Department of Psychiatry,College of Medicine, Chosun University, Kwangju, Korea
Section of Epidemiology, Institute of Psychiatry, London
Department of Psychiatry & Research Institute of Medical Science, Chonnam National University Medical School, Kwangju, Korea
Department of Psychiatry & Research Institute of Medical Science, Chonnam National University Medical School, Kwangju, Korea
Correspondence: Professor Jin-Sang Yoon, Department of Psychiatry, Chonnam University Medical School, 5 Hak-dong, Dong-Ku, Kwangju, 501-757, Republic of Korea. Tel: +82 62 220 6142; Fax: +82 62 225 2351; e-mail: jsyoon{at}chonnam.ac.kr
Declaration of interest Funded by the Ministry of Health and Welfare of Korea and Janssen Korea Limited.
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ABSTRACT |
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Aims To investigate the association between measures of vascular disease/risk and depression and confounding and effect modification by APOE genotype and cognitive function.
Method In a Korean community population aged 65+ (n=732), diagnosis of depression (Geriatric Mental State Schedule) and information on vascular status, disability, APOE genotype and cognitive function were obtained.
Results Previous stroke and lower high-densitylipoprotein cholesterol level (but neither hypertension nor diabetes) were significantly associated with depression (independently of disability and cognitive function). These associations were stronger in participants with borderline cognitive impairment, although not to a significant extent.
Conclusions Except for previous stroke and an atherogenic lipid profile, associations between depression and other common risk factors for cerebrovascular disease were not evident.
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INTRODUCTION |
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METHOD |
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Study population
Potential participants for this study were recruited from all inhabitants
aged 65 years or over recorded in national residents registration lists within
two areas (one urban, one rural) of Kwangju, South Korea, in 2001. The study
was approved by Chonnam National University Hospital Review Board. After
sending a letter explaining the purpose of the study to all eligible older
people, written informed consent was obtained from all participants.
Assessment procedures and measures
This study was conducted in two phases. Sixteen graduate-level research
assistants, trained and supervised by the project psychiatrist, carried out
home-based interviews with participants and their family members. This
included a fully structured diagnostic interview for depression, information
on vascular risk/disease and data on demographic characteristics, disability
and cognitive function. At a second interview (attempted in all participants),
further examination for vascular risk/disease and blood tests for APOE
genotype were administered by two expert teams consisting of a psychiatrist, a
senior nurse and a psychologist. At both stages, home visits were repeated on
at least two occasions if no contact was made. The mean (s.d.) interval
between the two interviews was 9 (5.4) days.
Depression
A community version of the Geriatric Mental State Schedule was used (GMS
B3; Copeland et al,
1986). This is a fully structured diagnostic interview designed
for administration by lay personnel that has been widely used and validated in
international settings (Copeland et
al, 1991). Procedures for its Korean translation and
validation have been described elsewhere
(Kim et al,
2003b). Case-level depression was defined using the
Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT)
algorithm, using standard (3+) cut-points for diagnostic confidence. This
computer algorithm has been designed to elicit the presence of depression of
clinical significance, incorporating both moderate and severe syndromes. The
AGECAT algorithm gives Stage 1 (non-hierarchical) and Stage 2 (hierarchical)
diagnoses of mental disorder. For the purposes of this analysis, depression
was classified using the Stage 1 output because we wished to include cognitive
function in the explanatory model and investigate rather than exclude
comorbidity.
Information on vascular risk/disease
Self-reported diagnoses of and treatment histories for stroke, heart
disease, hypertension and diabetes were recorded at the first phase of
interviews. For stroke, it was coded only if there was clear history of sudden
onset of unilateral paralysis and/or loss of speech and/or blindness lasting
for at least 2 days. Smoking history was ascertained.
Examinations for vascular risk/disease
Examinations were carried out at a second phase of interviews. Resting
blood pressure was taken with an automatic sphygmo-manometer on the left arm
in the sitting position. The lower of two consecutive readings was used.
Atherosclerotic vascular disease is associated with raised total cholesterol
and, in particular, with a profile of raised low-density lipoprotein (LDL)
cholesterol and low high-density lipoprotein (HDL) cholesterol. Blood tests
therefore were assayed for total, LDL and HDL cholesterol as well as glucose,
triglycerides and APOE genotype. Participants were instructed to be fasting,
and blood sampling was performed during the mornings when possible. Height,
weight, waist and hip were measured.
Other potential risk factors for depression
Demographic data on age, gender and education were recorded. Participants
were asked about any previous episodes of depression prior to age 60 years.
Disability was assessed using the Korean version of the World Health
Organization Disability Assessment Schedule II (WHODAS II), which has been
validated for assessing disability in old people and recommended for
international use (Epping-Jordan et
al, 2002). Cognitive function was evaluated using the Korean
version of the Mini-Mental State Examination (MMSE-K;
Park & Kwon, 1990), which
has been developed specifically for use in older Korean populations, with
revised items taking into account low educational attainment and high rates of
illiteracy. Standard cut-offs have been recommended for this measure
(Park et al, 1991),
with scores of 21-24 (out of 30) representing borderline cognitive function
and 20 or below representing significant impairment. All these measures were
taken at the first stage of interviews.
Statistical analysis
Vascular risk factors and the presence of clinical vascular disease were
compared according to case-level depression in all participants at the first
interview. All subsequent analyses were restricted to those who completed the
two interviews and the blood tests. Potential associations between vascular
risk/disease and depression (P<0.1 in univariate analysis) were
analysed further using stepwise logistic or linear regression models to
investigate confounding by demographic characteristics and mediation by
disability (WHODAS II) and cognitive function (MMSE-K). Secondary analyses
were carried out to investigate effect modification by cognitive function,
using recommended cut-offs for the MMSE-K
(Park et al, 1991)
for stratified analyses, and likelihood ratio tests for interaction terms
within regression models. As a final procedure, analyses were repeated by
excluding participants who reported any episode of depression occurring before
age 60 years.
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RESULTS |
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Of the participants in the first interview, 732 (61%) participated in the second, more-intensive examination. Of non-participants at this stage, contact could not be established with 321 (27%), 92 refused (8%), 4 had died in the interval (<1%) and data were missing for 55 (5%). The principal apparent reason for attrition was that contact could not be established because the person was repeatedly away from home at the time of research visits. Participants at both interviews were less educated than those present at the first interview only (mean (s.d.) years of education were 3.4 (4.2) and 4.0 (4.4), respectively; P=0.035) and had lower cognitive function (mean (s.d.) scores on the MMSE-K were 23.3 (5.0) and 24.3 (5.1), respectively; P=0.002). However, no significant differences were observed between the participants and non-participants in terms of age (mean ages of 72.8 and 72.2, respectively), gender (59% and 57% female), disability (mean WHODAS II scores of 7.1 and 5.9) and GMS depression (14% and 13%). There were also no substantial differences in associations between vascular risk factors (ascertained at the first phase) and depression between all participants of the first phase and the subgroup who were present at the second phase. For example, the odds ratios (95% CI) for the associations between depression and stroke, hypertension and diabetes were 4.57 (2.74-7.62), 1.32 (0.93-1.88) and 1.35 (0.82-2.23), respectively, for all participants in the first phase (n=1204) and 3.68 (1.99-6.79), 1.48 (0.97-2.27) and 1.67 (0.94-2.99) in those present at the second phase (n=732). Further analyses therefore were restricted to the subgroup present at both interviews.
Univariate associations with depression
Depression was present in 101 (14%) of the 732 participants at the second
interview. Univariate associations between depression and vascular
disease/risk are summarised in Table
1. Depression was associated significantly with reported stroke
and heart disease in the sample at both interviews. Depression was associated
positively with reported hypertension and diabetes, with associations
bordering on statistical significance. Depression was associated significantly
with a lower level of HDL cholesterol and a higher level of LDL
cholesterol.
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With respect to other independent variables, depression was associated significantly with female gender (odds ratio (OR)=2.02; 95% CI 1.28-3.30), a greater number of physical illnesses (OR per illness reported=1.39; 95% CI 1.22-1.58) and lower scores on the MMSE-K (OR per single point decrease=1.05; 95% CI 1.01-1.09). Associations with increased age (OR per year increase=1.03; 95% CI 0.99-1.07) and lower education (OR per year decrease=1.03; 95% CI 0.99-1.08) were of borderline significance.
Univariate associations with APOE genotype
The APOE genotype frequencies were as follows: e2/2, 1.5%; e2/3, 9%; e2/4,
1%; e3/3, 71%; e3/4, 16%; e4/4, 1.5%. The APOE e4 allele was present in 132
participants (18%). Previous stroke was reported more frequently in
participants with the e4 allele (11% v. 6%, P=0.067) and
mean body mass index levels were significantly lower in those with e4 than in
those without (mean (s.d.) 22.1 (3.6) and 22.8 (3.5) kg/m2,
respectively; P=0.041). There were no significant associations
between presence of the e4 allele and any of the other factors measured
(vascular risk/disease, depression, disability and cognitive function). The
APOE e4 allele was associated overall with a more atherogenic lipid profile,
but differences were not significant (P>0.1). Mean (s.d.) levels
of cholesterol were 180 (39) mg/dl in those with the e4 allele and 175 (34)
mg/dl in those without this allele. Respective levels (mg/dl) were: HDL
cholesterol, 47 (14) and 48 (14); LDL cholesterol, 100 (34) and 97;
triglycerides, 162 (105) and 150 (81).
Multivariate analysis of depression and vascular disease/risk factors
Results of regression analyses are summarised in
Table 2. All associations
between depression and vascular disease/risk were weakened by the inclusion of
confounding variables, particularly level of disability. The positive
associations with stroke and a lower level of HDL cholesterol remained
significant, whereas those with other vascular factors were substantially
diminished both in strength and significance. Further adjustment for the APOE
e4 allele made no substantial difference. The odds ratio (95% CI) for the
association between depression and previous stroke was 2.73 (1.37-5.59) in
Model 3 (see Table 2) after
further adjustment for the e4 allele. The B values for the
association between depression and HDL/LDL cholesterol levels were -4.17
(-7.34 to -1.01) and 5.10 (-1.93 to 12.14) in Model 3 after further adjustment
for e4.
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Stratification by APOE and MMSE-K (Table 3)
Associations between depression, stroke and lower HDL cholesterol were
stronger in the presence of the e4 allele. However, interaction terms did not
approach statistical significance (data not shown; P values for
interaction terms >0.1). Associations between depression and vascular risk
factors also were generally stronger in groups with borderline cognitive
impairment (MMSE-K, 21-24), although again no individual interaction terms
approached significance (Table
3; P values for interaction terms >0.1).
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Restriction by previous history of depression
Of the 732 participants at the second interview, a previous history of
depression prior to age 60 years was reported by 16 (16%) of the 101 with
current depression and by 17 (3%) of the 631 without current depression. No
marked or consistent differences were found in the results when the above
analyses were repeated in those without a past history of depression (data not
shown).
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DISCUSCUSSION |
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Methodological issues
Previous community studies investigating these research questions have been
limited by the use of brief screening instruments to define depression
(Stewart et al, 2001)
or have focused on specific sub-populations
(Kim et al, 2002). A
strength of this study was that depression was ascertained using a diagnostic
instrument that has been validated widely in a variety of international
settings. In terms of sample representativeness, government registration lists
represent a highly inclusive sampling frame for epidemiological research in
South Korea because an accurate entry is required for many daily needs,
including pension provision. The two-phase recruitment procedure potentially
reduced the representativeness of the participants compared with the source
population because of attrition between interviews, giving an overall response
rate of <50%. In retrospect, a single-stage procedure would have been
preferable. However, we feel that it is unlikely that the observed
associations are explained by selection bias because neither vascular risk
factor nor depression was associated with attrition. As well as this, the
strength of association between the first-phase measures of vascular risk and
depression were similar between the total sample and the analysed subgroup. It
is therefore likely (although cannot be concluded definitely) that
associations with factors measured at the second phase can be generalised to
the source population.
The study was cross-sectional in design, which limits the extent to which cause and effect relationships can be clarified. It also raises the issue of information bias, although we feel that this is unlikely because the risk factors at the first phase were ascertained before the diagnostic interview for depression was administered and, furthermore, the data at the second phase were collected by a professional who did not have knowledge of the GMS findings. Information on vascular risk factors such as hypertension and diabetes relied on self-reported diagnoses and so corroboration by medical records was not feasible. There are certain other limitations in inference that should be considered: most case participants will have had moderate levels of depression rather than the more severe forms that have been the focus for research in clinical samples; previous episodes of depression were ascertained by self-report, which is likely to have limited validity and the final restricted sample may not have had a truly late-onset disorder; and differential rates of institutionalisation and mortality might conceivably have obscured the association between vascular risk and depression in this cross-sectional community study. Institutions were not sampled in this survey because there were none within the sampling areas. However, in Korea, provision of institutional care is limited and care at home is preferred by residents and their families, even in severe dementia. Mortality is therefore more likely to be a source of prevalence bias than institutionalisation.
Stroke and depression
Depression occurs frequently following stroke, and the association between
previous stroke and depression observed in this sample has been reported in a
similar Korean sample with cognitive impairment
(Kim et al, 2002) and
in other community studies (Fuh et
al, 1997; Stewart et
al, 2001). The association was reduced following adjustment
for level of disability, but only partially so. This is consistent with
findings in other populations (Stewart
et al, 2001) and suggests that other mediating pathways
may be present, which may include the direct effect of an infarct on brain
structure or chemistry but might also include functional impairment specific
to stroke, or its psychological impact, which did not contribute to the
disability scale.
Cholesterol subfractions and depression
We found no association between total cholesterol levels and depression,
which was consistent with findings from some studies
(Brown et al, 1994;
McCallum et al, 1994;
Blazer et al, 2002),
although depression has been found to be associated with lower cholesterol
levels in others (Morgan et al,
1993; Partonen et al,
1999), including a prospective study
(Cervilla et al,
2000). One study of an elderly sample found depression to be
associated with lower levels of LDL cholesterol
(Äijänseppä et al,
2002). Another study of a younger sample (aged 31-65 years) found
an association with higher levels of HDL cholesterol
(Horsten et al,
1997). Our finding in the opposite direction might reflect racial
or age-related differences in the aetiology and/or salience of vascular risk
factors, but further research is required to clarify inconsistencies.
Vascular risk factors and depression
Depression in later life has been found to be associated with changes
suggestive of cerebrovascular disease, such as white matter hyperintensities
on neuroimaging (Steffens et al,
1999; de Groot et al,
2000). The vascular depression hypothesis also proposes a syndrome
where severe depression and vascular disease co-exist. In this analysis, we
did not set out to test the existence of such a syndrome, but to investigate
well-recognised risk factors for cerebrovascular disease as potential risk
factors for depression. If there is a vascular aetiology for depression in
late life, risk factors for cerebrovascular disease such as hypertension and
diabetes also may be important population-level risk factors for depression
because of high prevalence rates in many populations. However, there is
currently little evidence from community samples to suggest strong causal
relationships (Jones-Webb et al,
1996; Rajala et al,
1997; Stewart et al,
2001) and, where associations have been found, it is unclear
whether these are specific to disorders affecting the vasculature or whether
they are accounted for by well-recognised associations between depression and
general poor health and disability (Prince
et al, 1998). Hypertension and diabetes were associated
with increased likelihood of depression in our study at borderline levels of
statistical significance. However, these associations were substantially
reduced in strength after adjustment for the WHODAS II score. This suggests
that the impact of these disorders on depression may be mediated through
associated general disability rather than specific vascular effects. However,
it should be borne in mind that adjustment by disability in a
cross-sectional study such as this one may obscure associations with any
potential risk factor for depression because depression and reported
disability are strongly interrelated.
The association with decreased HDL cholesterol therefore does suggest a more atherogenic lipid profile in people with late-life depression, but other conventional risk factors for stroke were not associated with depression. Interestingly, a pathological study found late-life depression to be associated with arterial atheroma rather than microvascular disease (Thomas et al, 2001). It is therefore possible that specific vascular pathways may underlie the disorder and there may be other vascular risk factors for depression (such as cerebral haemodynamics, blood pressure regulation and inflammatory processes) that were not investigated in this study. However, the direction of causality underlying cross-sectional associations is unclear because there is strong evidence from prospective research that depressive symptoms earlier in life are associated with increased risk of stroke (Jonas & Mussolino, 2000). Associations in later life may be the consequence of complex interrelationships between vascular risk and affective state over a long period (Stewart, 2002).
Interactions with cognitive impairment and APOE genotype
The association between vascular risk factors and depression might
conceivably be explained by well-recognised associations between vascular risk
factors and dementia, and between depression and later dementia
(Stewart, 2002). This would
predict stronger associations between depression and vascular risk factors in
people at risk of cognitive decline (e.g. those with the APOE e4 allele or
those with cognitive function that is already impaired). Recently, a study
found no interactions between APOE e4 allele and cholesterol level in
associations with depression in cross-sectional and longitudinal analyses in a
biracial elderly community sample (Blazer
et al, 2002). To our knowledge, there has been no study
to investigate effect modification by APOE genotype for other vascular risk
factors and late-life depression. However, we found no evidence of substantial
confounding or effect modification by APOE e4 allele for the association of
interest. All vascular risk factors were associated more strongly with
depression in the presence of borderline (compared with normal) cognitive
function (MMSE-K, 21-24). These findings provide partial support for our
hypothesis and suggest that there might be an interface between vascular
disease, depression and early dementia. However, individual interactions were
not demonstrable at conventional levels of statistical significance and
further research is required to address this question.
Public health implications
Our findings support others in showing associations between late-life
depression and clinical stroke, that were only partially explained by level of
disablement. However, we found little evidence for associations with other
vascular risk factors such as hypertension or diabetes. From a public health
perspective regarding the prevention of depression, these support a focus on
post-stroke populations and on reducing levels of general disability rather
than on specifically targeting groups with vascular risk factors. The
direction of causation for the association between depression and an
atherogenic lipid profile cannot be concluded. However, at the very least it
suggests that attention should be paid to cardiovascular risk profiles and the
prevention of adverse vascular outcomes in older adults with depression.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication September 25, 2003. Revision received February 12, 2004. Accepted for publication February 21, 2004.
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