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The Natural History of Late-Life Depression
A 6-Year Prospective Study in the Community
Aartjan T. F. Beekman, MD, PhD;
Sandra W. Geerlings;
Dorly J. H. Deeg, PhD;
Jan H. Smit, PhD;
Robert S. Schoevers, MD;
Edwin de Beurs, PhD;
Arjan W. Braam, MD, PhD;
Brenda W. J. H. Penninx, PhD;
Willem van Tilburg, MD, PhD
Arch Gen Psychiatry. 2002;59:605-611.
ABSTRACT
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Background Accurate assessment of the natural history of late-life depression requires
frequent observation over time. In later life, depressive disorders fulfilling
rigorous diagnostic criteria are relatively rare, while subthreshold disorders
are common. The primary aim was to study the natural history of late-life
depression, systematically comparing those who did with those who did not
fulfill rigorous diagnostic criteria.
Methods Within the Longitudinal Aging Study Amsterdam, a large cohort of depressed
elderly persons (n = 277) was identified and followed up for 6 years, using
14 observations. Depression was measured using self-reports (the Center for
Epidemiological Studies Depression Scale) and diagnostic interviews (the Diagnostic
Interview Schedule). The natural history was assessed for symptom severity
(Center for Epidemiological Studies Depression Scale score), symptom duration,
clinical course type, and stability of diagnoses.
Results The average symptom severity remained above the 85th percentile of the
population average for 6 years. Symptoms were short-lived in only 14%. There
were remissions in 23%, an unfavorable but fluctuating course in 44%, and
a severe chronic course in 32% (percentages do not total 100 because of rounding).
Comparing the outcome, there was a clear gradient in which those with subthreshold
disorders had the best outcome, followed by those with major depressive disorder,
dysthymic disorder, and double depression. However, the prognosis of subthreshold
disorders was unfavorable in most cases, while this group was at high risk
of developing DSM affective disorders.
Conclusions The natural history of late-life depression in the community is poor. DSM affective disorders are relatively rare among elderly
persons, but do identify those with the worst prognosis. However, subthreshold
depression is serious and chronic in many cases.
INTRODUCTION
IN LATER LIFE, depression is a common disorder, with well-documented
consequences for well-being, daily functioning, mortality, and service utilization.1-10
Although depression is generally regarded to be highly treatable throughout
the life cycle,11-12 most elderly
persons with depression remain untreated.13-14
Because the primary aim of treatment is to change the prognosis of depression,
detailed information on its natural history is of vital importance. Most previous
studies have focused on younger adults recruited in treatment settings. The
results suggest that the long-term outcome is heterogeneous, with many patients
experiencing fluctuating symptom levels over time.15-16
The long-term risk of relapse may be as high as 80%.17
There is good reason to suspect that the prognosis of depression changes
with age. The prevalence of known prognostic factors, such as physical illness,
cognitive impairment, and lack of support, increases with age, suggesting
that the prognosis may deteriorate in later life.18-19
Several community-based studies20-27
focusing on elderly persons have recently reported data. In a meta-analysis13 of available studies, a 50% rate of chronicity was
found in those alive at follow-up. An important weakness of available studies
is that most relied on only 2 measurements, lacking information about the
intervening interval. More frequent observations are necessary to reliably
assess the prognosis of late-life depression. A second problem is the definition
and measurement of depression. It is often assumed that depression is a disorder
occurring at a continuum of severity. Recent studies1, 28-29
suggest that major depression is relatively rare, while subthreshold depressive
disturbances are particularly common in later life. These subthreshold disorders
seem to have similar consequences for the well-being and functioning of elderly
persons when compared with major depressive disorder (MDD).2, 4
Moreover, recent studies5, 10 of
mortality suggest that major depression has the stronger effect on mortality
but that subthreshold depression (SUBD) also has a unique and significant
effect on mortality in men.
These findings have led to a debate in the literature, with critics
suggesting that current criteria for affective disorders are less appropriate
for older than for younger adults.30-31
A test would involve systematically comparing the prognosis of depressive
states that do and do not fulfill rigorous DSM diagnostic
criteria in a prospective community-based study. The available follow-up studies
have not been able to do this, leaving a systematic comparison of the prognosis
of depression in later life, measured at different levels of caseness unstudied.
In the present community-based study, the natural history of depression
was assessed during a long interval (6 years), using 14 observations and standardized
screening and diagnostic instruments. At 3 points (baseline, 3 years, and
the end point), diagnostic interviews were administered, allowing a detailed
assessment of the prognosis of DSM disorders (MDD
and dysthymic disorder [DYSTHD]) and less well-defined depressive states (SUBD).
The primary aims of the study were to describe the natural history of late-life
depression in the community, systematically comparing the prognosis in those
who did and did not fulfill rigorous diagnostic criteria for affective disorders.
SUBJECTS AND METHODS
SUBJECTS AND PROCEDURES
The Longitudinal Aging Study Amsterdam is a 10-year prospective study
of the well-being and functioning of older people in the Netherlands.32 Sampling, response, and procedures have been detailed
elsewhere.4-5,33-35
A large (n = 3056) representative sample of community elderly persons (aged
55-85 years) was interviewed at baseline in 1992 or 1993. The sample was stratified
for age, sex, and level of urbanicity. At baseline, depression was assessed
both in terms of symptoms and at the diagnostic level. The follow-up consisted
of frequent (5-month) postal questionnaires and infrequent (3-year) home interviews
(Table 1).35-36
This procedure resulted in a maximum of 14 observations, including 3 diagnostic
assessments (at baseline, after 3 years, and after 6 years), covering 6 years.
Informed consent was obtained before the study, in accordance with legal requirements
in the Netherlands.
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Table 1. Response to Follow-up of a Community-Based Cohort of Depressed
Elderly Subjects: 14 Observations Covering 6 Years
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Eligible for inclusion in the depressed cohort were all subjects scoring
above the cutoff on the screener (Center for Epidemiological Studies Depression
Scale [CES-D] score of  16 points) at baseline (n = 448).33
However, inclusion was only deemed appropriate when a complete diagnostic
interview was available at baseline and when a minimum of 2 follow-up observations
was available. This reduced the sample to 277 depressed subjects (62% of the
original 448 depressed subjects). The mean number of valid observations was
9.81 (SD, 3.92). Data on the response per observation are summarized in Table 1. Most of the analyses were limited
to the depressed cohort. However, for some analyses, data from a similarly
studied nondepressed cohort were used as the control.35
This cohort was defined as a random sample of those scoring below the threshold
on the CES-D at baseline, which was similarly approached for diagnostic interviews
and thereafter similarly followed up for 3 years.
MEASURES
Depression was measured using a self-report rating scale (CES-D) and
a diagnostic instrument (Diagnostic Interview Schedule).37-38
The CES-D is a 20-item scale, developed to measure depressive symptoms in
the community. It has been widely used in older community samples and has
good psychometric properties in this age group.39-40
The Dutch translation had similar psychometric properties in 3 previously
studied elderly samples.41 Because of the emphasis
on affective items in the scale, the overlap with symptoms of physical illness
is minimal.42-43 The total score
on the CES-D ranges between 0 and 60. To identify those with clinically relevant
levels of symptoms, the generally used cutoff score of 16 or more was used.41-42 Using this score, the criterion validity
of the CES-D for MDD was excellent (sensitivity, 100%; and specificity, 88%).44 As described, the data were partly gathered in face-to-face
interviews and partly using postal questionnaires. Previous analyses36 demonstrated that there was a mode effect: the scores
derived from the postal questionnaires were systematically higher than those
from the interviews. Because postal questionnaires and interviews alternated,
it was possible to quantify the mode effect and make an appropriate adjustment,
using a generalized T-score transformation.35-36,45-46
To diagnose MDD and DYSTHD, the Diagnostic Interview Schedule was used. Those
with both MDD and DYSTHD were categorized separately as having double depression.
The Diagnostic Interview Schedule was designed for epidemiological research
and has been widely used among elderly persons. Interviewers were fully trained
by certified staff, using the official Dutch translation of the Diagnostic
Interview Schedule.47 For the present article,
the prognosis of MDD and DYSTHD will be systematically compared with that
of SUBD. Subthreshold depression was defined as a clinically significant level
of depressive symptoms (CES-D score of 16), but the subject did not fulfill
the diagnostic criteria for either MDD or DYSTHD.
The course of depression was described by symptom severity, symptom
duration, and clinical course type. Symptom severity was defined as the average
CES-D score over all observations over time. At the start of the study, it
was hoped that it would be possible to estimate the average duration of depressive
episodes. However, clearly delineated episodes were rare, most exhibiting
either a chronic or a fluctuating course of symptoms. Therefore, the percentage
of observations in which the subjects reported elevated symptom levels (CES-D
score of 16) was used to estimate the proportion of time they were depressed.
This was used as the measure of symptom duration. Clinically meaningful interpretation
of the data is enhanced when the observations within subjects are collapsed
into clinical types of course of depression. The course types distinguished
were remission, remission with recurrence, a chronic–intermittent course,
and a chronic course. A remission was defined as a combination of (1) a relevant
(described later) decline of symptoms and (2) the subject remaining nondepressed
(CES-D score of <16 and no DSM affective disorder
diagnosis) throughout the rest of the study. A remission with recurrence was
defined as a remission in which the subject had a relevant increase of symptoms
later on in the study. A chronic–intermittent course type was defined
as more than 1 remission, followed by a recurrence of symptoms. A chronic
course was defined as 80% or more depressed observations.
For the classification of course types, criteria to define a relevant
change had to be defined; these criteria had to be statistically sound and
clinically relevant. To prevent random fluctuation from having undue influence
on the results, a statistically relevant change was defined, taking into account
the reliability and the average score and SD of the CES-D in this cohort.48 The criterion for a reliable change thus calculated
was 3.4. To be clinically relevant, a change of 5 points would qualify as
a middle to large effect size in the literature on power analysis.36, 49 Therefore, a change of 5 CES-D points
was chosen as the criterion for a relevant change. This had the added advantage
that it is similar to what earlier studies21-22,50
using the CES-D have used as the criterion for a relevant change. For defining
course types, a further criterion was that the cutoff of symptoms that is
generally regarded to be clinically meaningful was crossed. Therefore, the
criterion for a relevant change was that, between measurements, the change
was 5 points or more, thereby crossing the cutoff of 16.
Variables used in subgroup analyses of baseline predictors of the course
of depression were age, sex, chronic physical illness (0 vs 1),51 functional impairment (0 vs 1),52
cognitive impairment (Mini-Mental State Examination score of <24),53 and the size of the network.54
STATISTICAL ANALYSES
When comparing the average severity and duration of symptoms across
diagnostic and course types, and in subgroup analyses of prognostic factors,
an analysis of variance,  2 statistics, and Spearman rank correlations
were calculated. In the analyses of factors predicting attrition of subjects,
bivariate (2 statistics, analysis of variance, and relative
risk estimates) and multivariate (logistic regression) analyses were used.
Effects of missing observations within participants were studied using correlations,
analysis of variance, Friedman rank tests, and Cochran statistics. In all
analyses, conventional criteria for statistical significance ( <.05)
and 2-tailed tests were used.
RESULTS
CHARACTERISTICS OF THE SAMPLE
Two types of attrition will be described: loss of subjects and loss
of observations within participating subjects. In bivariate analyses, the
characteristics of the 277 participants (Table 2) were compared with those of the 171 depressed subjects
who dropped out. For baseline depression level, the participants' average
CES-D score and the score of the dropouts did not differ significantly (22.6
vs 23.5) (F1,446 = 1.67, P = .20). There
were also no differences for sex (21 = 0.94, P = .33), marital status (21
= 1.98, P = .16), living in Amsterdam (21 = 0.47, P = .50), or chronic
physical illness (21 = 3.21, P = .07). Attrition was predicted by age (F1,446 = 9.08, P = .003), lower level of education (21 = 5.82, P = .02), living in an institution
(22 = 15.63, P<.001),
cognitive impairment (21 = 18.31, P<.001), and functional limitation (21
= 7.61, P = .006). In multivariate analyses (logistic
regression), only living in an institution ( , .89; SE, .39; P = .01) and cognitive impairment (, .77; SE, .27; P = .004) remained as unique predictors of attrition. Looking into
mortality, the percentage deceased on January 1, 2000, was 28% among participants
and 53% among those who dropped out (relative risk, 2.90; 95% confidence interval,
1.95-4.32). This illustrates that death and frailty were important reasons
for not being able to contribute to the study.
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Table 2. Baseline Characteristics of the 277 Study Subjects
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Looking at loss of observations within participants, 3 analyses were
performed. There was no correlation between the number of observations and
the baseline depression level (r = -0.05, P = .49). For the average level of depressive symptoms
over 6 years (r = -0.22, P<.001) and the time depressed (r = -0.26, P<.001), there was a clear association, indicating that
those with more persistent or more severe depression were more likely to miss
observations. For the course types, the average number of valid observations
was similar for those who experienced remission (8.84 observations), remission
plus recurrence (8.32 observations), and a chronic course (8.58 observations).
Those with a chronic–intermittent course type had more valid observations
(12.29 observations) (F3,273 = 21.99, P<.001).
At baseline, the average age of the participants was 71.8 years (SD,
8.8 years). Table 1 shows that
the average CES-D scores decreased considerably between the baseline interview
and the first follow-up (mean difference, 5.30; t204 = 7.87 [paired t test]; P<.001). After that, the average scores stabilized. Because this
may be confounded by attrition during follow-up, several tests were performed.
In those participating in all waves of the first 3 years of follow-up (n =
118), average scores were stable (Friedman rank test 25 = 4.48, P = .48). In those participating
in all 13 follow-up measures after baseline (n = 76), there was a small decline
(Friedman rank test 212 = 41.6, P<.001). Considering the diagnostic assessment in those with valid
measures at all 3 measurements (n = 97), the percentages with MDD (Cochran Q2 = 3.58, P = .17)
and DYSTHD (Cochran Q2 = 0.36, P = .84) were stable.
THE PROGNOSIS OF DEPRESSION: DEPRESSIVE SYMPTOMS
The average CES-D score of all respondents, averaged over all available
assessments during the 6-year follow-up period, was 17.28 (SD, 6.61). Compared
with the distribution in the whole Longitudinal Aging Study Amsterdam sample
at baseline, a score of 17.28 ranks within the top 15%.33
For the duration of symptoms, only 14% were depressed less than 20% of the
time, while 46% were depressed more than 60% of the time. For clinical course
types, there were only 23% remissions; 12% had a remission with recurrence,
32% had a chronic–intermittent course, and 32% had a chronic course
(percentages do not total 100 because of rounding). Statistical comparison
of the 4 course types revealed highly significant differences for average
symptom severity over time (F3,273 = 153.0, P<.001) and symptom duration (F3,273 = 244.0, P<.001). Regarding the potential biasing effects of loss of observations,
analyses were performed again in those with complete observations during the
first 3 years (n = 118) and in those with all 14 observations (n = 76). The
percentages who experienced stable remission and chronicity declined somewhat
when subjects with more available observations were selected, while the percentage
with a chronic–intermittent course type increased. Within course types,
the average level of symptoms and the average percentage time depressed were
unaffected by the completeness of the data.
In subgroup analyses of potential predictors of symptom severity, symptom
duration, and course types, there were no sex differences. Comparing 3 age
groups, the older old (75-85 years at baseline) had a higher average symptom
severity (F2,274 = 3.20, P = .04) and
duration of symptoms (F2,274 = 6.23, P
= .002), but there was no significant difference in course types (26 = 8.51, P = .20). Those with
cognitive impairment did not have a higher average symptom severity (F1,272 = 2.92, P = .09), but did have a longer
duration of symptoms (F1,272 = 4.68, P
= .03) and were more likely to have a chronic course type (23 = 9.25, P = .03). Functional limitation was
the strongest predictor for the severity (F1,270 = 7.07, P = .008) and duration (F1,270 = 9.19, P = .003) of symptoms and for a chronic course type (23 = 12.97, P = .005). In those
without functional limitations, only 26% had a chronic course type, which
compares with 74% in those with functional limitations. Chronic physical illness
did not predict the outcome. Those with smaller networks had more severe (r = 0.20, P = .002) and persistent
(r = 0.02, P = .02) symptoms
and were more likely to have a chronic course type (F3,252 = 2.65, P = .05).
DIAGNOSES
Comparing the severity and duration of symptoms across diagnostic subgroups,
there was a gradient, in which those with SUBD had the lowest severity and
duration of symptoms, while those with double depression had the highest severity
of symptoms and were the most likely to have a chronic course type (Table 3). Statistical testing confirmed
this for the associations between diagnosis and symptom severity (F3,273 = 19.40, P<.001) and duration (F3,273 = 10.15, P<.001). The percentage of remissions
was highest in those with SUBD and MDD, lower in those with DYSTHD, and even
lower in those with double depression. The percentage with an unfavorable
but fluctuating course (remission and recurrence plus chronic-intermittent
course) was highest in those with SUBD (49%), decreasing from 44% in those
with MDD to 36% in those with DYSTHD and to 19% in those with double depression.
A severe chronic course was least prevalent among those with SUBD (25%), increasing
in those with MDD (35%) and DYSTHD (52%), to 77% among those with double depression.
Statistical testing confirmed the statistical significance of the association
between diagnosis and course type (29 = 31.52, P<.001). Regarding potential bias due to loss of observations,
all analyses were performed again in those with complete observations during
the first 3 years (n = 118) and in those with all 14 observations (n = 76).
Selecting subjects with more available observations had little effect (results
not shown).
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Table 3. Clinical Diagnosis at Baseline, by CES-D Scores Over 6 Years,
Depression Scores, and Course Type, for the 277 Subjects*
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Considering the stability and change of the diagnoses across the 3 diagnostic
assessments, those with SUBD at baseline were the most likely to be well at
3 and 6 years (46% and 48%, respectively). For those with SUBD at baseline,
the risk of developing either one of the DSM diagnoses
was 18% at 3 years and 16% at 6 years. This compares with 31% and 40% for
those with MDD, 60% and 69% for those with DYSTHD, and 73% and 67% for those
with double depression at baseline, respectively.
SUBTHRESHOLD DEPRESSION
A final set of analyses was performed to compare the prognosis of those
with SUBD with the prognosis of a random sample of those not depressed at
baseline. During the first 3 years of follow-up, the average CES-D score in
the cohort with SUBD was 17.39, while the score of the nondepressed cohort
was 6.91 (F1,577 = 546.4, P<.001).
The percentage time depressed among those with SUBD was 61.8%, which compares
with 8.1% in the nondepressed group (F1,577 = 40.97, P<.001). Of those not depressed at baseline, 5% were diagnosed as
having either MDD or DYSTHD at the 3-year follow-up, which increased to 12%
at the 6-year follow-up. In those with SUBD, the corresponding figure was
27% at 3 and at 6 years. Therefore, those with SUBD were clearly at risk of
developing DSM affective disorders.
COMMENT
The overall conclusion of the study must be that the prognosis of late-life
depression in the community is poor. The average level of symptoms remained
clearly elevated throughout the study. Almost half the sample was depressed
more than 60% of the time. Considering clinical course types, 23% had true
remissions, 12% had remissions with recurrence, 32% had a chronic-intermittent
course, and 32% had chronic depression (percentages do not total 100 because
of rounding). These findings suggest that the prognosis is even more serious
than previous studies among elderly persons in the community have reported.
The difference is caused by the fact that this is the first study, to our
knowledge, combining frequently repeated measurements over a long period,
within a rigorous epidemiological design. If only 2 interviews had been available,
with a 3-year interval (wave 1 and wave 8 in Table 1), the result would have been that 51% of those depressed
at baseline had remitted. This would have resulted in a far more optimistic
outcome, similar to previous studies13 among
older people with a 2-wave design. Compared with findings among younger adults,
our conclusion is similar in that most subjects experienced prolonged fluctuating
symptoms.15 However, in the National Institute
of Mental Health–Collaborative Depression Studies,15
subjects with MDD were symptom free or had returned to their usual selves
41% of the time during 12 years of follow-up. Although the methods of the
present study were different, it does seem that the prognosis was worse. Within
the present study, modest effects were found for age and age-related prognostic
factors, which supports the idea that the outcome is worse in later life.
Comparing the prognosis across levels of caseness, a clear gradient
was found. Those with SUBD experienced the least level of symptoms, followed
by those with MDD, DYSTHD, and, finally, double depression. Comparing average
symptom levels cross-sectionally, MDD and DYSTHD were similar. Over time,
the average level of (CES-D) symptoms was higher in those with DYSTHD than
in those with MDD. This is due to the longer duration of symptoms in persons
with DYSTHD. The category of double depression carried a grave prognosis in
all analyses. There were few remissions, while the average level of symptoms
was extremely high. Although all the indexes of prognosis used occurred on
a continuum of severity, the DSM categories clearly
predicted the severity and duration of symptoms. However, the evidence also
supports critics who have argued that DSM identifies
too narrow a range of clinically relevant depressive syndromes in older people.28-31 Those
with SUBD at baseline were much closer to those with DSM disorders in their outcomes than to a similarly followed up group
of nondepressed elderly persons. Moreover, as in younger adults, they were
clearly at risk of developing DSM affective disorders.55 Therefore, the term minor depression, often used to denote this heterogeneous group of affective states,
is probably a misnomer. This conclusion is supported by previous studies2, 4, 29 of the consequences
of minor and major depression, suggesting that the consequences of so-called
minor depression are serious and comparable to the consequences of MDD in
many areas.
The strong points of the study are that it was a prospective follow-up
of a large community-based sample of elderly depressed subjects, in whom depression
was measured using symptom rating scales and established diagnostic instruments.
Moreover, to our knowledge, in no previous community study have so many observations,
covering so long a period, been made available. A limitation of the community
setting is that treatment could not be controlled or monitored in any detail.
At baseline, 19% of those with MDD and 3% of those with SUBD were using antidepressants;
10% (MDD) and 3% (SUBD) had been referred to community mental health centers,
and 15% (MDD) and 3% (SUBD) had consulted a psychiatrist in the 6 months preceding
the interview.4 These data were not used as
predictors of outcome, because the level of treatment was low; no data on
compliance, intensity, or duration of treatment were available; and interventions
were not assigned in a way compatible with an adequate study of their effects.
Moreover, assuming that treatment is not harmful in most cases, the effect
of disregarding treatment would be that severity and chronicity are, if anything,
underestimated. A second limitation of the study is that there was considerable
attrition at all stages of the study. Because loss of depressed subjects and
loss of observations within subjects may have influenced the findings, both
were studied. For loss of subjects, the level of depressive symptoms at baseline
did not predict attrition. However, those who were older and more functionally
impaired were at a higher risk of attrition. This is similar to earlier analyses
of nonresponse, in which invariably the oldest and most frail subjects were
at highest risk of dropping out of the study.5, 33-35
Looking at loss of observations within participants, there was no association
with baseline level of depression. However, during the study, those with more
severe and more persistent depression were more likely to miss observations.
Another way to examine potential effects of attrition is through subgroup
analyses of subjects at risk for a poor prognosis. The data suggest that the
most frail elderly persons (the older old, those with cognitive impairment
and functional limitations, and those with the smallest contact networks)
had the poorest outcome. Therefore, although loss of data limits somewhat
the generalizability of the findings, the results of the analyses pertaining
to attrition suggest that, if anything, the true prognosis of late-life depression
is underestimated. A third limitation is that the criterion for remission
may be too liberal, leaving some subjects so classified with residual symptoms.
The advantage of the criteria used is that they enhance comparability with
previous studies21-22,50
and that effects of random change are eliminated. The effect of misclassification
would again be that the data underestimate the true severity of the prognosis
of late-life depression.
The implications of the study are that the burden of depression for
elderly persons in the community is even more severe than previously thought. DSM affective disorders are relatively rare among elderly
persons, but do represent the group with the worst prognosis. Subthreshold
depression, which is by far the larger group, is serious and chronic in many
cases. The data clearly demonstrate the need for interventions that are helpful,
acceptable, and economically feasible to be performed on a larger scale. Especially
in the area of nonmajor depression, designing and testing such interventions
should have a high priority.
AUTHOR INFORMATION
Submitted for publication January 10, 2001; final revision received
September 7, 2001; accepted October 1, 2001.
This study included data that were collected in the context of the Longitudinal
Aging Study Amsterdam, which is financed primarily by the Netherlands Ministry
of Welfare, Health, and Sports.
Corresponding author: Aartjan T. F. Beekman, MD, PhD, Department
of Psychiatry, Vrije Universiteit, Valerius Clinic, Valeriusplein 9, 1075
BG, Amsterdam, the Netherlands (e-mail: aartjanb{at}ggzba.nl).
From the Department of Psychiatry and the Institute of Extramural Medicine
(Drs Beekman, Deeg, Schoevers, de Beurs, Braam, Penninx, and van Tilburg and
Ms Geerlings) and the Department of Sociology and Social Gerontology (Drs
Deeg and Smit), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands;
and the Sticht Center on Aging, Wake Forest University School of Medicine,
Winston-Salem, NC (Dr Penninx).
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