcholinesterase inhibitor has been initiated (in secondary care):

The dose is titrated up over 4–12 weeks (depending on which drug is used) to a usual maintenance dose.

For more information, see Dose and titration.

The person is monitored by the specialist for treatment response and tolerability.

The person is stabilized on drug treatment.

Once the person has been stabilized, the general practitioner may be requested to:

Prescribe medication at monthly intervals.

Monitor compliance.

Liaise with the specialist regarding any adverse effects.

Contact the specialist team or consultant if any of the following occur:

Sudden deterioration in cognitive function.

Intolerance or adverse effects to medication.

Non-compliance.

Signs or symptoms of toxicity (for example anxiety, restlessness, insomnia, tiredness, dizziness, headache, nausea, vomiting, abdominal colic, diarrhoea, sweating, and hypersalivation).

Initiation of potentially interacting medication.

Do not prescribe risperidone for people with mild-to-moderate non-cognitive symptoms and:

Dementia with Lewy bodies (DLB) — because there is an increased risk of severe adverse effects (such as development or worsening of extrapyramidal features or acute severe physical deterioration) [NICE, 2006].

Alzheimer's disease, vascular dementia, or mixed dementia — because the increased risk of stroke and death outweighs the benefit of treatment [NICE, 2006].

Give a starting dose of 0.25 mg twice a day. Titrate the dose up, by 0.25 mg twice a day every other day, to a maximum of 1 mg twice a day. The usual maintenance dose is 0.5 mg twice a day.

[ABPI Medicines Compendium, 2008]

Increased risk of stroke and death

All antipsychotics, including risperidone, are associated with an increased risk of stroke and death when used in elderly people with dementia [National Collaborating Centre for Mental Health, 2007].

In clinical trials, concomitant use of risperidone and furosemide was associated with a higher incidence of death (7.3%) compared with risperidone alone (3.1%). No pathological mechanism has been identified to explain these findings.

One large study estimates that treatment with risperidone was responsible for two extra strokes per 1000 person-years of treatment [Herrmann et al, 2004]. This would suggest that risperidone would cause a stroke in two or three of each 10,000 people treated over the first 6 weeks.

Changes in cognition — the use of antipsychotic drugs seems to be associated with accelerated cognitive decline in people with Alzheimer's dementia [National Collaborating Centre for Mental Health, 2007].

Extrapyramidal symptoms (EPS)

Dystonia and parkinsonism — can be alleviated by antimuscarinic drugs, such as procyclidine (these should not be prescribed routinely).

Akathisia — may be relieved by reducing the dose of risperidone. If this is ineffective, consider seeking specialist advice.

Tardive dyskinesia — the emergence of acute EPS is a strong risk factor for later tardive dyskinesia: consider stopping or reducing the dose of risperidone if tardive dyskinesia occurs.

Orthostatic hypotension — may occur particularly during the initial dose titration. The dose should be titrated gradually.

Weight gain — common with all antipsychotics. Calorie restriction or a low glycaemic diet may help to reduce weight gain.

Dyslipidaemia — risperidone increases lipid levels. Offer dietary advice and consider treatment with a statin according to national guidelines. For more information, see the CKS topic on Lipid modification - CVD prevention. If severe hyperlipidaemia develops, seek specialist advice.

Hyperprolactinaemia — risperidone has a potent prolactin-elevating effects. This may lead to galactorrhea, gynaecomastia, hypogonadism, and an increased risk of osteoporosis.

Sedation — tolerance to sedation usually develops.

Anticholinergic effects — such as dry mouth, blurred vision, urinary retention, constipation, and cutaneous flushing.

Postural hypotension — is commonly associated with risperidone.

Hypertension — hypertension can occur as:

A small, steady increase in blood pressure over time (may be associated with weight gain), or

An unpredictable, sharp increase in blood pressure on starting a new drug.

Reduced seizure threshold — seizures are a recognized adverse effect of all antipsychotics (the higher the dose, the greater the risk).

Impaired glucose tolerance — hyperglycaemia, and sometimes diabetes, can occur in people taking risperidone. Appropriate clinical monitoring is advisable for those with diabetes or risk factors for diabetes.

QT interval prolongation — this is the most widely reported cardiac conduction defect caused by antipsychotics and is considered to be a class effect. It increases the risk of torsades de pointes, a potentially fatal arrhythmia.

Avoid co-prescribing drugs that prolong the QT interval.

Hypokalaemia also increases the risk of Torsade de Pointes arrhythmias. Monitor potassium levels closely if the person is taking drugs known to lower potassium levels.

People taking antipsychotics who experience palpitations or any other symptoms that suggest cardiac disease should undergo electrocardiography.

Avoid antipsychotics (or consider dose reduction) if the QT interval is prolonged.

Neuroleptic malignant syndrome — a very rare (less than 1% of people) but life-threatening adverse effect that can occur with any antipsychotic.

Symptoms include hyperthermia, muscle rigidity, autonomic instability, and fluctuating consciousness.

Mortality without treatment is 20%; urgent medical treatment is therefore needed.

[ABPI Medicines Compendium, 2008; BNF 58, 2009; Taylor et al, 2009]

Drugs with a sedative action (such as alcohol, analgesics, tricyclic antidepressants, and sedating antihistamines) will increase the sedative effects of risperidone.

Drugs with a hypotensive effect (for example antihypertensives) will increase the hypotensive effect of risperidone.

Drugs that prolong the QT interval, such as antiarrhythmics, macrolides (for example erythromycin), and tricyclic antidepressants may have a synergistic effect on the QT interval. Avoid co-prescribing drugs that prolong QT intervals.

Diuretics may cause hypokalaemia, which may increase the risk of arrhythmias; monitor potassium levels in people taking diuretics. For more information, see Drugs known to lower potassium levels.

Levodopa — risperidone may antagonize the effect of levodopa. Use the lowest effective dose of each treatment.

Benzodiazepines can be used with antipsychotics but be aware of potential adverse effects like additive sedative effects, hypotension, and respiratory depression.

Carbamazepine

Carbamazepine reduces plasma levels of risperidone by half; monitor the person's symptoms to ensure that the antipsychotic remains effective.

Carbamazepine levels are increased by risperidone; monitor the person for signs of carbamazepine toxicity (dysarthria, ataxia, nystagmus, drowsiness, and violent behaviour with tachycardia, dilated pupils, and hyperreflexia).

Selective serotonin reuptake inhibitors (SSRIs) — risperidone levels are increased by fluvoxamine, fluoxetine, and paroxetine; the person should be monitored for adverse effects of risperidone and the dose of risperidone adjusted accordingly if these occur.

[ABPI Medicines Compendium, 2008; BNF 58, 2009; Taylor et al, 2009]

The National Institute for Health and Clinical Excellence recommends that treatment with risperidone should be time-limited and that the person should be reviewed regularly (every 3 months or according to clinical need).

Baseline measurements for risperidone

Body weight — then monitor at 3 months, and yearly. If weight gain occurs, consider changing the antipsychotic and/or dietary or pharmacological intervention.

Serum electrolytes and urea — then monitor yearly. Any abnormalities should be investigated.

Full blood count — then monitor yearly, due to the risk of blood dyscrasias. Stop the drug if neutrophils decrease to below 1.5 x 10⁹/L. Refer to the specialist if neutrophils decrease to below 0.5 x 10⁹/L.

Plasma glucose — then monitor at 4–6 months, and yearly. If plasma glucose is increased, obtain a fasted sample (or a non-fasted sample and haemoglobin A_1c); treat accordingly.

Blood pressure — and monitor frequently during dose titration. If severe hypertension (blood pressure greater than 180/110 mmHg) is observed, slow the rate of titration.

Electrocardiography — then monitor after dose changes and if there is evidence of other risk factors (such as relevant personal or family history, co-prescription of drugs that prolong QT intervals, or drugs that lower potassium levels). Refer to a cardiologist if abnormalities are detected.

Prolactin — then monitor at 6 months and yearly. Switch drugs if hyperprolactinaemia is confirmed and symptomatic.

Liver function tests — then monitor yearly. Stop the antipsychotic if liver function tests indicate liver damage.

Creatine phosphokinase — measure again only if neuroleptic malignant syndrome (NMS) is suspected.

Symptoms include hyperthermia, muscle rigidity, autonomic instability, and fluctuating consciousness.

Mortality without treatment is 20%; urgent medical treatment is therefore needed.

If the person has dementia with Lewy bodies (DLB), monitor for severe untoward reactions, particularly neuroleptic sensitivity reactions (development or worsening of extrapyramidal features or acute, severe physical deterioration).

[National Collaborating Centre for Mental Health, 2007; Taylor et al, 2009]

Severe hepatic impairment — lorazepam is contraindicated in severe hepatic impairment.

Lorazepam is also contraindicated in respiratory depression, marked neuromuscular respiratory weakness (including unstable myasthenia gravis), and sleep apnoea syndrome.

[BNF 58, 2009]

The recommended dose is 0.5 mg to 4 mg daily, in divided doses [Burns and Iliffe, 2009a].

Drowsiness and lightheadedness (usually occurs the next day), confusion, ataxia, and muscle weakness.

Occasionally, people may also experience headaches, vertigo, hypotension, salivation changes, gastrointestinal disturbances, tremor, incontinence, urinary retention, and jaundice.

[Genus Pharmaceuticals, 2004; BNF 58, 2009]

Alcohol should be avoided when taking lorazepam. Alcohol can increase the sedative effects of lorazepam.

Drugs that have a central nervous system (CNS) suppressant effect — additive CNS depressant effects occur when lorazepam is given with other medications that produce CNS depressant effects (such as barbiturates, antipsychotics, sedatives, antidepressants, sedative antihistamines, and anticonvulsants). Concomitant use is not recommended.

Do not use haloperidol to treat mild-to-moderate psychotic symptoms in elderly people.

Haloperidol is contraindicated in comatose states, central nervous system depression, and in people with clinically significant cardiac disorders, such as:

Recent acute myocardial infarction.

Uncompensated heart failure or second- or third-degree heart block.

Arrhythmias treated with class IA antiarrhythmic drugs (for example disopyramide, procainamide, quinidine) or class III antiarrhythmic drugs (for example amiodarone, sotalol), or a history of ventricular arrhythmia or torsades de pointes.

QT interval prolongation.

Clinically significant bradycardia.

Uncorrected hypokalaemia.

[MHRA, 2008]

Haloperidol should be used at the minimum dose that is clinically effective [MHRA, 2008].

For agitation and restlessness in elderly people with dementia, prescribe 0.5 mg to 4 mg daily [Burns and Iliffe, 2009a].

Extrapyramidal symptoms (Parkinsonism) are common, and are more likely and more severe in dementia with Lewy bodies and frontotemporal dementia. Acute dystonias may occur early in treatment. Tardive dyskinesia may develop during therapy or after the drug has been discontinued.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea and gynaecomastia.

Cardiac adverse effects — dose-related hypotension is uncommon, but can occur, particularly in elderly people who are more susceptible to the sedative and hypotensive effects.

Gastrointestinal effects — nausea, loss of appetite, weight changes, and dyspepsia have been reported with haloperidol.

Other adverse effects — haloperidol may impair alertness, particularly with higher doses at the start of treatment, and may be potentiated by alcohol.

[MHRA, 2008; BNF 58, 2009]

Central nervous system (CNS) effects

Haloperidol can increase the CNS depression produced by other CNS depressant drugs (including alcohol, hypnotics, sedatives, and strong analgesics).

Tricyclic antidepressants

The metabolism of tricyclic antidepressants may be impaired by haloperidol.

Diuretics

Diuretics may cause hypokalaemia, which may increase the risk of arrhythmias; monitor potassium levels in people taking diuretics. For more information, see Drugs known to lower potassium levels.

Drugs that prolong the QT interval

Drugs that prolong the QT interval (such as antiarrhythmics, macrolides [for example erythromycin], and tricyclic antidepressants) may have a synergistic effect on the QT interval. Avoid co-prescribing drugs that prolong QT intervals.

Memantine is contraindicated in people with severe hepatic impairment and in those with severe renal failure (eGFR less than 5 mL/minute/1.73m²).

Caution is recommended in people with a history of convulsions.

[ABPI Medicines Compendium, 2011; BNF 62, 2011]

The usual starting dose is 5 mg daily. The dose is usually titrated upwards weekly in steps of 5 mg until the maintenance dose is reached. The maximum dose is 20 mg daily.

The dose of memantine should be reduced in people with renal impairment:

If eGFR is 30–49 mL/minute/1.73 m², the dose should be reduced to 10 mg daily; if well tolerated after at least 7 days the dose can be slowly increased to 20 mg daily.

If eGFR is 5–29 mL/minute/1.73 m², the dose should be reduced to 10 mg daily.

[ABPI Medicines Compendium, 2011; BNF 62, 2011]

Memantine is generally well tolerated.

Common adverse effects include: dizziness, headache, constipation, dyspnoea, drowsiness, and constipation.

Less common adverse effects include: fungal infections, confusion, hallucinations, abnormal gait, cardiac failure, vomiting, fatigue, and venous thrombosis and thromboembolism.

Seizures, pancreatitis, depression, psychosis, and suicidal ideation have been rarely reported .

Ability to drive — memantine may have a minor or moderate influence on driving ability.

[ABPI Medicines Compendium, 2011; BNF 62, 2011]

There is an increased risk of central nervous system (CNS) toxicity when memantine is given with:

Ketamine

Dextromethorphan.

Dopaminergic drugs, selegiline, and amandatine.

Memantine possibly enhances the effect of warfarin and anticholinergics and possibly reduces the effect of antipsychotics, barbiturates, and hydrochlorothiazide.

Memantine may modify the effects of baclofen and dantrolene.

[ABPI Medicines Compendium, 2011; BNF 62, 2011]