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The Relationship Between Donepezil and Behavioral Disturbances in Patients With Alzheimer's Disease
The Relationship Between Donepezil and Behavioral Disturbances in Patients With Alzheimer’s Disease Jeffrey L. Cummings, M.D. Jane A. Donohue, Ph.D. Rachelle L. Brooks, M.A.
The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer’s disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezil for 6 months (n⳱84) were compared with patients not on donepezil (n⳱248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (Pⱕ0.01). Specifically, donepezil patients were described as significantly (Pⱕ0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (Pⱕ0.05). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD. (Am J Geriatr Psychiatry 2000; 8:134–140)
P
atients with Alzheimer’s disease (AD) exhibit neuropsychological deficits, manifesting the insidious onset and gradual progression of disturbances in memory, language, visuospatial skills, and executive function.1,2 Also, they develop a plethora of neuropsychiatric symptoms, including agitation, delusions, anxiety, depression, irritability, agitation, and apathy.3–5 Neuropsychiatric symptoms are an important dimension of AD because they produce substantial distress in caregivers and are a common cause of institutionalization of AD patients.6–9 Residential care is responsible for the largest proportion of direct costs of AD. Thus, behavioral disturbances result in early nursing home placement, pro-
long the period of institutional residence, and increase the expense of this disorder.10,11 Improved control of behavioral abnormalities from neuropsychiatric symptoms in AD could be predicted to reduce caregiver distress, defer institutionalization, enhance patient and caregiver quality of life, and reduce the total direct cost of AD. Conventional psychotropic medications may be used to treat behavioral disturbances in AD.12 However, these agents have substantial side effects and may produce sedation, increase confusion, and lead to gait disturbances, falls, and fractures.13,14 Development of agents with fewer side effects would provide welcome
Received January 22, 1999; revised April 6, 1999; accepted July 22, 1999. From the Departments of Neurology and Psychiatry, University of California, Los Angeles School of Medicine, Los Angeles, California. Address correspondence to Dr. Donohue, Consumer Health Sciences, 346 Wall Street, Princeton, NJ 08540. e-mail: [email protected] Copyright 䉷 2000 American Association for Geriatric Psychiatry
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Cummings et al. alternative treatments for behavioral disturbances in patients with AD. Cholinesterase inhibitors have been shown to reduce or temporarily stabilize cognitive impairment in AD.15–18 These agents enhance cognitive function by inhibiting acetylcholinesterase, prolonging intrasynaptic residence of acetylcholine, and enhancing the interaction between acetylcholine and the post-synaptic cholinergic receptor. Recently, cholinergic compounds have been studied from a behavioral perspective. Physostigmine, tacrine, and metrifonate are cholinesterase inhibitors reported to ameliorate behavioral disturbances in patients with AD.6,19–23 Confirming behavioral benefit from the administration of cholinergic compounds would allow construction of therapeutic approaches that simultaneously address cognitive and behavioral disturbances in AD, reducing the need for polypharmacy and the risk of drug interactions and drug-related side effects. The efficacy of anti-dementia agents has been established by randomized double-blind, placebo-controlled parallel group studies demonstrating the superiority of test agents over placebo in AD.15–18,24 Donepezil and other cholinesterase inhibitors have been shown to improve or reduce the rate of decline in both cognitive performance and global functioning in clinical trials using this methodology.17,18 These efficacy studies establish the ability of an agent to improve cognition in an ideal population of AD patients. However, patients participating in clinical trials are younger, more highly educated, wealthier, and have fewer behavioral manifestations and comorbid medical conditions than AD patients in general.24,25 Thus, it is difficult to extrapolate conclusions from efficacy trials to “real world” populations of AD patients with confidence. At the time of Food and Drug Administration (FDA) approval and marketing, there are many unanswered questions regarding the utility of pharmacologic agents for typical patients: what symptoms respond best to the drug, what educational techniques are needed for patient and family for optimal compliance, how the treatment response is affected by comorbid medical illness or co-administration of other pharmacologic agents; what the usual side effects are in a typical population; how long treatment should be continued; and how the medicine should be stopped.26 These and related questions are addressed through “effectiveness research,” defined as studies that measure the probability of benefit to persons in a defined population from the use of
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medical technology or interventions for a specific medical problem under ordinary conditions.27 In the case of anti-dementia drugs, effectiveness research examines the benefit to representative populations of AD patients of cholinesterase inhibitors or other anti-dementia agents. Effectiveness research depends on patient outcomes that are systematically altered by an intervention. Cost reduction, patient satisfaction, quality of care, and quality of life are among the types of outcomes assessed in effectiveness research. Effectiveness studies are particularly relevant in contemporary dementia care, where managed-care organizations and other health care providers or payers are most interested in the effectiveness of medical therapies in typical populations, not the efficacy in idealized patient groups.28 In the current study, we used cross-sectional data to examine the outcome of donepezil therapy in community-dwelling patients with AD. We assessed the relationship between donepezil treatment and behavioral disturbances in patients with AD. We tested the hypothesis that patients receiving donepezil would have fewer behavioral disturbances than those not receiving the agent.
PATIENTS AND METHODS The caregivers of the patients completed a self-administered questionnaire at two different times, April and November 1997. The questionnaires were designed by Consumer Health Sciences, Princeton, New Jersey, and a board of experts on AD. The overall project addressed AD history and current symptoms, patient and caregiver health and health care utilization, and caregiving activities and burden. This analysis, focusing on AD symptoms and patient drug use, relies almost exclusively on the cross-sectional data (Wave 2) gathered in November 1997. Alzheimer’s disease results in the deterioration of the patient’s mental capacity, and patients often cannot accurately report on their state of illness or treatment regimens in a survey. Therefore, primary caregivers were chosen as the survey respondents because they are a reliable contact for acquiring information about the AD patient. Research has demonstrated that proxy respondents for aged subjects, including patients with
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Donepezil and Behavioral Disturbance dementia, accurately report on medical information for these subjects.29 The first survey was mailed in April 1997 to 29,270 individuals who had previously indicated on a nationwide consumer marketing questionnaire that someone in their household suffered from AD. Of the households receiving the first questionnaire, 3,176 evaluable questionnaires were returned (an 11% response rate). Evaluable questionnaires were those completed by an unpaid caregiver that were at least 80% complete. A follow-up interview was attempted for a random sample of almost 1,500 nonresponders. Forty-nine percent (n⳱730) reported that they did not care for an AD patient. A total of 106 nonrespondents were reached who were AD patient caregivers. They answered a sample of 13 questions from the survey during a brief phone interview. Nonresponders reported caring more hours per week for their patient, and they were in better general health (P⬍0.05) than those who had responded. On the other hand, there were no significant differences on items reflecting severity of AD symptoms among patients, including frequency of potentially dangerous behavior, appearing sad or depressed, and forgetting what day it is. Ninety-three percent of caregivers who responded to the initial survey indicated that they would like to continue to participate in the project. A second survey was sent 6 months later, in November 1997. A total of 1,494 evaluable surveys were returned, a 47% response rate. When those who responded to the second survey were compared with those who discontinued participation after the first survey, the two groups were similar. The patients of the caregivers responding to the second survey had similar frequencies of disease symptoms and similar levels of psychotropic drug use. The largest difference that emerged was that “continuers” were more often related to the patients as spouses: 42% vs. 30% (P⬍0.001). Behavioral Data The surveys included the Revised Memory and Behavior Problems Checklist (RMBPC),30 an instrument for measuring the frequency of dementia-related problems and how caregivers react to them. The RMBPC lists 24 problems common to dementia; these can be grouped into three main categories: memory loss, depression, and behavioral disruption. For this checklist, caregivers are asked to indicate how often these behav-
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iors occurred within the past week (ranging from 0⳱“never” to 4⳱“daily or more often”), and how upsetting the behaviors are to the caregiver (ranging from 0⳱“not at all” to 4⳱“extremely”). The RMBPC was chosen for measuring behavioral disturbances because it provides an efficient, comprehensive assessment tool that can be completed by the caregiver. Examples of queries on memory include trouble remembering recent events, losing or misplacing things, and forgetting what day it is. Depression queries included crying or being tearful, commenting about death of self or others, and appearing sad or depressed. Behavior problems queried included destroying property, doing embarrassing things, and waking household members up at night. The RMBPC was used to obtain two average scores for each of the three domains: memory, depression, and behavioral disturbances. One score represents the frequency with which problems in each domain occur. The other score indicates how bothered or upset caregivers are by the problems in each category. As per guidelines, reaction scores were tallied only for behaviors that had occurred in the past week.30 Tolerance for missing data was two items for memory scales and three items for other scales. The individual’s scale mean was substituted for missing items. Other Patient and Caregiver Data Caregivers also reported demographic data of their own and for their patients, including age, gender, education, income, and the patient’s living situation. Also, they provided information about their caregiving practices and their patients’ treatment regimens. Information on medication usage was elicited by queries on current use of over 20 medications commonly prescribed to treat the symptoms of AD. Subsequently, researchers categorized medications by drug class. Presence of diagnosed comorbid conditions among patients was obtained in response to a list of conditions and was part of Wave 1 data. Sample Selection Using data from both surveys, a subgroup of patients taking donepezil was matched approximately 1to-3 with a sample of non-donepezil users. Patients were identified for inclusion in the donepezil group if they were using the drug when both surveys were completed. This sample of patients (n⳱84) was matched
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Cummings et al. with non-donepezil users (n⳱248), defined as those who did not report the use of donepezil in either survey. The match was based on age (Ⳳ1 year), gender, and number of comorbid medical conditions (at Wave 1). To help ensure that patients with marked behavioral disturbances were not overrepresented in either group, patients using an antipsychotic drug at the time of either survey were excluded. No patient was living in a nursing home at the time the first survey was completed. Statistical Methods In this study, as is typical, availability of treated subjects was more restricted than availability of untreated individuals. By using a larger sample of untreated subjects, the standard errors of the estimates for the control group were reduced and, consequently, the power of statistical tests was increased. We used t-tests to perform group comparisons on mean scores for all six RMBPC subscales. Also, t-tests were used to compare mean scores of groups on individual questions of the RMBC behavior subscales. All tests were two-tailed at a probability level 0.05.
RESULTS Demographics of the Sample The average age for the two groups was approximately 75 years, and there were fewer than 2 comorbid conditions per patient (Table 1). About half of both groups were female, and between 85% and 90% of all patients were white. Nearly 8 in 10 caregivers had a household income of less than $50,000, and about half had no more than a high school education. In terms of their living situation, most donepezil and non-donepezil patients (83% and 80%, respectively) were living with their caregivers. The remainder were living alone, with a paid companion, or in a nursing home. Also, nearly all caregivers were the spouses or the adult children of the AD patients. However, the patients in the donepezil group were significantly more likely to be cared for by their spouses (Pⱕ0.001). About half of the non-donepezil patients had spouse caregivers, whereas 69% of the donepezil group were cared for by spouses. Adult-child caregivers were 45% and 24% of caregivers, respectively.
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The average time elapsed since caregivers first noticed the symptoms of AD was 53 months for donepezil and 61 months for non-donepezil patients. Prescription Product Use The prescription products used by donepezil and non-donepezil patients were very similar (Table 2). As previously described, patients using an antipsychotic drug were excluded. About one-quarter of each group TABLE 1.
Group comparisons for demographics and patient health status Donepezil (nⴔ84)
Non-Donepezil (nⴔ248)
75Ⳳ6.8
76Ⳳ7.3
Demographics Age, years, meanⳲSD Gender, % women
49
52
Race, % white
90
85
Patient living situation, % With caregiver In nursing home
83 5
80 6
Caregiver relationship to patient, % Spousea Adult childa
69 24
47* 45*
Caregiver level of education % high school or less
48
53
Caregiver household income % less than $50,000
78
78
Months since caregiver first noticed symptoms of AD, meanⳲSD
53Ⳳ32.8
61Ⳳ37.3
Number of comorbid conditions
1.6Ⳳ1.2
1.8Ⳳ1.2
Patient health status
Note: Comparisons: t-tests for continuous and chi-square tests for categorical variables. *P⬍0.001. a Chi-square comparisons reflect spouse vs. other, adult child vs. other.
TABLE 2.
Group comparisons (percent) for prescription product use by drug class (%)a Donepezil Group
Non-Donepezil Group
Antianxiety
12
15
Antidepressants
25
27
Estrogen
10
6
Anti-parkinsonian
5
6
Sedatives
0
5*
Note: Patients using an antipsychotic medication were excluded from the study. a Chi-square or Fisher’s exact test (cell size ⬍5). *Pⱕ0.05.
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Donepezil and Behavioral Disturbance was taking an antidepressant (25% and 27%, respectively), and 12% and 15% were taking an antianxiety product. There was a statistically significant difference between the groups for the use of sedatives. Whereas 5% of the non-donepezil group was taking sedatives, no one in the donepezil group was being treated with sedatives (Pⱕ0.05). Frequency of Behavioral Disturbances and Caregiver Reactions When the mean scores on the subscales of the RMBPC were compared for the two patient groups (Figure 1 and Figure 2), the donepezil group had a mean frequency score of 0.83Ⳳ0.69, vs. a score of 1.08Ⳳ0.85 for the non-donepezil group (Pⱕ0.01). A higher score represents a greater frequency of occurrence; thus the non-donepezil caregivers reported behavioral disturbances among their patients more often than did the donepezil caregivers. A similar pattern of difference emerged for the caregiver reaction scores, although it did not reach statistical significance. Although donepezil caregivers had an average score of 1.78Ⳳ0.83, the non-donepezil caregivers scored 1.91Ⳳ0.85. We also investigated the eight individual components of the behavioral disturbance factors (Table 3 and Table 4). First, we calculated for both groups a mean score for each of the eight questions, with a response of “never” receiving a value of 0, consecutively through FIGURE 1.
a response of “daily or more often” receiving a value of 4. For seven of the eight symptoms, the donepezil patients had a lower mean score than that of the nondonepezil group, and in three cases the differences were statistically significant. Specifically, donepezil caregivers reported the following behaviors in their patients significantly less often when compared with the non-donepezil patients: threatening to hurt others (P⬍0.05), talking loudly and rapidly (P⬍0.01), and destroying property (P⬍0.01). The mean reaction scores for caregivers also were calculated, with a reaction of “not at all upset” receiving a score of 0 through a reaction of “extremely upset” receiving a score of 4. The severity of reaction for the donepezil patients’ caregivers was less pronounced for seven of the eight symptoms, with the reaction to one behavioral symptom significantly lower (Pⱕ0.05) for the caregivers of donepezil patients. Specifically, the caregivers were less upset when their patients did embarrassing things.
DISCUSSION This comparison of a matched sample of AD patients yielded support for the growing body of evidence that cholinesterase inhibitors reduce or ameliorate the emergence of behavioral disturbances. The frequency of the FIGURE 2.
Mean frequency scores on the Revised Memory and Behavioral Problems Checklist (RMBC).
Mean caregiver reaction scores on the Revised Memory and Behavioral Problems Checklist for the two patient groups.
4
4 3
RMBC Score
2.81
RMBC Score
2.94
3
2 1.20
1.08* 1
1.18
2
1.78
1.98 2.08
1.91 1.64* 1.32
1
0.83 0 Behavioral Disturbance
0 Behavioral Disturbance
Memory
Donepezil
Depression
Donepezil
Depression
Non-Donepezil
Non-Donepezil
Note: Donepezil: n⳱80 for all scales; non-Donepezil: n⳱239 for behavior and memory; n⳱238 for depression. t-test: *Pⱕ0.01.
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Memory
Note: Donepezil: n⳱23 for behavior; n⳱72 for memory; n⳱27 for depression. Non-Donepezil: n⳱83 for behavior; n⳱196 for memory; n⳱82 for depression. t-test: *Pⱕ0.01.
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Cummings et al. introduced by self-selection of respondents. We addressed this effect by querying nonrespondents and found few differences between this sample and our sample of respondents. Also, we compared data at Wave 1 for continuers (to Wave 2) and noncontinuers and found substantial similarity. Treatment with donepezil was linked to a consistent pattern of lower agitation-related symptoms on the RMBPC subscale. The consistency of this symptom profile increases confidence that respondents’ reports were not idiosyncratic. Also, the particular disturbances of threatening to hurt others, destroying property, and talking loudly and rapidly were significantly less frequent among the donepezil patients. This study showed lower reaction to memory problems among donepezil caregivers vs. respondents whose patients were not treated with this agent. Nevertheless, no difference was found between the two groups on the frequency of memory symptoms. Lower reaction without lower frequency of problems is plau-
reported disturbances was lower in the donepeziltreated group. The difference with respect to caregivers’ reactions to behavioral disturbances did not reach significance, but was in the hypothesized direction. Causation cannot be inferred from this study design, and, as a result, we cannot rule out several competing hypotheses. First, it is possible that patients with behavioral disturbances are less likely to be treated with donepezil, and the differences could reflect a patient selection bias rather than the effect of the drug. However, this bias is minimized by eliminating patients receiving antipsychotics from the study and by establishing that the duration of symptoms was similar in the two groups. Second, patients receiving donepezil and their caregivers could be subject to placebo effects that would be absent in the group not receiving donepezil. Doubleblind efficacy studies, however, show that placebo effects disappear within the first 6 weeks of treatment with donepezil.17,18 Third, there may have been a bias TABLE 3.
Group comparisons for frequency of individual behavioral disturbances (RMBPC Behavior Subscale) Donepezil
Frequency items
n
MeanⴣSD
Non-Donepezil n
MeanⴣSD
Destroys property
80
0.39Ⳳ0.79
234
0.68Ⳳ1.10***
Does embarrassing things
80
1.21Ⳳ1.12
237
1.47Ⳳ1.39*
Wake up others at night
81
1.43Ⳳ1.52
239
1.43Ⳳ1.44
Talking loudly and rapidly
80
0.46Ⳳ1.01
236
0.87Ⳳ1.28***
Engaging in dangerous behavior
80
0.51Ⳳ0.89
238
0.73Ⳳ1.11*
Threatening to hurt others
80
0.16Ⳳ0.58
238
0.33Ⳳ0.78**
Being verbally aggressive to others
80
0.83Ⳳ0.96
238
1.07Ⳳ1.32*
Arguing/being irritable/complaining
80
1.70Ⳳ1.50
241
2.00Ⳳ1.50
Note: RMBPC⳱Revised Memory and Behavioral Problem Checklist. t-tests: *Pⱕ0.10; **Pⱕ0.05; ***P⬍0.01.
TABLE 4.
Group comparisons for reaction to individual behavioral disturbances on the Revised Memory and Behavioral Problem Checklist Donepezil
Reaction items
n
MeanⴣSD
Destroys property
20
Does embarrassing things
53
Wakes up others at night
Non-Donepezil n
MeanⴣSD
1.25Ⳳ0.97
78
1.67Ⳳ1.22
1.38Ⳳ1.10
145
1.74Ⳳ1.09*
43
1.70Ⳳ1.10
141
1.77Ⳳ1.16
Talking loudly and rapidly
18
1.39Ⳳ1.29
84
1.42Ⳳ1.17
Engaging in dangerous behavior
24
2.08Ⳳ1.35
81
2.15Ⳳ1.34
8
2.25Ⳳ1.49
41
1.71Ⳳ1.31
Being verbally aggressive to others
38
1.95Ⳳ1.21
105
2.12Ⳳ1.15
Arguing/being irritable/complaining
53
2.04Ⳳ1.11
163
2.30Ⳳ1.21
Threatening to hurt others
Note: t-test: *Pⱕ0.05.
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Donepezil and Behavioral Disturbance sible. Memory effects may be sufficient to reduce distress, although not sufficient to alter report of memory difficulties. This research supports efficacy studies and case observations suggesting that cholinesterase inhibitors have beneficial psychotropic properties. The donepezil group had reduced agitation and less use of sedative medications. These effects may, over the long term, translate into deferred institutionalization and improved quality of life for patients and caregivers.
This study was based on data from the Alzheimer’s Disease Caregiver Project, Consumer Health Sciences, Princeton, NJ. Funding was provided by Pfizer Inc., New York, NY, and Eisai Inc., Teaneck, NJ. Dr. Cummings also received support from a National Institute on Aging Alzheimer’s Disease Center grant (AG 16570), an Alzheimer’s Disease Research Center of California grant, and the Sidell-Kagan Foundation.
References 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 2. Cummings JL, Benson DF: Dementia: A Clinical Approach. Boston, MA, Butterworth-Heinemann, 1992 3. Mega M, Cummings JL, Fiorello T, et al: The spectrum of behavioral changes in Alzheimer’s disease. Neurology 1996; 46:130–135 4. Reisberg B, Borenstein J, Salob SP, et al: Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry 1987; 48:9–15 5. Teri L, Borson S, Kiyak A, et al: Behavioral disturbance, cognitive dysfunction, and functional skill: prevalence and relationship in Alzheimer’s disease. J Am Geriatr Soc 1989; 37:109–116 6. Kaufer D. Cummings JL, Christine D: Differential neuropsychiatric symptom responses to tacrine in Alzheimer’s disease: relationship to dementia severity. J Neuropsychiatry Clin Neurosci 1998; 10:55–63 7. Teri L: Behavior and caregiver burden: Behavioral problems in patients with Alzheimer’s disease and its association with caregiver distress. Alzheimer Dis Assoc Disord 1997; 11(suppl 4):S35–S38 8. Steele C, Rovner B, Chase GA, et al: Psychiatric problems and nursing home placement of patients with Alzheimer’s disease. Am J Psychiatry 1990; 147:1049–1051 9. Baker FM, Kokmen E, Chandra V, et al: Psychiatric symptoms in cases of clinically diagnosed Alzheimer’s disease. J Geriatr Psychiatry Neurol 1991; 4:71–78 10. Ernst RL, Hay JW: The U.S. economic and social costs of Alzheimer’s disease revisited. Am J Public Health 1994; 84:1261–1264 11. Max W: The economic impact of Alzheimer’s disease. Neurology 1993; 43:S6–S10 12. Wright MT, Cummings JL: Neuropsychiatric disturbances in Alzheimer’s disease and other dementias: recognition and management. Neurologist 1996; 2:207–218 13. Avorn J, Gurwitz J: Principles of pharmacology, in Geriatric Medicine, 2nd Edition. Edited by Cassel CK, Riesenberg DE, Sorenwen LB, et al. New York, Springer-Verlag, 1992, pp 66–88 14. Avorn J: Drug prescribing, drug taking, adverse reactions, and compliance in elderly patients, in Clinical Geriatric Psychopharmacology, 3rd Edition. Edited by Salzman C. Baltimore, MD, Williams & Wilkins, 1998, pp 21–47 15. Farlow M, Gracon SI, Hershey LA, et al: A controlled trial of tacrine in Alzheimer’s disease. JAMA 1992; 268:2523–2529 16. Knapp MJ, Knopman DS, Solomon PR, et al: A 30-week random-
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ized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA 1994; 271:985–994 17. Rogers SL, Friedhoff LT, Donepezil Study Group: The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a U.S. multicenter, randomized, double-blind, placebo-controlled trial. Dementia 1996; 7:293–303 18. Rogers SL, Farlow MR, Doody RS, et al: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 1998; 50:136–145 19. Cummings JL, Gorman DG, Shapira J: Physostigmine ameliorates the delusions of Alzheimer’s disease. Biol Psychiatry 1993; 33:536– 541 20. Gorman DG, Read S, Cummings JL: Cholinergic therapy of behavioral disturbances in Alzheimer’s disease. Neuropsychiatry Neuropsychol Behav Neurol 1993; 6:229–234 21. Kaufer DI, Cummings JL, Christine D: Effect of tacrine on behavioral symptoms in Alzheimer’s disease: an open-label study. J Geriatr Psychiatry Neurol 1996; 9:1–6 22. Raskind MA, Sadowsky CH, Sigmund WR, et al: Effect of tacrine on language, praxis, and noncognitive behavioral problems in Alzheimer’s disease. Arch Neurol 1997; 54:836–840 23. Morris JC, Cyrus PA, Orazem J, et al: Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer’s disease. Neurology 1998; 50:1222–1230 24. Albert SM, Sano M, Marder K, et al: Participation in clinical trials and long-term outcomes in Alzheimer’s disease. Neurology 1997; 49:38–43 25. Schneider LS, Olin JT, Lyness SA, et al: Eligibility of Alzheimer’s disease clinic patients for clinical trials. J Am Geriatr Soc 1997; 45:923–928 26. Klein DF: Clinical psychopharmacologic practice: the need for developing a research base. Archives of Geriatric Psychiatry 1993; 50:491–494 27. Brook RH, Lohr KN: Efficacy, effectiveness, variations, and quality: boundary-crossing research. Med Care 1985; 23:710–722 28. Berman GD, Kottke T, Ballard DJ: Effectiveness research and assessment of clinical outcome: a review of federal government and medical community involvement. Mayo Clin Proc 1990; 65:657– 663 29. Corder LS, Woodbury MA, Manton KG: Proxy response patterns among the aged: effects on estimates of health status and medical care utilization from the 1982–1984 Long-Term Care Surveys. J Clin Epidemiol 1996; 49:173–182 30. Teri L, Truax P, Logsdon R, et al: Assessment of behavioral problems in dementia: The Revised Memory and Behavior Problems Checklist. Psychol Aging 1992; 7:622–631
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The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer’s disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezil for 6 months (n⳱84) were compared with patients not on donepezil (n⳱248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (Pⱕ0.01). Specifically, donepezil patients were described as significantly (Pⱕ0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (Pⱕ0.05). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD. (Am J Geriatr Psychiatry 2000; 8:134–140)
P
atients with Alzheimer’s disease (AD) exhibit neuropsychological deficits, manifesting the insidious onset and gradual progression of disturbances in memory, language, visuospatial skills, and executive function.1,2 Also, they develop a plethora of neuropsychiatric symptoms, including agitation, delusions, anxiety, depression, irritability, agitation, and apathy.3–5 Neuropsychiatric symptoms are an important dimension of AD because they produce substantial distress in caregivers and are a common cause of institutionalization of AD patients.6–9 Residential care is responsible for the largest proportion of direct costs of AD. Thus, behavioral disturbances result in early nursing home placement, pro-
long the period of institutional residence, and increase the expense of this disorder.10,11 Improved control of behavioral abnormalities from neuropsychiatric symptoms in AD could be predicted to reduce caregiver distress, defer institutionalization, enhance patient and caregiver quality of life, and reduce the total direct cost of AD. Conventional psychotropic medications may be used to treat behavioral disturbances in AD.12 However, these agents have substantial side effects and may produce sedation, increase confusion, and lead to gait disturbances, falls, and fractures.13,14 Development of agents with fewer side effects would provide welcome
Received January 22, 1999; revised April 6, 1999; accepted July 22, 1999. From the Departments of Neurology and Psychiatry, University of California, Los Angeles School of Medicine, Los Angeles, California. Address correspondence to Dr. Donohue, Consumer Health Sciences, 346 Wall Street, Princeton, NJ 08540. e-mail: [email protected] Copyright 䉷 2000 American Association for Geriatric Psychiatry
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Cummings et al. alternative treatments for behavioral disturbances in patients with AD. Cholinesterase inhibitors have been shown to reduce or temporarily stabilize cognitive impairment in AD.15–18 These agents enhance cognitive function by inhibiting acetylcholinesterase, prolonging intrasynaptic residence of acetylcholine, and enhancing the interaction between acetylcholine and the post-synaptic cholinergic receptor. Recently, cholinergic compounds have been studied from a behavioral perspective. Physostigmine, tacrine, and metrifonate are cholinesterase inhibitors reported to ameliorate behavioral disturbances in patients with AD.6,19–23 Confirming behavioral benefit from the administration of cholinergic compounds would allow construction of therapeutic approaches that simultaneously address cognitive and behavioral disturbances in AD, reducing the need for polypharmacy and the risk of drug interactions and drug-related side effects. The efficacy of anti-dementia agents has been established by randomized double-blind, placebo-controlled parallel group studies demonstrating the superiority of test agents over placebo in AD.15–18,24 Donepezil and other cholinesterase inhibitors have been shown to improve or reduce the rate of decline in both cognitive performance and global functioning in clinical trials using this methodology.17,18 These efficacy studies establish the ability of an agent to improve cognition in an ideal population of AD patients. However, patients participating in clinical trials are younger, more highly educated, wealthier, and have fewer behavioral manifestations and comorbid medical conditions than AD patients in general.24,25 Thus, it is difficult to extrapolate conclusions from efficacy trials to “real world” populations of AD patients with confidence. At the time of Food and Drug Administration (FDA) approval and marketing, there are many unanswered questions regarding the utility of pharmacologic agents for typical patients: what symptoms respond best to the drug, what educational techniques are needed for patient and family for optimal compliance, how the treatment response is affected by comorbid medical illness or co-administration of other pharmacologic agents; what the usual side effects are in a typical population; how long treatment should be continued; and how the medicine should be stopped.26 These and related questions are addressed through “effectiveness research,” defined as studies that measure the probability of benefit to persons in a defined population from the use of
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medical technology or interventions for a specific medical problem under ordinary conditions.27 In the case of anti-dementia drugs, effectiveness research examines the benefit to representative populations of AD patients of cholinesterase inhibitors or other anti-dementia agents. Effectiveness research depends on patient outcomes that are systematically altered by an intervention. Cost reduction, patient satisfaction, quality of care, and quality of life are among the types of outcomes assessed in effectiveness research. Effectiveness studies are particularly relevant in contemporary dementia care, where managed-care organizations and other health care providers or payers are most interested in the effectiveness of medical therapies in typical populations, not the efficacy in idealized patient groups.28 In the current study, we used cross-sectional data to examine the outcome of donepezil therapy in community-dwelling patients with AD. We assessed the relationship between donepezil treatment and behavioral disturbances in patients with AD. We tested the hypothesis that patients receiving donepezil would have fewer behavioral disturbances than those not receiving the agent.
PATIENTS AND METHODS The caregivers of the patients completed a self-administered questionnaire at two different times, April and November 1997. The questionnaires were designed by Consumer Health Sciences, Princeton, New Jersey, and a board of experts on AD. The overall project addressed AD history and current symptoms, patient and caregiver health and health care utilization, and caregiving activities and burden. This analysis, focusing on AD symptoms and patient drug use, relies almost exclusively on the cross-sectional data (Wave 2) gathered in November 1997. Alzheimer’s disease results in the deterioration of the patient’s mental capacity, and patients often cannot accurately report on their state of illness or treatment regimens in a survey. Therefore, primary caregivers were chosen as the survey respondents because they are a reliable contact for acquiring information about the AD patient. Research has demonstrated that proxy respondents for aged subjects, including patients with
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Donepezil and Behavioral Disturbance dementia, accurately report on medical information for these subjects.29 The first survey was mailed in April 1997 to 29,270 individuals who had previously indicated on a nationwide consumer marketing questionnaire that someone in their household suffered from AD. Of the households receiving the first questionnaire, 3,176 evaluable questionnaires were returned (an 11% response rate). Evaluable questionnaires were those completed by an unpaid caregiver that were at least 80% complete. A follow-up interview was attempted for a random sample of almost 1,500 nonresponders. Forty-nine percent (n⳱730) reported that they did not care for an AD patient. A total of 106 nonrespondents were reached who were AD patient caregivers. They answered a sample of 13 questions from the survey during a brief phone interview. Nonresponders reported caring more hours per week for their patient, and they were in better general health (P⬍0.05) than those who had responded. On the other hand, there were no significant differences on items reflecting severity of AD symptoms among patients, including frequency of potentially dangerous behavior, appearing sad or depressed, and forgetting what day it is. Ninety-three percent of caregivers who responded to the initial survey indicated that they would like to continue to participate in the project. A second survey was sent 6 months later, in November 1997. A total of 1,494 evaluable surveys were returned, a 47% response rate. When those who responded to the second survey were compared with those who discontinued participation after the first survey, the two groups were similar. The patients of the caregivers responding to the second survey had similar frequencies of disease symptoms and similar levels of psychotropic drug use. The largest difference that emerged was that “continuers” were more often related to the patients as spouses: 42% vs. 30% (P⬍0.001). Behavioral Data The surveys included the Revised Memory and Behavior Problems Checklist (RMBPC),30 an instrument for measuring the frequency of dementia-related problems and how caregivers react to them. The RMBPC lists 24 problems common to dementia; these can be grouped into three main categories: memory loss, depression, and behavioral disruption. For this checklist, caregivers are asked to indicate how often these behav-
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iors occurred within the past week (ranging from 0⳱“never” to 4⳱“daily or more often”), and how upsetting the behaviors are to the caregiver (ranging from 0⳱“not at all” to 4⳱“extremely”). The RMBPC was chosen for measuring behavioral disturbances because it provides an efficient, comprehensive assessment tool that can be completed by the caregiver. Examples of queries on memory include trouble remembering recent events, losing or misplacing things, and forgetting what day it is. Depression queries included crying or being tearful, commenting about death of self or others, and appearing sad or depressed. Behavior problems queried included destroying property, doing embarrassing things, and waking household members up at night. The RMBPC was used to obtain two average scores for each of the three domains: memory, depression, and behavioral disturbances. One score represents the frequency with which problems in each domain occur. The other score indicates how bothered or upset caregivers are by the problems in each category. As per guidelines, reaction scores were tallied only for behaviors that had occurred in the past week.30 Tolerance for missing data was two items for memory scales and three items for other scales. The individual’s scale mean was substituted for missing items. Other Patient and Caregiver Data Caregivers also reported demographic data of their own and for their patients, including age, gender, education, income, and the patient’s living situation. Also, they provided information about their caregiving practices and their patients’ treatment regimens. Information on medication usage was elicited by queries on current use of over 20 medications commonly prescribed to treat the symptoms of AD. Subsequently, researchers categorized medications by drug class. Presence of diagnosed comorbid conditions among patients was obtained in response to a list of conditions and was part of Wave 1 data. Sample Selection Using data from both surveys, a subgroup of patients taking donepezil was matched approximately 1to-3 with a sample of non-donepezil users. Patients were identified for inclusion in the donepezil group if they were using the drug when both surveys were completed. This sample of patients (n⳱84) was matched
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Cummings et al. with non-donepezil users (n⳱248), defined as those who did not report the use of donepezil in either survey. The match was based on age (Ⳳ1 year), gender, and number of comorbid medical conditions (at Wave 1). To help ensure that patients with marked behavioral disturbances were not overrepresented in either group, patients using an antipsychotic drug at the time of either survey were excluded. No patient was living in a nursing home at the time the first survey was completed. Statistical Methods In this study, as is typical, availability of treated subjects was more restricted than availability of untreated individuals. By using a larger sample of untreated subjects, the standard errors of the estimates for the control group were reduced and, consequently, the power of statistical tests was increased. We used t-tests to perform group comparisons on mean scores for all six RMBPC subscales. Also, t-tests were used to compare mean scores of groups on individual questions of the RMBC behavior subscales. All tests were two-tailed at a probability level 0.05.
RESULTS Demographics of the Sample The average age for the two groups was approximately 75 years, and there were fewer than 2 comorbid conditions per patient (Table 1). About half of both groups were female, and between 85% and 90% of all patients were white. Nearly 8 in 10 caregivers had a household income of less than $50,000, and about half had no more than a high school education. In terms of their living situation, most donepezil and non-donepezil patients (83% and 80%, respectively) were living with their caregivers. The remainder were living alone, with a paid companion, or in a nursing home. Also, nearly all caregivers were the spouses or the adult children of the AD patients. However, the patients in the donepezil group were significantly more likely to be cared for by their spouses (Pⱕ0.001). About half of the non-donepezil patients had spouse caregivers, whereas 69% of the donepezil group were cared for by spouses. Adult-child caregivers were 45% and 24% of caregivers, respectively.
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The average time elapsed since caregivers first noticed the symptoms of AD was 53 months for donepezil and 61 months for non-donepezil patients. Prescription Product Use The prescription products used by donepezil and non-donepezil patients were very similar (Table 2). As previously described, patients using an antipsychotic drug were excluded. About one-quarter of each group TABLE 1.
Group comparisons for demographics and patient health status Donepezil (nⴔ84)
Non-Donepezil (nⴔ248)
75Ⳳ6.8
76Ⳳ7.3
Demographics Age, years, meanⳲSD Gender, % women
49
52
Race, % white
90
85
Patient living situation, % With caregiver In nursing home
83 5
80 6
Caregiver relationship to patient, % Spousea Adult childa
69 24
47* 45*
Caregiver level of education % high school or less
48
53
Caregiver household income % less than $50,000
78
78
Months since caregiver first noticed symptoms of AD, meanⳲSD
53Ⳳ32.8
61Ⳳ37.3
Number of comorbid conditions
1.6Ⳳ1.2
1.8Ⳳ1.2
Patient health status
Note: Comparisons: t-tests for continuous and chi-square tests for categorical variables. *P⬍0.001. a Chi-square comparisons reflect spouse vs. other, adult child vs. other.
TABLE 2.
Group comparisons (percent) for prescription product use by drug class (%)a Donepezil Group
Non-Donepezil Group
Antianxiety
12
15
Antidepressants
25
27
Estrogen
10
6
Anti-parkinsonian
5
6
Sedatives
0
5*
Note: Patients using an antipsychotic medication were excluded from the study. a Chi-square or Fisher’s exact test (cell size ⬍5). *Pⱕ0.05.
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Donepezil and Behavioral Disturbance was taking an antidepressant (25% and 27%, respectively), and 12% and 15% were taking an antianxiety product. There was a statistically significant difference between the groups for the use of sedatives. Whereas 5% of the non-donepezil group was taking sedatives, no one in the donepezil group was being treated with sedatives (Pⱕ0.05). Frequency of Behavioral Disturbances and Caregiver Reactions When the mean scores on the subscales of the RMBPC were compared for the two patient groups (Figure 1 and Figure 2), the donepezil group had a mean frequency score of 0.83Ⳳ0.69, vs. a score of 1.08Ⳳ0.85 for the non-donepezil group (Pⱕ0.01). A higher score represents a greater frequency of occurrence; thus the non-donepezil caregivers reported behavioral disturbances among their patients more often than did the donepezil caregivers. A similar pattern of difference emerged for the caregiver reaction scores, although it did not reach statistical significance. Although donepezil caregivers had an average score of 1.78Ⳳ0.83, the non-donepezil caregivers scored 1.91Ⳳ0.85. We also investigated the eight individual components of the behavioral disturbance factors (Table 3 and Table 4). First, we calculated for both groups a mean score for each of the eight questions, with a response of “never” receiving a value of 0, consecutively through FIGURE 1.
a response of “daily or more often” receiving a value of 4. For seven of the eight symptoms, the donepezil patients had a lower mean score than that of the nondonepezil group, and in three cases the differences were statistically significant. Specifically, donepezil caregivers reported the following behaviors in their patients significantly less often when compared with the non-donepezil patients: threatening to hurt others (P⬍0.05), talking loudly and rapidly (P⬍0.01), and destroying property (P⬍0.01). The mean reaction scores for caregivers also were calculated, with a reaction of “not at all upset” receiving a score of 0 through a reaction of “extremely upset” receiving a score of 4. The severity of reaction for the donepezil patients’ caregivers was less pronounced for seven of the eight symptoms, with the reaction to one behavioral symptom significantly lower (Pⱕ0.05) for the caregivers of donepezil patients. Specifically, the caregivers were less upset when their patients did embarrassing things.
DISCUSSION This comparison of a matched sample of AD patients yielded support for the growing body of evidence that cholinesterase inhibitors reduce or ameliorate the emergence of behavioral disturbances. The frequency of the FIGURE 2.
Mean frequency scores on the Revised Memory and Behavioral Problems Checklist (RMBC).
Mean caregiver reaction scores on the Revised Memory and Behavioral Problems Checklist for the two patient groups.
4
4 3
RMBC Score
2.81
RMBC Score
2.94
3
2 1.20
1.08* 1
1.18
2
1.78
1.98 2.08
1.91 1.64* 1.32
1
0.83 0 Behavioral Disturbance
0 Behavioral Disturbance
Memory
Donepezil
Depression
Donepezil
Depression
Non-Donepezil
Non-Donepezil
Note: Donepezil: n⳱80 for all scales; non-Donepezil: n⳱239 for behavior and memory; n⳱238 for depression. t-test: *Pⱕ0.01.
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Memory
Note: Donepezil: n⳱23 for behavior; n⳱72 for memory; n⳱27 for depression. Non-Donepezil: n⳱83 for behavior; n⳱196 for memory; n⳱82 for depression. t-test: *Pⱕ0.01.
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Cummings et al. introduced by self-selection of respondents. We addressed this effect by querying nonrespondents and found few differences between this sample and our sample of respondents. Also, we compared data at Wave 1 for continuers (to Wave 2) and noncontinuers and found substantial similarity. Treatment with donepezil was linked to a consistent pattern of lower agitation-related symptoms on the RMBPC subscale. The consistency of this symptom profile increases confidence that respondents’ reports were not idiosyncratic. Also, the particular disturbances of threatening to hurt others, destroying property, and talking loudly and rapidly were significantly less frequent among the donepezil patients. This study showed lower reaction to memory problems among donepezil caregivers vs. respondents whose patients were not treated with this agent. Nevertheless, no difference was found between the two groups on the frequency of memory symptoms. Lower reaction without lower frequency of problems is plau-
reported disturbances was lower in the donepeziltreated group. The difference with respect to caregivers’ reactions to behavioral disturbances did not reach significance, but was in the hypothesized direction. Causation cannot be inferred from this study design, and, as a result, we cannot rule out several competing hypotheses. First, it is possible that patients with behavioral disturbances are less likely to be treated with donepezil, and the differences could reflect a patient selection bias rather than the effect of the drug. However, this bias is minimized by eliminating patients receiving antipsychotics from the study and by establishing that the duration of symptoms was similar in the two groups. Second, patients receiving donepezil and their caregivers could be subject to placebo effects that would be absent in the group not receiving donepezil. Doubleblind efficacy studies, however, show that placebo effects disappear within the first 6 weeks of treatment with donepezil.17,18 Third, there may have been a bias TABLE 3.
Group comparisons for frequency of individual behavioral disturbances (RMBPC Behavior Subscale) Donepezil
Frequency items
n
MeanⴣSD
Non-Donepezil n
MeanⴣSD
Destroys property
80
0.39Ⳳ0.79
234
0.68Ⳳ1.10***
Does embarrassing things
80
1.21Ⳳ1.12
237
1.47Ⳳ1.39*
Wake up others at night
81
1.43Ⳳ1.52
239
1.43Ⳳ1.44
Talking loudly and rapidly
80
0.46Ⳳ1.01
236
0.87Ⳳ1.28***
Engaging in dangerous behavior
80
0.51Ⳳ0.89
238
0.73Ⳳ1.11*
Threatening to hurt others
80
0.16Ⳳ0.58
238
0.33Ⳳ0.78**
Being verbally aggressive to others
80
0.83Ⳳ0.96
238
1.07Ⳳ1.32*
Arguing/being irritable/complaining
80
1.70Ⳳ1.50
241
2.00Ⳳ1.50
Note: RMBPC⳱Revised Memory and Behavioral Problem Checklist. t-tests: *Pⱕ0.10; **Pⱕ0.05; ***P⬍0.01.
TABLE 4.
Group comparisons for reaction to individual behavioral disturbances on the Revised Memory and Behavioral Problem Checklist Donepezil
Reaction items
n
MeanⴣSD
Destroys property
20
Does embarrassing things
53
Wakes up others at night
Non-Donepezil n
MeanⴣSD
1.25Ⳳ0.97
78
1.67Ⳳ1.22
1.38Ⳳ1.10
145
1.74Ⳳ1.09*
43
1.70Ⳳ1.10
141
1.77Ⳳ1.16
Talking loudly and rapidly
18
1.39Ⳳ1.29
84
1.42Ⳳ1.17
Engaging in dangerous behavior
24
2.08Ⳳ1.35
81
2.15Ⳳ1.34
8
2.25Ⳳ1.49
41
1.71Ⳳ1.31
Being verbally aggressive to others
38
1.95Ⳳ1.21
105
2.12Ⳳ1.15
Arguing/being irritable/complaining
53
2.04Ⳳ1.11
163
2.30Ⳳ1.21
Threatening to hurt others
Note: t-test: *Pⱕ0.05.
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Donepezil and Behavioral Disturbance sible. Memory effects may be sufficient to reduce distress, although not sufficient to alter report of memory difficulties. This research supports efficacy studies and case observations suggesting that cholinesterase inhibitors have beneficial psychotropic properties. The donepezil group had reduced agitation and less use of sedative medications. These effects may, over the long term, translate into deferred institutionalization and improved quality of life for patients and caregivers.
This study was based on data from the Alzheimer’s Disease Caregiver Project, Consumer Health Sciences, Princeton, NJ. Funding was provided by Pfizer Inc., New York, NY, and Eisai Inc., Teaneck, NJ. Dr. Cummings also received support from a National Institute on Aging Alzheimer’s Disease Center grant (AG 16570), an Alzheimer’s Disease Research Center of California grant, and the Sidell-Kagan Foundation.
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