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Comparisons of Alzheimer’s treatment options

Depression, Men's Health, Age related illnesses, Mental Health, Women's Health | May 17, 2016 | Author: The Super Pharmacist

age related, mental health, depression

Comparisons of Alzheimer’s treatment options

The U.S. Food and Drug Administration (FDA) has approved five medications (listed below) to treat the cognitive symptoms (memory loss, confusion, and problems with thinking and reasoning) of Alzheimer's disease. To date, only symptomatic therapies for Alzheimer disease are available. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer disease (AD) modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate (NMDA) antagonist.Donepezil, galantamine, and rivastigmine all belong to the class of medications called acetylcholinesterase inhibitors. Memantine is an NMDA (N-methyl-D-aspartate) receptor antagonist. The medicines which are subsidised through the Pharmaceutical Benefits Scheme (PBS) for treating dementia in Alzheimer’s disease include the cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the N-methyl-D-aspartate receptor antagonist, memantine.

How Do These Drugs Work?

Cholinesterase Inhibitors

Acetylcholine helps to send messages between certain nerve cells. In Alzheimer’s there is also a loss of the nerve cells that use acetylcholine. Falling acetylcholine levels and progressive loss of these nerve cells are linked to worsening symptoms. There have been clear demonstrations that cholinergic neurons are diminished in critical areas of the brain of AD patients. While acetylcholine deficiency plays a role in AD, there is increased recognition that this occurs within a complex milieu of neurotransmitter changes in the brains of AD patients.The cholinesterase inhibitors all prevent an enzyme called acetylcholinesterase from breaking down acetylcholine in the brain. As a result, an increased concentration of acetylcholine leads to increased communication between nerve cells. This may temporarily alleviate or stabilise some symptoms of Alzheimer disease.

NMDA receptor antagonist

The action of memantine is different from that of donepezil, rivastigmine and galantamine. Glutamate is another chemical that helps to send messages between nerve cells. Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer disease. This causes the brain cells to be damaged further. Memantine protects brain cells by blocking the effects of excess glutamate. The current Pharmaceutical Benefits Scheme (PBS) restriction allows subsidised cholinesterase inhibitors and memantine for patients who have a specialist diagnosis of Alzheimer’s disease and a score of >10 in the Mini-Mental State Examination (MMSE), a commonly used test of mental function. Continuing treatment beyond six months is restricted to patients who show an improvement of 2 or more points in the MMSE (or equivalent cognitive improvement in the AD Assessment Scale–Cognitive sub-scale [ADAS-Cog]).

How Well Do These Drugs Work?

Cholinesterase inhibitors

Outcome measures that show benefit with cholinesterase inhibitor therapy include cognition (as measured by the Alzheimer Disease Assessment Scale cognitive subscale and the Mini-Mental Status Examination), clinician's interview-based impression of change, activities of daily living (ADL), disability, quality of life and nursing home placement. The magnitude of response appears to be a stabilisation or slowing of disease progression that is equivalent to 6 months of cognitive decline with this disease.While most of these are short-term studies, there are several studies demonstrating durability of response for 1 to 2 years.11,12,15,16 Emerging evidence suggests that long-term treatment with cholinesterase inhibitors not only improves cognitive and behavioural domains, but may influence neuronal function and survival. There are no randomised double-blind trials comparing cholinesterase inhibitors to one another. Two open label studies have been recently published. The first showed no difference in efficacy between donepezil and rivastigmine, while the second suggested that patients on donepezil performed better on cognitive testing and ADL functioning than patients on galantamine. While these open label results are suggestive, double-blind studies are necessary before concluding that one cholinesterase inhibitor is superior to another.

NMDA receptor antagonist

There is increasing evidence that disturbances in glutamatergic neurotransmission contribute to the pathogenesis and cognitive deficits in AD. Glutamine is an excitatory neurotransmitter that activates the N -methyl-d-aspartate receptor. Glutamatergic transmission is thought to be important in learning and memory, but glutamatergic overstimulation appears to be toxic to neurons.28 Based on this theory, the N -methyl-d-aspartate receptor antagonist, memantine, has been tested in the treatment of AD. There have been three randomised placebo-controlled trials demonstrating that memantine is moderately effective in slowing the progression of AD. In the first study, 166 demented nursing home patients (49% AD; 51% vascular dementia) were randomised to 10 mg of memantine or placebo. At 12 weeks the treated patients had improved clinician's global impression scores independent of the etiology of dementia.29 In another study, 252 patients with moderate to severe AD were randomized to memantine or placebo. At 28 weeks, patients treated with memantine had better ADL function and disability scores. Clinician's impression scores were also improved in the treatment group, but this difference did not reach statistical significance.30 In the most recent study, 403 patients with moderate to severe AD who were already taking donepezil (stable dose of 5 or 10 mg) were randomised to an additional therapy with memantine or placebo in a blinded fashion. After 24 weeks of follow-up, the memantine-treated group had better cognitive, functional, and behavioural scores compared with the monotherapy group. Whether memantine is effective with other cholinesterase inhibitors is unproven, but there is no reason to expect different results with other cholinesterase inhibitors. Clinical trials are under way to address this issue. Memantine is well tolerated with a side effect profile similar to placebo. The beneficial effects seen with memantine reflect a slower decline in treated patients rather than improvement, which is sometimes seen in patients treated with cholinesterase inhibitors. Thus, cholinesterase inhibitors remain the treatment of choice for patients with AD, although treatment with memantine may be a useful adjunct in later stage disease. There is limited data regarding memantine use in early AD, and it is not recommended for these patients. Since the beneficial effects of cholinesterase inhibitors are only modest, there has been interest in whether combinations of therapies may have additive or even synergistic effects in the treatment of AD. As seen above, the addition of memantine to donepezil in later stage disease has benefit.30 Unfortunately, adding vitamin E or hormone replacement therapy to cholinesterase therapy has not resulted in further benefit over monotherapy.

What Are the Side Effects of these Drugs?

Donepezil, rivastigmine, and galantamine share common cholinergic-mediated side effects. The most common cholinergic side effects include nausea, vomiting, diarrhea, anorexia, and abdominal pain. Slow titration of these drugs to therapeutic doses may alleviate many of these symptoms since patients tend to develop tolerance to these gastrointestinal symptoms.Two small open label studies have suggested that of the three commonly used cholinesterases, donepezil is associated with fewer side effects leading to discontinuation of the drug, but these studies require confirmation with prospective randomized double-blinded studies. Because the cholinesterase inhibitors increase acetylcholine and may increase parasympathetic tone, these drugs should be used cautiously in patients with bronchospasm, active peptic ulcer disease, bradycardia or cardiac conduction disturbances. In addition, care should be exercised if patients taking cholinesterase inhibitors undergo general anaesthesia since these drugs may prolong the effects of neuromuscular blocking agents.

What Are the Specific Indications for these Drugs?

Treatment of Mild to Moderate Disease: Early diagnosis and treatment allows AD patients to maintain the highest levels of cognitive and functional ability possible. Cholinesterase inhibitors and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD. All cholinesterase inhibitors have shown modest benefit on measures of cognitive function and activities of daily living. Patients on cholinesterase inhibitors have shown slower declines on cognitive and functional measures than patients on placebo. However, cholinesterase inhibitors do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The cholinesterase inhibitors may also alleviate the non-cognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior. Although the usefulness of cholinesterase inhibitors was originally expected to be limited to the early and intermediate stages of AD (because the cholinergic deficit becomes more severe later in disease and because fewer intact cholinergic synapses are present), they are also helpful in advanced disease. are also helpful in patients with AD with concomitant infarcts and in patients with dementia with Lewy bodies. Frequently, AD and dementia with Lewy bodies occur in the same patient; this is sometimes called the Lewy body variant of AD. In summary, donepezil, rivastigmine and galantamine are moderately effective in the treatment of mild to moderate AD, but there is little evidence to recommend one drug over another. A realistic discussion of the benefits of therapy, focusing on disease stabilization, as well as side effects, is warranted in all patients diagnosed with mild to moderate AD. Cholinesterase inhibitor therapy should be started early and there is emerging data that efficacy extends to the late stages of the disease. When and if cholinesterase therapy should be discontinued remains controversial.

 

Treatment of Moderate to Severe Disease: The partial N -methyl-D-aspartate (NMDA) antagonist memantine is believed to work by improving the signal-to-noise ratio of glutamatergic transmission at the NMDA receptor. Blockade of NMDA receptors by memantine is thought to slow the intracellular calcium accumulation and thereby help prevent further nerve damage. This agent is approved by the FDA for treating moderate and severe AD. The beneficial effects seen with memantine reflect a slower decline in treated patients rather than improvement, which is sometimes seen in patients treated with cholinesterase inhibitors. Thus, cholinesterase inhibitors remain the treatment of choice for patients with AD, although treatment with memantine may be a useful adjunct in later stage disease. There is limited data regarding memantine use in early AD, and it is not recommended for these patients. Several studies have demonstrated that memantine can be safely used in combination with cholinesterase inhibitors. The combination of memantine with a cholinesterase inhibitor has been shown to significantly delay institutionalisation in AD patients. Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD40 but not in mild to moderate AD. Dizziness, headache, and confusion are some of the most common side effects of memantine. In June 2013, the FDA approved rivastigmine transdermal for severe AD. Approval was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer's Type) study, in which a higher dose of the drug (13.3 mg/24 hr) demonstrated statistically significant improvement in overall cognition and function compared with a lower dose (4.6 mg/24 hr).

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