On a hypothetical morning, you've arrived early at your office to answer e-mails and respond to prescription requests without interruptions. The following voice mail, left for you much earlier that day, awaits your attention: "Doctor, I need to discuss my mother's behavior with you. The medications she's taking might be calming her down during the days, but she's not okay at night."
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.
Atypical and conventional antipsychotics
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 (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 (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.
There are a couple of brighter spots in the otherwise glum conclusions of this study. In contrast to the decline in cognitive functions with placebo observed over the 12-week study among placebo-treated patients, cognition as measured by the Severe Impairment Battery and the Standardized Mini-Mental State Examination improved a little with donepezil, supporting similar claims for an effect on cognitive impairment in patients with severe dementia who have AD reported earlier by another group.13
Given widespread concerns about the adverse effects of the cholinesterase inhibitors, it is also worth highlighting this study's finding of a low level of significant GI adverse effects. Nausea, vomiting, and anorexia occurred in 2.3% of donepezil recipients and in 0.8% of placebo recipients, which suggests the infrequent clinical significance of that effect in this population. A clinical adverse effect's impact is sometimes expressed as the number needed to harm (NNH), and the relevant calculation here would yield an NNH of 67, meaning that 67 of these patients would have had to be treated with donepezil instead of placebo in order to yield one serious case of nausea, vomiting, or anorexia not attributable to background placebo effect. Furthermore, in light of concerns regarding pharmaceuticals' effects on mortality, it is reassuring that no excess deaths occurred in the cholinesterase inhibitor group in this study.
Finally, the response of 13.7% of subjects to a minimal caregiver psychosocial intervention is consistent with the work of Mittelman's group2 and others, and should encourage our promotion of psychoeducation and intervention in patients' support systems. Perhaps the inclusion of the psychosocial intervention and elimination of psychosocial responders from the medication phase resulted in a study cohort of individuals with more resistant agitation.
My suspicion, consistent with my own clinical experience, is that patients with severe and established agitation are not as capable as less severely affected individuals of benefiting from treatment for agitation with cholinesterase inhibitors. These medications, and perhaps memantine (Namenda) as well, may be more relevant as preventive interventions to defer the worsening of mild agitation or its emergence in patients not agitated at baseline.
Previous studies of NCBS in patients with dementia have offered few medication alternatives to the antipsychotics and cholinesterase inhibitors. Use of citalopram (Celexa)14 or carbamazepine (Carbatrol, Tegretol, others)15 has been advocated. The evidence bases for divalproex sodium (Depakote)16 and trazodone (Desyrel)17 are mixed. Case reports or small series extol the potential but largely untested values of opiates,18 cannabinoids,19 and electroconvulsive therapy (ECT)20 in treating agitation and other NCBS. These approaches are in need of more extensive evaluation.
What to do?
How you will answer your voice mail, therefore, depends to some degree on your level of optimism, your level of risk averseness, and your belief in a set of current treatment options that is of only limited effectiveness in many cases. The first approach, it is agreed, should be medical evaluation and behavioral intervention. Caregiver education and the use of distraction, redirection, and environmental manipulations designed to guide rather than teach acceptable behaviors may be sufficient.
If medications are needed and enough time is available to permit use of an algorithmic sequence of treatments, a cholinesterase inhibitor should be considered-not solely for its effectiveness but rather for the relatively low level of risk. Next, several of the atypical antipsychotics remain reasonable choices when used in patients whose vascular risk factors do not outweigh their behavioral treatment needs. The atypical antipsychotics have not been proved to control agitation over an extended period of time and should be used at the lowest effective doses and for the shortest interval necessary, with sufficient psychoeducation and disclosure of risks to caregivers and relatives.
If these medications offer insufficient relief, it appears a toss-up whether to proceed to a conventional antipsychotic, an SSRI antidepressant, a less thoroughly investigated medication, or even ECT. The future, which holds just beyond current reach a set of agents with alternative mechanisms for attacking the pathophysiology of AD, may provide additional and more effective ways to address agitation.
Jost BC, Grossberg GT. The evolution of psychiatric symptoms in Alzheimer's disease: a natural history study.
J Am Geriatr Soc.
Mittelman MS, Haley WE, Clay OJ, et al. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease.
Jeste DV, Blazer D, Casey D, et al. ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia.
Neuropsychopharmacology advance online publication.
18 July 2007; doi: 10. 1038;sj.npp.1301492.
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.
N Engl J Med.
Schneeweiss S, Setoguchi S, Brookhart A, et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients.
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs atypical antipsychotic medications.
N Engl J Med.
Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the treatment of agitation in Alzheimer's disease.
N Engl J Med.
Cummings JL, Schneider L, Tariot PN, et al. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer's disease.
Am J Psychiatry.
Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
Herrmann N, Rabheru K, Wang J, Binder C. Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials.
Am J Geriatr Psychiatry.
Trinh NH, Hoblyn J, Mohanty S, et al. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis.
Birks J. Cholinesterase inhibitors for Alzheimer's disease.
Cochrane Database Syst Rev.
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study.
Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia.
Am J Geriatr Psychiatry.
Olin JT, Fox LS, Pawluczyk S, et al. A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzhei-mer disease.
Am J Geriatr Psychiatry.
Alexopoulos GS, Jeste DV, Chung H, et al. The expert consensus guideline series. Treatment of dementia and its behavioral disturbances. Introduction: methods, commentary, and summary.
Teri L, Logsdon RG, Peskind E, et al. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial.
Manfredi PL, Breuer B, Wallenstein S, et al. Opioid treatment for agitation in patients with advanced dementia.
Int J Geriatr Psychiatry.
Walther S, Mahlberg R, Eichmann U, et al. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia.
Grant JE, Mohan SN. Treatment of agitation and aggression in four demented patients using ECT.