Alzheimer’s is an incurable, but treatable disease. The use of medications is increasing, but clinicians and healthcare organizations must realize that supportive care must extend beyond prescriptions. Support includes providing caregivers with practical advice on a variety of issues such as where to obtain financial planning and how to access respite care. Caregiver education and emotional support are essential elements of the treatment package. Medications can be combined with behavioral and environmental interventions. Some agents enhance cognition and may afford neuroprotection as well as dementia. Treatment goals help caregivers and patients set realistic expectations. Treatments that enhance cognition and improve behavior lead to symptomatic improvement. After initial improvement most patients eventually continue to decline, though the rate varies depending on the patient. One can expect the progression of the disease to be slowed, but should not anticipate arrest. Stabilization or a temporary delay in progression is the most notable outcome of treatment.

Cognition Enhancers

The brain of a patient suffering from Alzheimer’s disease exhibits damaged neurons and reduced levels of the neurotransmitter acetylcholine (Ach) as well as the enzyme that synthesizes Ach. This is an essential finding in the cholinergic hypothesis which states that cognitive function may be preserved if levels of Ach are maintained, though increasing the level of Ach is not yet possible. The main cognitive enhancement therapies today are cholinesterase inhibitors donepezil and rivastigmine. Those medications and cholinesterase inhibitors, such as galantamine, are the most thoroughly studied medications used to treat the disease. Tacrine is an older less selective agent in that class but is now rarely used. Stabilization from treatment with cholinesterase inhibitors may persist for up to a year.

Donepezil was first marketed in January 1997 and is the preeminent drug in its class. During a half-year trial, more than 4 of 5 patients receiving treatment showed improvement or no decline in cognitive function. Treatment with Donepezil produced improvements in secondary outcomes such as on the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Scale Sum of the Boxes. In clinical practice, improvement is usually noticed even sooner, in about 6 weeks after the start of the treatment. Side effects from the treatment were usually transient and generally mild, and cholinergic adverse events (mostly diarrhea, nausea, and vomiting) were more frequent in the group that received the higher dose. Rivastigmine is the second selective cholinesterase inhibitor. It’s duration lasts about 10 hours and is administered twice daily, unlike donepezil, which is only administered once. The side effects from this treatment are similar to donepezil, although a conservative dose titration schedule is recommended to avoid significant gastrointestinal intolerance.

Galantamine is an Ach esterase inhibitor that has been approved for use and has also proven to improve cognitive function. Early initiation of treatment is beneficial and it has been shown to modulate nicotinic cholinergic activity. How this relates to the efficacy of the drug is unknown. The use of cholinesterase inhibitors can provide a significant improvement in cognitive and functional performance of Alzheimer’s disease patients. The drugs are well tolerated, and though the target is a secondary degenerative effect of the disease, they are one of the few pharmacologic tools for delaying the cognitive decline of patients with Alzheimer’s disease.

Antioxidants

Other therapeutic strategies have been another approach to treatment of Alzheimer’s disease through reduction of oxidative stress within the brain. Agents in various antioxidant neuroprotective strategies for the treatment of Alzheimer’ s disease have included aipha-tocopherol (vitamin E); selegiline, a selective monoamine oxidase inhibitor; ascorbic acid; coenzyme Q; ginkgo biloba; and estrogen.

Vitamin E and selegiline are currently used by many clinicians and is based partly on the results from a large clinical trial involving the two of them. The administration of selegiline or vitamin E delayed progression in all endpoints. The most interesting finding of the study was that vitamin E delayed the progression of nursing home placement by approximately 7 months. Because vitamin E is safer and usually less expensive than selegiline, that finding has prompted the widespread clinical use of vitamin E in patients with Alzheimer’s disease. The dose of vitamin E that was used in the study was particularly high (1000 II] twice a day). Patients that have bleeding problems or are taking heparin must use vitamin E with caution. Vitamin K deficiency is the main contradiction to vitamin E therapy.

Estrogen

In addition to its potential antioxidant properties is thought to possess other properties that possibly could inhibit the progression of Alzheimer’s disease. For example, it’s potentiating reductions in the apolipoprotein E plasma level, inflammation, and beta­amyloid accumulation. It did not slow disease progression and it did not improve cognitive or functional outcomes.

lB Profin I

This treatment is based on the wide spectrum of activated inflammatory components (eg, compliment cytokines, acute phase proteins).

Prednisone has been of particular interest as a potential agent, but the recent published results involving its use as a treatment of Alzheimers disease were also negative. Cholinesterase inhibitors will continue to offer patients with early stages the best hope for slowing the progression.

Table 1

Medications for Target Symptoms

Antipsychotics (eg, risperidone, olanzapine, cholinergics)

- Delusions

- Hallucinations

- Aggression

Antidepressants (eg, citalopram, sertraline)

- Depression

- Dysphoric agitation

- Lability of affect

- Anxiety

- Apathy

Anticonvulsants (eg, divaiproex sodium)

- Mania

- Impulsivity

- Irritability

- Lability of affect

- Agitation

Managing the behavioral problems associated with Alzheimer’s Disease

This is an important issue. Behavioral disabilities are also closely linked to the functional impairments of Alzheimer’s disease, such as agitation or combativeness. This can be ameliorated to a degree with medications.

Essential steps in managing psychiatric behavior disturbance:

1. Help caregiver recognize and characterize the psychiatric symptoms of Alzheimer’ s disease
2. Caregivers must recognize what triggers these symptoms
3. What can be done to relieve them
4. Simple clear terminology when describing symptoms to clinicians
5. After a behavior has been recognized a treatment plan is designed
6. It is a treatment plan that must include
   • medication
   • behavioral techniques
   • environmental changes

Classes of medication have been used in the management of specific symptom clusters in patients have been reviewed and are summarized above (Table 1)

Risperidone

Despite a lack of formal sanction, compelling evidence now supports the use of risperidone or olanzapine in patients with Alzheimer’s disease who exhibit significant delusions, hallucinations, or aggressive behavior. In a multicenter study involving 625 patients, most had been diagnosed but in some, the diagnosis was vascular dementia or mixed dementia. All patients studied exhibited significant behavioral symptoms or psychosis.

Those who received 1 or 2 mg/day showed improvement that was superior to the placebo- treated group.

Olanzapine

A key study evaluating the efficacy of olanzapine for the treatment of psychosis and agitation in patients with Alzheimer’s disease recently indicated results similar to those of the study on risperidone. Patients receiving fixed doses of 5 or 10 mg/day responded better than those receiving placebo. The main side effects of treatment were somnolence and change in gait.

Antidepressants

These psychotropic are of some value in treating patients with Alzheimer’s Disease who have depression, dysphoric agitation, and lability of affect, anxiety, and maybe apathy. The use of the selective seritonin reuptake inhibitor citalopram (S SRI) in patients with dementia had reported significant efficacy. SSRI sertraline have positive results after administration to patients with Alzheimer’s disease who had dysphoric affect and agitation.

Anticonvulsants

This group of psychotropics can be effective in the control of impulsivity, irritability, lability of affect and agitation. Divalproex sodium was given to nursing home residents with behavioral disturbances, including manic behavior were given the anticonvulsant at 20 mg/kg/day for 10 days.

CONCLUSION

There is little doubt that the disease is eminently treatable. The care of the patient can do much to relieve the burden of the disease by providing a strong, consistent, multifaceted level of support for the caregiver. Pharmacotherapy can augment thoughtful and structured care interventions. In particular, treatment with cholinesterase inhibitors and vitamin E may be effective in slowing the progression of Alzheimer’ s disease.

Frequently asked Questions

How do you respond to patients and families who don’t feel they see a change since the initiation of treatment?

Even if the patient does not improve after 9-12 months that is significant. Since the disease is progressive, that delay in progression is considered a meaningful and positive outcome.

How long should the medication treatment trial last? How do you decide to continue medication?

If the medication is well tolerated and the disease has stabilized after 6 months, the patient should continue the therapy. If there was not evidence of benefit, then the therapy should be discontinued. If the patient’s disease became worse after the treatment was terminated, then the therapy should be reinitiated.

Some managed care organizations use a Mini Mental Status Examination (MMSE) for approval of the pharmacy benefit. Sometimes a medical director requires evidence that the patient had an exam score between 5 and 20 to obtain approval for drug benefits for that patient. Is this reasonable?

Although the Mini Mental Status Exam is an inappropriate standard for approval because scores vary by education, eligibility should be determined by a clinical diagnosis of probable Alzheimer’s disease. The whole current approach to treatment for Alzheimer’s disease is actually counterintuitive in the context of therapy for most chronic diseases. Imagine a patient with arthritis who, 3 or 5 years after treatment initiation, experiences disease progression and worsening of symptoms. Do you withdraw the nonsteroidal anti­flammatory drug and deny treatment because the disease has progressed? Similarly the cholinesterase inhibitors don’t affect the progression of Alzheimer’s disease as far as we know, but they may improve cognition at all stages of the disease. A drug holiday after a certain period of time has elapsed is an imperfect idea. Patients sometimes return to their pre-holiday status when treatment is resumed. The FDA indicates the use of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer’ s disease, although physicians in practice can use medicines for any indication. Donepezil clearly benefits patients with other forms of dementia not just those with Alzheimer’ s.

Is there FDA approval on the use of antidementia drugs in the managed care environment? What about those not approved by the FDA for the treatment of dementia such as ginkgo biloba and other agents that demonstrate some efficacy but not enough for FDA approval?

The American Psychiatric Association treatment committee recommended the use of vitamin E and then went against the use of selegiline, primarily because of safety issues.

Can antipsychotic drugs delay the progression of Alzheimer Disease?

Patients may actually deteriorate cognitively and functionally with the use of some conventional neuroleptics. With olanzapine, a suggestion of cognitive improvement in some patients who were using the drug to treat behavioral changes associated with Alzheimer’s disease display significant cognitive and functional improvements are observed in depressed patients with Alzheimer’s who receive treatment with anti depressants.

Is there a real difference between the effect of olanzapine and that of resperidone in terms of extrapyramidal and other symptoms?

Yes, research shows when greater than resperidone 2 mg/day is given. The patient detiorates because of the occurrence of frequent side effects like: extrapyramidal symptoms, somnolence and mild peripheral edema.

References available on request