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Preservation of Cognitive Function With Antihypertensive Medications
A Longitudinal Analysis of a Community-Based Sample of African Americans
Michael D. Murray, PharmD, MPH;
Kathleen A. Lane, MS;
Sujuan Gao, PhD;
Rebecca M. Evans, MD;
Frederick W. Unverzagt, MD;
Kathleen S. Hall, PhD;
Hugh Hendrie, MB, ChB
Arch Intern Med. 2002;162:2090-2096.
ABSTRACT
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Background Results of previous studies of white older adults suggest that antihypertensive
medications preserve cognition. We assessed the long-term effect of antihypertensive
medications on cognitive function in a community sample of African American
older adults.
Methods We conducted longitudinal surveys and clinical assessment of cognitive
function in a random sample of 2212 community-dwelling African Americans 65
years and older. We identified 1900 participants without evidence of cognitive
impairment at baseline, 1617 of whom had subsequent follow-up information,
and 946 of whom had blood pressure measurements. Cognitive function was measured
at baseline and at 2 and 5 years by means of scores on the Community Screening
Instrument for Dementia and neuropsychological and clinical assessment for
dementia and cognitive impairment. Prescription and nonprescription medication
use was derived from in-home inspection of medications and participant and
informant reports.
Results Of 1900 participants, 288 (15.2%) developed incident cognitive impairment.
Using logistic regression to control for the effects of age, sex, education,
baseline cognitive scores, and hypertension and angina or myocardial infarction,
we found that antihypertensive medications reduced the odds of incident cognitive
impairment by 38% (odds ratio, 0.62; 95% confidence interval, 0.45-0.84).
Corresponding analysis using blood pressure measurements on the subset of
participants was inconclusive.
Conclusion Antihypertensive medication use is associated with preservation of cognitive
function in older African American adults.
INTRODUCTION
CHRONIC VASCULAR diseases such as hypertension that are prevalent with
aging adversely affect cognitive function.1-3 Although
these chronic vascular disorders are risk factors for cerebrovascular insults
such as strokes, which are known to cause cognitive impairment and dementia,4 they appear to contribute to cognitive decline even
in stroke-free older adults.5 The relationship
between blood pressure and cognitive decline is particularly complex, and
it appears that cognitive impairment can occur with hypotension or hypertension.6-7
Hypertension is more prevalent among African Americans than whites.
African Americans develop hypertension when they are younger and the disease
tends to be more severe.8 For example, compared
with white persons, the prevalence of hypertension is 60% greater in African
Americans, and their risk of stroke is 80% greater. The association between
hypertension and cognitive impairment coupled with the greater prevalence
of hypertension in African Americans provides a good rationale for the prevention
and control of hypertension in older African Americans.
Therapeutic strategies aimed at improving the control of hypertension
would lead to preservation of cognitive function in older adult African Americans.
An important question is whether pharmacotherapy for hypertension in older
adult African Americans also prevents progression of cognitive decline and
dementia. Although an increasing volume of evidence is accumulating to suggest
this, findings have varied by study design and there has been little inclusion
of African American participants.3, 5, 9-18
Recently, our group published the results of a cross-sectional study
of the association between cognitive impairment and vascular protective drugs
in a random sample of 2212 African Americans 65 years or older from Indianapolis,
Ind.19 After controlling for age, education,
and a diagnosis of stroke, we found that vascular protective medications were
associated with a reduced risk of cognitive impairment and dementia primarily
owing to the effect of antihypertensive medications. However, such a cross-sectional
study is more likely to reveal associations wherein the timing between cognitive
assessment and drug use is near (ie, acute effects), whereas a longitudinal
design would be better suited to ascertain the temporal relationship of long-term
drug effects. Because we now have 5 years of longitudinal data with assessments
at baseline, 2 years, and 5 years, we conducted a longitudinal analysis to
ascertain the long-term effects of antihypertensive medications used by members
of the same cohort of older adult African American participants as in our
previous cross-sectional analysis.19 The purpose
of this study is to report the long-term effects of antihypertensive medications
on cognitive performance in older adult African Americans by means of a longitudinal
study design.
SUBJECTS AND METHODS
PARTICIPANTS
The target geographic sampling frame for the study was 29 contiguous
census tracts within Indianapolis. According to the 1990 US Census, 80% of
the population within these census tracts was African American, representing
two thirds of all elderly African Americans living within the city. Using
data provided by the Indianapolis Water Company, we drew a simple random sample
of 60% of the residents. The sample was representative of elderly African
Americans throughout Indianapolis and Indiana in its age, sex, and socioeconomic
composition. Interviewers who were members of the targeted community canvassed
the neighborhoods and, with randomized address lists, identified homes to
interview African American participants 65 years and older. When possible,
a close relative within the subject's household participated in the interview
as an informant to provide, verify, or supplement data.
Of the 7590 residential addresses provided by the public utility, 4915
households were ineligible because none of the members of the household were
65 years or older and 383 households had no African American family members
(282 households had 2 interviews and 4 households had 3 interviews). Of the
2582 eligible participants, 249 refused participation and 121 were too ill
to participate. A total of 2212 participants completed the baseline in-home
interviews, and 1495 of these participants had accompanying informants during
their interviews.
RESEARCH DESIGN
The Indiana University–Purdue University at Indianapolis Institutional
Review Board approved the study, and all participants provided their written
informed consent. The research design has been comprehensively described previously.20 For the purposes of this article, an overview of
relevant methods is provided. Figure 1 shows
the study design. All study waves (baseline, wave 1, and wave 2) were conducted
in a 2-stage design involving an initial screen for cognitive impairment (stage
1) followed by clinical assessment (stage 2). To determine the prevalence
of dementia, baseline interviews were conducted from 1992 to 1993 in participants'
homes by trained interviewers to screen for cognitive and functional impairment,
ascertain medical and medication histories, and determine activities of daily
living. Within a year of the stage 1 baseline screening interview, stage 2
in-home clinical assessments were conducted by means of a sampling scheme
that oversampled persons with a high likelihood of dementia (Figure 1). The rationale for oversampling was to assess participants
with the greatest propensity for dementia given limits on resources to conduct
comprehensive assessments. These clinical assessments included a neuropsychological
evaluation, a physical examination, and a structured interview with the informant.
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Participant flow through prospective follow-up. CSID indicates Community
Screening Instrument for Dementia; CI, cognitive impairment. Numbers in parentheses
are the numbers of people who composed the "preserved cognition" group from
each category. The boldface compartments show the numbers of participants
meeting criteria for incident cognitive impairment.
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To determine incident cases of dementia after the baseline interview
and clinical assessments, 2 waves of follow-up interviews were conducted between
1994 and 1995 (wave 1) and again between 1997 and 1998 (wave 2). As with the
baseline prevalence study, these incidence studies were performed in 2 stages:
in-home screening followed by a full diagnostic evaluation primarily of those
with a high probability of dementia.
On the basis of cognitive and clinical assessments as described below,
we excluded 65 participants who were diagnosed as having dementia, 106 as
having cognitive impairment, and 141 participants who were poor performers
at baseline as defined below. As shown in Figure 1, of the 1900 participants in the inception cohort, 323
participants were unavailable for wave 1 cognitive or clinical assessments
because of death (n = 133), refusal of assessment (n = 58), or our inability
to locate them or other reasons (n = 132). Of these 323 participants, 129
who were unavailable at wave 1 were reascertained for wave 2. At wave 2, 447
participants were unavailable for cognitive and clinical assessments.
COGNITIVE AND CLINICAL ASSESSMENT
The screening instrument used at stage 1 of each wave was the Community
Screening Instrument for Dementia, developed by Hall and colleagues21 while studying the Cree in Manitoba and subsequently
harmonized for African Americans in Indianapolis. The instrument was developed
to measure 2 primary dimensions, cognition and function. The cognitive scale
excluded literacy-dependent items to assess language, memory, recall, orientation,
judgment, comprehension, and construction. A separate section completed by
the informant assessed the subject's activities of daily living and social
function. The scores from the cognitive scale and activities of daily living
were combined into a single screening outcome measurement (the cognitive score).20, 22 A discriminant function score was
derived from the combined cognitive and informant scores, which in one study
demonstrated 100% sensitivity and 79% specificity in distinguishing demented
and nondemented persons.21 For this study,
we used the same methods for distinguishing performance group as we have for
previous studies.20, 23 When informants
were available, we used discriminant scores to distinguish 3 performance groups
at baseline and at each wave (poor, intermediate, and good). When informants
were unavailable, we used cognitive scores only to distinguish performance
groups. The performance groups for follow-up also take into account participants'
decline from previous waves.
Clinical assessment of the participant at stage 2 of each wave was conducted
with the informant present and had 4 components: history of the subject's
cognitive function, performance of activities of daily living, a review of
the medical and medication history (vide infra), and history of the participant's
dementia-related conditions. The interview was based on the Cambridge Mental
Disorders of the Elderly Examination,24 the
test battery of the Consortium to Establish a Registry for Alzheimer's Disease,25 and the Mini-Mental State Examination.26 Dementia
was diagnosed with both International Classification of
Diseases, 10th Revision27 and Diagnostic and Statistical Manual of Mental Disorders, Revised
Third Edition28 criteria, whereas participants
with Alzheimer disease met National Institute of Neurological and Communicative
Diseases and Stroke–Alzheimer's Disease and Related Disorders Association
criteria.29-30
END POINT
Incident cognitive impairment was defined as
the first time a participant was in the poor performance group by screening
or was classified as cognitively impaired or demented by clinical diagnosis
as defined in the previous section at follow-up waves 1 or 2. Participants
in the good or intermediate group at all participating waves were considered
cognitively unimpaired. Since we removed participants who were diagnosed as
having dementia or cognitive impairment and those who were in the poor performance
group at baseline, this cohort consisted of participants who were cognitively
intact at baseline. The bold-type compartments of Figure 1 show the numbers of participants meeting criteria for incident
cognitive impairment. Overall, 1617 participants were seen at least once at
wave 1 or wave 2 and thus reached their end point.
MEDICATION INTERVIEW
Information on medication use was available on all 1617 participants.
Trained interviewers asked participants and informants to retrieve from the
rooms of the home all prescription and nonprescription medications that were
currently being taken by the participant at the time of the interview. Interviewers
recorded the names of medications from the labels of each medication container.
Only the names of drugs were recorded from the labels; there was no attempt
to record dosage, frequency, and duration of drug use. When drug containers
were unavailable, the interviewer recorded the drug name as reported by the
participant or informant or from active drug lists kept by participants. During
the clinical assessment interview, interviewers recorded medications used
by participants from informants only.
Continuous use of drug was defined as participant or informant indicating
that the participant used the drug at all participating waves. Intermittent
use of drug was defined as the participant or informant indicating that the
participant used the drug at one, but not all, participating waves. Before
their blood pressure assessment at wave 2, participants were asked whether
they had taken a blood pressure medication within the preceding 24 hours.
The primary focus of this study was on antihypertensive medications.
However, we previously reported on the effects of a broad category of vascular
risk factor–mediating medications that included antihypertensive, antidiabetic,
antihyperlipidemic, and antiplatelet medications.19 Therefore,
we provide information on these latter medications as well. (A document giving
the classification of these medications is available on request from the authors.)
BLOOD PRESSURE MEASUREMENT AND HYPERTENSION
Blood pressure was measured during all clinical assessments and during
the screening interview at wave 2. However, only the blood pressure measurement
taken during the wave in which the end point was reached was used in the analysis.
At each assessment, blood pressure was measured twice and the average of the
measurements was recorded. Of the 1617 participants, 471 (29.1%) reached their
end point at wave 1 and 1146 (70.9%) reached it at wave 2. Of the 471 participants
from wave 1, 96 had a clinical assessment, of whom 86 had their blood pressure
measured at that point. Of the 1146 from wave 2, 891 had their blood pressure
measured at their end point. When the variable describing medication use on
all participating visits was added, 86 participants from wave 1 and 860 participants
from wave 2 had complete medication information. Thus, 946 participants were
available for the analysis involving blood pressure.
The presence of hypertension was determined on the basis of results
from the screening interview at baseline. We asked both the subject and the
informant whether a physician had ever told the subject that he or she had
either hypertension or high blood pressure. If either answered yes, then the
subject was considered to have hypertension.
ANALYSIS
We compared demographic characteristics and vascular risk factors for
participants with or without incident cognitive impairment by means of t tests for continuous variables and  2 tests
for categorical variables. Age was the participant's age at end point. Using
logistic regression, we ascertained the effect of baseline and follow-up medication
use on the risk of incident cognitive impairment. Odds ratios, 95% confidence
intervals, and P values were calculated from models
controlling for participant age, total years of education, sex, baseline cognitive
scores from the Community Screening Instrument for Dementia, history of angina
or myocardial infarction, and hypertension. Many medications used to control
hypertension may also be used for other cardiovascular disorders, such as
coronary artery disease, or even noncardiovascular disorders, such as the
use of  -adrenergic antagonists for migraine headache. Because hypertension
is a risk factor for dementia as well as a confounding bias in the way drugs
are prescribed, we controlled for hypertension and angina or myocardial infarction.
Since these analyses were exploratory, not confirmatory, we did not adjust
the significance levels used for each test to control for the overall type
I error.
A separate analysis was also performed on participants who had blood
pressure measurements taken at their end point. Antihypertensive medication
usage was categorized into 6 levels by a combination of the blood pressure
measurements at the end point and the subject's antihypertensive medication
usage throughout the study. If either the average systolic level was greater
than or equal to 140 mm Hg or the average diastolic level was greater than
or equal to 90 mm Hg, then the subject was considered to have uncontrolled
blood pressure at that time. Participants who used antihypertensive medication
during all waves were classified into 2 levels: continuous usage with controlled
blood pressure and continuous usage with uncontrolled blood pressure. Similarly,
intermittent usage was also broken into 2 levels: intermittent usage with
controlled blood pressure and intermittent usage with uncontrolled blood pressure.
The last 2 levels included participants who did not use antihypertensive medications
with controlled blood pressure, and those who did not use antihypertensive
medications but had uncontrolled blood pressure.
We used 2 tests for categorical variables and t tests for continuous variables to compare participants
with blood pressure measurements and participants without this information.
Logistic regression was then used to identify differences in incident cognitive
impairment among the 6 antihypertensive medication usage groups described
in the preceding paragraph. The reference group was the group of participants
with uncontrolled blood pressure who reported no use of antihypertensive medication.
The model controlled for participants' age, total years of education, sex,
baseline cognitive scores from the Community Screening Instrument for Dementia,
history of angina or myocardial infarction, and hypertension.
RESULTS
Incident cognitive impairment occurred in 288 (15.2%) of the 1900 participants
in wave 1 (n = 108) and wave 2 (n = 180). Of 1577 participants available for
cognitive screening and clinical assessment at wave 1, 18 (1.1%) met our criteria
for dementia, 22 (1.4%) were cognitively impaired, and 68 (4.3%) were poor
performers. At wave 2, of 1151 participants available for cognitive screening
and clinical assessment, 50 (4.3%) met our criteria for dementia, 51 (4.4%)
were cognitively impaired, and 79 (6.9%) were poor performers. Table 1 compares demographic and vascular factors for participants
with and without incident impaired cognition. Participants with incident cognitive
impairment were older, had fewer years of formal education, and had lower
baseline cognitive scores from the Community Screening Instrument for Dementia.
Although not statistically significant, participants with incident cognitive
impairment were less likely at baseline to have diabetes or use alcohol.
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Table 1. Demographics and Vascular Risk Factors by Cognitive Status
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EFFECTS OF ANTIHYPERTENSIVE MEDICATIONS
Table 2 shows the long-term
effect of medications on incident cognitive impairment. Antihypertensive medications
reduced the odds of cognitive impairment by 38% compared with persons not
using these drugs (odds ratio, 0.62; 95% confidence interval, 0.45-0.84).
Effects of the individual antihypertensive medication subclasses were not
statistically significant, but each odds ratio for subgroups was less than
1, suggesting a trend of protective effect on cognition among subclasses.
The exception was -adrenergic antagonists, which was slightly but not
significantly higher than 1.
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Table 2. Risk of Incident Cognitive Impairment by Reported Baseline
Medication Use in 1617 African Americans*
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In our previous analysis of cross-sectional data from this same cohort,
we observed a reduced odds of cognitive impairment among participants prescribed
vascular risk factor–mediating medications (antidiabetic, antihypertensive,
antihyperlipidemic, and antiplatelet medications). In the current study of
longitudinal data, this broad group of medications reduced the odds of incident
dementia by 40% compared with those not using these drugs (odds ratio, 0.60;
95% confidence interval, 0.45-0.81). As in our earlier study, this protective
effect on cognition largely derived from the medications used for the treatment
of hypertension.
Because some participants had changes to their baseline prescription
regimens, we conducted separate analyses to compare the risk of cognitive
impairment from drugs administered either continuously or intermittently to
the risk in participants who had reported never receiving these medications.
Of these participants, 46 were not used in the analysis because they were
missing medication data at wave 1 but had data at wave 2. As shown in Table 3, the effects of continuous administration
of antihypertensive drugs were consistent with the favorable effects observed
in Table 2.
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Table 3. Risk of Incident Cognitive Impairment by Continuous or Intermittent
Antihypertensive Medication Usage Patterns in 1571 African Americans*
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EFFECTS ON BLOOD PRESSURE CONTROL
Table 4 contains the results
of the analysis of reported antihypertensive medication use and blood pressure
control. Of the 946 participants with blood pressure measurements, 116 (12.3%)
were considered to have continuous usage with controlled hypertension, 274
(29.0%) had continuous usage but uncontrolled hypertension, 100 (10.6%) were
intermittent users with controlled hypertension, 214 (22.6%) were intermittent
users with uncontrolled hypertension, 91 (9.6%) did not take antihypertensive
medications and had controlled blood pressure, and 151 (16.0%) did not take
antihypertensive medications but had uncontrolled blood pressure. Incident
cognitive impairment was 6.1% greater among participants who did not receive
antihypertensive medications and whose blood pressure was uncontrolled than
among those with continuous use and controlled blood pressure, but this odds
ratio was not statistically significant (odds ratio, 0.63; 95% confidence
interval, 0.31-1.25).
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Table 4. Risk of Incident Cognitive Impairment by Reported Antihypertensive
Medication Use and Blood Pressure (BP) in 946 Participants
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As shown in Table 5, differences
in demographic and vascular risk factors between participants with and without
blood pressure data were not statistically significant. Baseline cognitive
scores were greater in participants in the blood pressure assessment study
than in participants not in the blood pressure study. However, these scores
were controlled in the analysis of data in Table 4.
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Table 5. Demographics and Vascular Risk Factors Between Participants
Included in the Analysis of Blood Pressure (BP) Measurements
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COMMENT
A cornerstone of geriatric medicine is the preservation of cognitive
function.31 The most common and devastating
threats to cognition in elderly people are vascular dementias and Alzheimer
disease.20, 32-33 Even
though the many recent advances in medicine prolong life, their impact is
dampened by a lack of progress in preventing cognitive decline.34 Thus,
it is especially relevant to search for strategies to preserve cognition in
older adults.
The results of this longitudinal analysis of long-term drug effects
indicate that antihypertensive medications reduce the risk of cognitive impairment
in older African Americans. Previous longitudinal analyses of older adult
cohorts indicate that the beneficial effects of antihypertensive medications
on preservation of cognitive function are due to their effects in controlling
blood pressure in midlife.13-14,16, 18, 35-38 We
attempted to replicate these previous findings by using blood pressure measurements
taken at the last screening or clinical contact with the participants. Unfortunately,
our results were inconclusive. These discrepant findings may be explained
by the shorter duration of blood pressure monitoring in our study. To demonstrate
that the effect of antihypertensive medications is mediated through blood
pressure control, it is probable that blood pressure monitoring would need
to be conducted over a longer period than occurred in our study.
Most longitudinal studies of cognitive function in older adults have
been conducted in populations predominated by whites. This study is, to our
knowledge, the largest longitudinal study of the cognitive effects of drugs
in older adult African Americans. It is widely known that African Americans
have a greater prevalence of hypertension, which is more severe, results in
poorer outcomes, and responds differently to pharmacotherapy.8, 39-42 It
is also well-known that effective treatment of hypertension protects African
Americans from adverse vascular outcomes associated with prolonged exposure
to high blood pressure such as stroke, myocardial infarction, and end-stage
renal disease. The results of our study indicate that antihypertensive therapy
may also preserve cognitive function.
Recently, Knopman and colleagues2 published
their findings from the Atherosclerosis Risk in Communities Study involving
8729 white and 2234 African American participants primarily from Jackson,
Miss. Their 6-year multiracial longitudinal study showed that hypertension
and diabetes are risk factors for cognitive impairment even among younger
persons. However, this study was limited by a lack of cognitive follow-up
on 40% of their African American cohort. Furthermore, the effects of antihypertensive
medications were not specifically addressed. Finally, ascertainment of medication
use in the study was conducted by asking participants to bring their medications
to the clinic, which has recently been shown to be inaccurate.43
Our findings are consistent with our previous cross-sectional analysis.19 In the earlier study, we found a protective effect
of the broad category of vascular risk factor–mediating medications.
However, this effect was predominantly due to antihypertensive medications.
In this more rigorous longitudinal analysis of incident cognitive impairment
in a cohort of cognitively intact individuals, the protective effect of antihypertensive
medications was confirmed.
The one exception between our earlier cross-sectional study and the
current longitudinal analysis was that, in the current study, centrally acting
sympathomimetic drugs such as clonidine and methyldopa were not risk factors
for cognitive impairment or dementia. There are 2 primary reasons for this
finding. First, the longitudinal analysis is more appropriate for ascertainment
of long-term drug effects, whereas cross-sectional analysis is more appropriate
for associations between the acute effects of drugs and cognitive effects.
Centrally acting sympathomimetic drugs are not necessarily known to have a
greater propensity to produce hypotension compared with other antihypertensive
medications. However, withdrawal of clonidine can produce rebound hypertension,44-45 which could produce unfavorable effects
on cognition. Yet, patients tolerating these drugs may have the same long-term
preservation of cognitive function as occurs with other antihypertensive medications.
Limitations of this study must be noted. First, medication data were
limited to the names of drugs reportedly being used by participants at the
time of their interview. We do not have data on indication, precise duration
of use, frequency of administration, dosage, and adherence of the participant
to prescribed regimens. Although ascertainment of medication use by participant
report is limited by participant recall, our interviews were conducted in
participant homes where interviewers recorded most medication names directly
from the container labels of prescription and nonprescription drugs currently
being used by participants.
Second, blood pressure measurements were available primarily at wave
2, thereby limiting our inferences pertaining to blood pressure. Although
we lack longitudinal blood pressure measurements, data from longitudinal studies
already exist that demonstrate the complex relationship between blood pressure
and cognitive function and reinforce the critical impact of blood pressure
control with medications in preserving cognitive function.6
Despite these limitations to our data, we conclude that use of antihypertensive
medications is associated with the preservation of cognition in older adult
African Americans. Although we cannot state with certainty from our study
that this effect is mediated by blood pressure control, the results provide
additional rationale and impetus for guidelines indicating the need for heightened
efforts to detect hypertension, adequately treat it, and carefully monitor
patients with the disease. In doing so, not only would known adverse outcomes
from poorly controlled vascular disorders such as stroke, myocardial infarction,
and end-stage renal disease be prevented, but it is also likely that cognitive
function would be preserved in persons who are at greatest risk of suffering
vascular insult, namely, older African Americans.
AUTHOR INFORMATION
Accepted for publication April 3, 2002.
This study was supported by grant PHS RO1 AG09956 from the National
Institute on Aging, Bethesda, Md. Dr Murray also receives support from grants
PHS RO1 AG19105 and AG07631 from the National Institute on Aging and PHS RO1
HL69399 from the National Heart, Lung, and Blood Institute, Bethesda.
This study was presented at the 17th International Conference on Pharmacoepidemiology,
Toronto, Ontario, August 26, 2001.
Corresponding author and reprints: Hugh Hendrie, MB, ChB, Regenstrief
Institute for Health Care, Regenstrief Health Center, Sixth Floor, 1050 Wishard
Blvd, Indianapolis, IN 46202-2872 (e-mail: hhendri{at}iupui.edu).
From the Departments of Psychiatry (Drs Evans, Unverzagt, Hall, and
Hendrie) and Medicine (Drs Murray and Gao and Ms Lane), Indiana University
School of Medicine, Department of Pharmacy Practice, Purdue University School
of Pharmacy (Dr Murray), and Regenstrief Institute for Health Care (Drs Murray
and Hendrie), Indianapolis, Ind.
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