WASHINGTON, DC— Historically, the behavioral disturbances associated with Alzheimer's disease (AD) have been relatively neglected by researchers, at least in comparison with the cognitive dysfunction that defines the disease. However, these disturbances have been the focus of increasing attention. The recent completion of two major multicenter trials examining the effects of psychotropic medication on AD-related behavioral problems has ushered in a new era in the treatment of the disease; indeed, in March, a Food and Drug Administration (FDA) advisory committee recommended that the agency designate psychosis as a formal target for pharmacologic intervention in patients with AD.

At a symposium at the World Alzheimer Congress 2000, Jeffrey L. Cummings, MD, Professor of Neurology and Director of the UCLA School of Medicine Alzheimer's Disease Center in Los Angeles. reviewed the treatment of behavioral disturbances in this population, noting that these problems are extremely common. "This is a major treatment challenge in the disease," he stated, adding that behavioral problems are not only distressing to AD patients and their caregivers but are a major reason patients are institutionalized. Fortunately, most behavioral problems appear to respond well to standard psychotropic medications and other pharmacologic treatments, although large controlled trials are generally lacking.

DELUSIONS

One frequent problem associated with AD is delusions, which have a point prevalence of 25% to 50% and a lifetime prevalence as high as 70%. The content of the delusions does not differ from that in other illnesses; typical themes include infidelity, theft, and phantom boarders. Delusions are usually associated with hallucinations, agitation, and other destructive behaviors.

Conventional antipsychotics can be used but present the risk of significant adverse effects, such as parkinsonism and tardive dyskinesia. Atypical antipsychotics cause fewer extrapyramidal symptoms but are associated with sedation. Risperidone, olanzapine, and quetiapine are the most commonly used atypicals in this setting; clozapine is less often prescribed because of its blood monitoring requirement.

Notable treatment studies for AD-related delusions include the first two multicenter, double-blind, placebo-controlled trials of psychotropic medication for behavioral disturbances in AD patients. The first trial found that 1- or 2-mg doses of risperidone were superior to placebo for reducing the frequency of delusions, although a 0.5-mg dose was not.

In the second study, researchers examined the effects of olanzapine on patients' Neuropsychiatric Inventory combined score for delusions, hallucinations, and agitation. They found that doses of 5 or 10 mg were effective in reducing these symptoms, but a 15-mg dose proved no better than placebo.

AGITATION

The most common behavioral disturbance associated with AD is agitation, which affects nearly three fourths of patients and typically increases in severity as the disease progresses. Agitation often co-occurs with anxiety, delusions, and irritability. However, Dr. Cummings pointed out, clinicians should be sure to exclude potential causes unrelated to AD, such as pain, medical illness, or environmental provocation.

Numerous agents have been used for treating agitation in AD patients, including antipsychotic medications, anxiolytics, and anticonvulsants. However, only anticonvulsants and atypical antipsychotics have been shown in double-blind, placebo-controlled trials to be beneficial.

In one study, flexible dosages (0.5 to 4 mg/d) of risperidone were significantly superior to placebo in reducing patients' scores on the Cohen-Mansfield Agitation Inventory; similar doses of haloperidol were not beneficial. Since haloperidol use also resulted in a 2-point decrease in Mini Mental State Examination scores, "there does appear to be a treatment advantage in both efficacy and side effects in using the atypical antipsychotics," Dr. Cummings said.

In the previously mentioned olanzapine study, 5 or 10 mg of olanzapine also reduced agitation scores on the Neuropsychiatric Inventory by about 4 points, twice the benefit seen with placebo. However, once again the 15-mg dose was not efficacious, indicating that there may be a therapeutic window with this agent.

While the neuroanatomic basis of AD-related agitation is poorly understood, Dr. Cummings reported that he and his colleagues recently identified some "exciting" clues. "We've been looking at postmortem samples of patients with autopsy-confirmed AD and then doing a retrospective Neuropsychiatric Inventory," he said. After controlling for the presence of other behavioral disturbances (eg, depression, irritability, psychosis), "we find that there is a higher tangle burden in the frontal cortex of patients with agitation compared to those without agitation." The remaining cortical lobes were not affected, and the burden of amyloid plaques did not differ between affected and unaffected patients. Nonetheless, Dr. Cummings said, "we think we are getting closer to understanding the neurobiology of some of the behavioral symptoms of Alzheimer's disease."

DEPRESSION

Compared to psychotic symptoms, major depressive disorder is relatively infrequent in AD, affecting 6% to 10% of patients. However, about 40% of patients have depressive symptoms,which can greatly exacerbate functional disability. "So there is reason to treat these patients, not only for the mood changes but also the functional disability associated with it," Dr. Cummings said.

Therapeutic options appropriate for AD patients with major depression or depressive symptoms include the selective serotonin reuptake inhibitors, tricyclics that have few anticholinergic side effects, and combined reuptake inhibitors such as venlafaxine. However, very few double-blind trials have been conducted in this population. In one of the few studies that have been published, citalopram significantly reduced symptoms after six weeks of treatment.

NEW KIDS ON THE BLOCK: CHOLINESTERASE INHIBITORS

Although cholinesterase inhibitors are typically used for their effects on cognition, they can also reduce behavioral symptoms. While some of the evidence supporting their use is indirect, "there are many ways of trying to understand the impact of these drugs," Dr. Cummings noted. For example, an epidemiologic study of community-dwelling AD patients revealed that subjects receiving donepezil were less likely than nonusers to be concurrently taking antidepressants, anxiolytics, sedative hypnotics, or antipsychotics. "So that is one type of evidence that patients exhibit fewer behavioral disturbances" while using cholinesterase inhibitors, Dr. Cummings said.

Of note among clinical trials was one in which nursing home residents with AD and a score of at least 3 on the Neuropsychiatric Inventory received rivastigmine. By week 52, mean levels of disinhibition had declined—as had rates of delusions, hallucinations, apathy, and aberrant motor behavior. Surprisingly, agitation did not respond to treatment. "So we are beginning to see some of our assumptions about how symptoms fit together being challenged by these differential therapeutic responses," Dr. Cummings stated.

AN ALPHABET SOUP OF NONPHARMACOLOGIC OPTIONS

Although his presentation focused primarily on pharmacologic approaches, Dr. Cummings noted that "it is important to try nonpharmacologic interventions, since they have the fewest side effects." He suggested using the "three Rs" (repeat, reassurance, and redirection) to modify patient behavior and the "ABCs" (examining the antecedent, the behavior itself, and its consequences) to try to understand the behavior.

Finally, Dr. Cummings emphasized that at present "there are no FDA-approved agents for behavioral disturbance in AD." However, in March the agency's Psychopharmacological Drugs Advisory Committee (of which Dr. Cummings is a member) reviewed the various behavioral syndromes and symptoms associated with AD; the committee's consensus was that AD-related psychotic symptoms constitute a specific clinical entity and that the FDA should consider approving drugs targeted at these symptoms. The FDA will not approve these new indications for existing drugs, of course, until the pharmaceutical companies have run clinical trials in AD patients. To date, Dr. Cummings noted, only the aforementioned olanzapine and risperidone trials meet the class I standard of evidence that will be needed for approval. However, "over the next few years, I think we will begin to see actual claims for efficacy of psychotropic agents in AD," Dr. Cummings said. "But you should know that all of the prescribing that we currently do is off-label."

—Peter Doskoch

Suggested Reading
1. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology.1999;53:946-955.
2. Mega MS, Masterman DM, O'Connor SM, et al. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol. 1999;56:1388-1393.

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