Agitation in Dementia: Update and Prospectus

Two years ago, probable Alzheimer disease (AD) was diagnosed in the mother to whom this message refers. Her family has made a brave effort, despite her declining comprehension and diminishing ability to care for herself, to honor an earnest plea she made at that time. Increasingly aware of her cognitive difficulty, she asked her family to do everything possible to avoid ever sending her to a nursing home, a setting associated in her mind with very unpleasant memories of her grandmother's final years.

The debilitating effects of AD are not restricted to loss of memory. Increasing forgetfulness, in fact, is not the greatest burden imposed by dementia. Apathy, depression, and behavioral changes frequently precede the dementia diagnosis, and more than 80% of patients with AD will eventually display irritability, agitation, or aggression.¹

Ever since the hospitalization of "Auguste D," Alzheimer's first autopsied patient with the disease that later bore his name, the significance of "noncognitive behavioral symptoms" or "behavioral and psychological symptoms of dementia" (now written about so frequently as to be known as NCBS or BPSD) has been appreciated. The NCBS of a patient with dementia usually determine the timing of a necessary transition to a long-term-care setting. While undoubtedly preferred for some individuals, such a setting may offer greater security and safety while sacrificing some of the comforts and supportive relationships that might accompany continued residence among relatives in a familiar home setting.

The usual evaluation of an agitated patient with dementia assesses the presence of infections or other diseases that tip the behavioral balance toward distress and disinhibition. Distressing bodily or environmental conditions are ruled out. Behavioral interventions are planned and implemented, sometimes with considerable success. Simply supporting and educating caregivers about how to interact with an AD-affected elder, for example, can defer the transition to institutional care.² Then, of course, there is the use of medications that are effective or modestly beneficial for some, less valuable for others, and associated with potential hazards about which we have learned a great deal in the past few years.

Although no medication is FDA-indicated for the treatment of agitation in dementia, the most frequently used agents are probably still the atypical antipsychotics. In 2003, however, concerns were raised about their potential for increasing cerebrovascular adverse effects in geriatric patients with dementia. By 2005, the FDA warned of an increase in overall mortality associated with the use of these medications in elderly patients with dementia-related psychosis. Subsequent studies and meta-analyses have resulted in a consensus that several if not all of the atypicals increase overall mortality to a significant if small degree when they are used to treat psychosis or agitation in elderly patients who have dementia.³ For some patients, even the limited mortality risk is considered unacceptable in light of our knowledge that efficacy, as well, can be quite limited, as was demonstrated by CATIE-AD and other studies.^4,5

Some clinicians briefly advocated a return to the conventional antipsychotics, but these medications, too, are associated with significant adverse effects and perhaps no less an increase in mortality rate.^5,6 As yet, no definitive data indicate whether these medications present similar hazards when used with elderly patients without dementia who have schizophrenia, depression, or mania.

Searching for safer and more effective alternatives, some clinicians have explored the use of cholinesterase inhibitors in treating agitation. The latest addition to a confusing and contradictory literature on this topic, however, reported a failure of donepezil(Drug information on donepezil) (Aricept) to reduce agitation in patients with severe dementia.⁷ Eligible subjects in this well-designed, prospective, double-blind comparison study were randomized to placebo or donepezil (5 mg/d for the first 4 weeks, then 10 mg/d for a remaining 8 weeks). Both treatment groups showed similar small changes in agitation, the primary outcome measure. No significant differences emerged on secondary measures either, including Neuropsychiatric Inventory (NPI) total and NPI Caregiver Distress Scale scores.

In light of earlier reports that had suggested a beneficial effect of cholinesterase inhibitors on NCBS, this newer study is bound to cause some consternation in the geriatric psychiatry community. Previous studies had documented a reduced emergence of behavioral and psychiatric symptoms in patients with dementia who were treated with cholinesterase inhibitors,⁸ a worsening in NPI scores among patients whose cholinesterase inhibitor was discontinued,⁹ and behavioral benefits of galantamine(Drug information on galantamine) (Razadyne) in treating agitation.¹⁰ Furthermore, two meta-analyses agreed that cholinesterase inhibitors may have a modest but significant beneficial effect on agitation and other neuropsychiatric symptoms.^11,12

The contrary findings by Howard and colleagues⁷ should push us to re-evaluate the role of cholinesterase inhibitors in treating agitation as well as to question why their findings differed from those reported in other apparently related studies. Their stringent eligibility criteria required the presence of severe agitation and non-response to a 4-week psychosocial intervention that provided limited but valuable information to caregivers regarding the meanings of agitated behavior and simple behavioral responses. The focus on patients already showing severe agitation is clinically relevant but differs from those studies in which prevention of NCBS emergence was the measured outcome.