The identification of cholinergic contributions to the dysfunction in patients with Alzheimer's disease (AD) appears straightforward at first. However, complicating questions arose more than a decade ago. For example, why, if AD patients indeed experienced cholinergic damage, was the number of cholinergic receptors similar in both AD patients and normal controls at autopsy? Researchers speculated about the possibility of an upregulation of cholinergic receptors in response to the loss of functional receptors subsequent to presynaptic cholinergic neuronal loss. This led to research on the consequences of administering a cholinergic antagonist rather than an agonist in AD patients as a pharmacologic challenge test in an attempt to test the functional sensitivity of the remaining cholinergic receptors.

This article outlines information on the use of anticonvulsants, including carbamazepine and divalproex sodium, to treat agitation in dementia.

Depression, psychosis, agitation, and aggression are fundamental clinical aspects of Alzheimer's disease (AD) and other dementia syndromes. Although behavioral, environmental, and pharmacologic interventions often help ameliorate these symptoms, the efficacy of specific interventions is uncertain, and adverse effects of medications are common.

In patients with dementia who develop psychosis and behavioral problems, conventional neuroleptics have been the mainstay of pharmacologic management.

Behavioral and psychological symptoms of dementia (BPSD) are among the most prominent and invasive features of dementia, and increasingly form a target for therapeutic intervention in this cognitively impaired population. Aggression and other behavioral symptoms of dementia (e.g., agitation, purposeless activity, wandering, pacing, psychotic symptoms) are important features of this illness, severely affect patient and caregiver quality of life, and complicate effective medical management. Behavioral symptoms have been described by caregivers as the primary predictor of caregiver burden and cause for negative feelings toward their dependents. In fact, the behavioral symptoms of dementia, particularly aggression and agitation, are the most common reason for admission to the hospital or residential care.

Behavioral and psychological symptoms of dementia (BPSD) have a significant impact on patients and their families. These symptoms affect quality of life and medical and social service utilization, and determine time of institutionalization. Over the past three decades, academic-based clinical investigators have conducted trials of almost all classes of marketed psychotropics in an attempt to ameliorate these symptoms. With few exceptions, these studies suffered from serious methodologic shortcomings, such as small patient populations or too many outcome measurements (Stern et al., 1997). Despite these flaws and equivocal findings, a consensus has emerged, and antipsychotics have become the most commonly prescribed drugs for this condition (see consensus statement in this issue). Unfortunately, a meta-analysis of trials of conventional neuroleptics has revealed that this class of drugs is barely superior to placebo (see article by Lon Schneider in this issue). In addition, conventional neuroleptics cause extrapyramidal adverse effects, tardive dyskinesia, sedation, and cardiovascular instability, adverse effects to which the elderly are particularly vulnerable.

Numerous rating scales are available to assess specific behavioral and psychological symptoms of dementia (BPSD) and BPSD in general. One of the most commonly used scales is the Brief Psychiatric Rating Scale (BPRS), which was developed nearly 40 years ago and has been partially validated for use in patients with dementia. Dr. Tariot commented that use of the BPRS requires extensive clinical training to conduct the semistructured interviews and to probe, gauge, and weigh data in a way that reflects clinical reasoning, thinking, and judgment. In contrast, a scale such as the Neuropsychiatric Inventory, which covers a broad spectrum of BPSD, can be administered by a healthcare professional without extensive clinical training; this is both a strength and a weakness. Dr. Sultzer recognized the value of both types of scales, those that require semistructured interviews and those that are largely observational, and suggested that using different combinations of scales in research studies may be valuable. Although the BPRS is an older scale that some researchers believe is inappropriate for use in patients with dementia, Dr. Mintzer noted that the BPRS and its subscales have been used successfully over the past few years to differentiate drug effects from placebo in this patient population.

By definition, anxiolytics are drugs capable of treating anxiety and anxiety related disorders. The precise role of anxiolytics, particularly in comparison with other drug classes (e.g., antipsychotics and antidepressants) and other therapeutic approaches (e.g., psychotherapy, behavioral therapy, and relaxation) in treating behavioral and psychological symptoms of dementia (BPSD) needs to be determined. If anxiolytics are used for BPSD, the clinician must decide whether they should be used as an emergency measure, as long-term therapy, or both. Also, whether anxiolytics are useful in treating anxiety and its consequences in both the early and advanced stages of dementia must be considered.

Several hormones have the potential for influencing the behavioral and psychological symptoms of dementia (BPSD). Endocrine disorders stemming from the thyroid and parathyroid glands, for example, can be identified through screening laboratory tests, and if the underlying abnormalities are treated, symptoms may improve. The hormone that has received the greatest attention, however, regarding its potential for treating both cognitive and mood symptoms in older persons is estrogen. Recent data suggest that estrogen may facilitate treatment of depression in cognitively intact postmenopausal women and may decrease the risk of Alzheimer's disease in postmenopausal women. In part because testosterone is converted to estrogen in men, recent studies suggest that treating hypogonadal men with testosterone may improve their cognitive function.

When the International Psychogeriatric Association (IPA) held its consensus meeting in 1996, we reviewed the placebo-controlled, double-blind, randomly assigned clinical drug trials on the behavioral and psychological symptoms of dementia (BPSD) in the worldwide literature (Finkel, 1996). We learned that prior to 1990, only seven such studies utilizing antipsychotic medications were published. Those occurred between 1960 and 1982 (Schneider et al., 1990), and only one (Barnes et al., 1982) took place in a nursing home. These early studies suffered from many shortcomings, including the use of high doses of medication for this population, measurements and scales developed for younger schizophrenic and bipolar patients, and lengths of studies that were too short to allow full washout in those elderly previously taking medication (Devanand, 1996; Finkel, 1996). Further, six of the seven studies utilized the softer diagnostic criteria characteristic of DSM-I and DSM-II. Several other clinical trials examined benzodiazepines (Schneider & Sobin, 1991) which, overall, showed a lesser therapeutic effect than the neuroleptic medication. None of these research studies appeared to be financially supported by industry.

Whether we need another meta-analysis of clinical trials of antipsychotic treatment of patients with behavioral and psychological symptoms of dementia (BPSD) depends on how we define meta analysis and our expectations for the results of such an analysis.

Data presented by Dr. Allain indicated that benzodiazepines are associated with an increased risk of Alzheimer's disease (AD). Dr. Cohen asked whether any mechanism had been proposed for this finding. “No mechanism was proposed by the investigators,” said Dr. Allain. He noted that the investigators in this study, which has now enrolled more than 5,000 patients, are analyzing drug use among patients before and during the study. He also pointed out that the finding of an association between benzodiazepines and AD contrasts with the results of a previous trial, which found no such association.

The global regulatory environment strongly affects the development of effective medications to treat behavioral and psychological symptoms of dementia (BPSD) (Whitehouse, 1998b). Since its inception in 1994, the International Working Group for Harmonization of Dementia Drug Guidelines (IWG) has been working to foster dialogue on dementia drug development among academics, regulators, industry representatives, and patients and their families. In this overview, I describe the IWG's mission, people, and recent activities (Whitehouse, 1998c), and its activities concerning BPSD in several regions throughout the world.

In 1995, a new European system for the authorization of medicinal products went into effect. After 10 years of cooperation between National Registration Authorities at the European Union (EU) level and 4 years of negotiation, in June 1993 the Council of the EU adopted three directives and a regulation that together form the legal basis of the current system. The European Medicines Evaluation Agency (EMEA) was established on July 22, 1993, and London was chosen as its coordinating center, housing the Committee for Proprietary Medicinal Products (CPMP), which is the body that advises the European Licensing Authority (European Commission). The EMEA has the opportunity to harness the expertise and resources of member states and their ability to oversee local implementation.

In 1996, the Japanese Ministry of Health and Welfare organized a working group to develop guidelines to assess the clinical efficacy of drugs used to treat dementia. The major issues discussed at that time included the definition of antidementia drugs, outcome measures, concomitant treatments, and placebo issues. Because the primary objective of this group was to develop guidelines for the symptomatic treatment of the disease, issues related to slowing of disease progression and behavioral and psychological symptoms of dementia (BPSD) were not discussed in detail. In 1997, the group submitted a draft report to the Japanese Ministry of Health and Welfare. It is hoped that in the future, this group will address issues not discussed in the draft guidelines.

The entity, behavioral and psychological symptoms of dementia (BPSD), is a useful concept in that it focuses attention on an aspect of dementia that has long been ignored in both research and treatment. Although it is useful as a broad category that includes a number of more specific clinical entities, BPSD is too broad a target to serve as an indication for a particular drug. Labeling with such a claim would be potentially misleading because it would not be clear what specific patient population would likely benefit from treatment.

A considerable portion of this discussion was devoted to whether symptoms such as depression, agitation, and psychosis are different in patients with dementia compared with those without dementia, and whether such symptoms warrant approval as new drug indications. Dr. Schneider noted that the U.S. Food and Drug Administration (FDA) recognizes depressive syndrome, psychosis, and mania within dementia, and will consider applications to add such indications to existing drug labeling. Dr. Whitehouse agreed that the FDA has been responsive to how the scientific community conceptualizes symptoms in dementia. The FDA has endorsed the notion of behavioral and psychological symptoms of dementia (BPSD) as an umbrella term, and also recognizes more specific target behavioral symptoms. Dr. McKeith believes that the target symptom approach would be accepted in Europe, although he was concerned about an excessive need for defining each symptom, which would unnecessarily prolong the review and approval process.

Since 1987, the New York University Alzheimer's Disease Center Caregiver Research Program has evaluated the benefits of a multifaceted, structured treatment program for spouse-caregivers of patients with Alzheimer's disease (AD). This intervention strategy for caregivers was based on the clinical experience of counselors who worked with families of AD patients both individually and in support groups for many years. The unifying theme of the intervention is that improving social support and mastery improves the ability of the caregiver to withstand the difficulties of caregiving. The intervention takes into account the diversity and variability in caregiver problems, and is not time limited.

Most patients with Alzheimer's disease (AD) are cared for in their own homes. The costs of this care can be documented in several different ways—financial, time spent in the caregiving role, and strain or burden on the caregiver. This strain and burden on caregivers can manifest in a variety of ways, including increased use of prescribed medication and more primary care visits (Haley, 1997). Vulnerability to strain is heightened by a previous history of psychiatric disorder in the caregiver (Baumgarten et al., 1992; Hooker, 1992). Depression is a particularly common accompaniment to the caregiving role, affecting between 25% and 70% of caregivers (Dura et al., 1990; Teri, 1994). Physical manifestations of caregiving burden include impaired immune function, elevated blood pressure, abnormal plasma lipid levels, and poor self-care (e.g., sleeplessness and lack of exercise) (Haley, 1997).

We performed a selective review of the research literature on psychosocial interventions for behavioral and psychological symptoms of dementia (BPSD). The review is limited to: (a) only papers published since 1996; (b) studies that target behavioral excess; and (c) studies with some measure of experimental control.