Chapter 5
Does depression in old age increase cardiovascular mortality ?
Vinkers DJ, Stek ML, Gussekloo J, van der Mast RC, W estendorp RG.
Does depression in old age increase only cardiovascular mortality ? The Leiden 85-plus Study.
Int J Geriatr Psychiatry 2004; 19: 852-57.
Does depression in old age increase cardiovascular mortality ?
41
Abstract
Background Depression in old age is associated with an increased mortality risk of
cardiovascular disease but the mortality risk from non-cardiovascular causes is disputed.
Objective To investigate the effect of depression on cardiovascular and non-cardiovascular
mortality in old age.
M ethods We prospectively followed 500 subjects from age 85 years onwards within the
population-based Leiden 85-plus Study. Depressive symptoms were assessed annually with
the 15-item Geriatric Depression Scale (GDS-15). Mortality risks were estimated in a Cox
proportional-hazards model with the annual assessment of depression (GDS-15 4 points) as
a time-dependent covariate.
Results During 1654 person-years of follow-up (mean per person, 3.2 years), depression was
associated with a two-fold increase of all cause mortality (Relative Risk [RR], 1.83; 95 %
Confidence Interval [CI], 1.24 - 2.69) that was not explained by comorbid conditions. Both
cardiovascular mortality and non-cardiovascular mortality contributed equally to the excess
mortality (RR 1.95 and 1.75 respectively).
ConclusionDepression in old age contributes to an increase of both cardiovascular and non-
cardiovascular mortality. Motivational depletion may play an important role in the increased
mortality in elderly with depression.
Chapter 5
42
Introduction
The presence of depressive symptoms in the elderly is associated with increased mortality1 2
.
Relatively little is known about the etiological relationship between depression and mortality3.
Depression could influence mortality through various behavioural and biological mediators or
by accompanying medical illness and disability, which are related to increased mortality4 5 6 7
.
Population-based studies demonstrated an increased cardiovascular mortality in elderly
persons with depressive symptoms8 9 10 11 12
. These findings supported the view that excess
mortality in depression is due to cardiovascular mechanisms such as low heart rate variability,
elevated plasma catecholamines, hypothalamic-pituitary-adrenal (HPA) axis disturbances, and
platelet and immune activation13 14 15
. Other studies, however, showed that depressive
symptoms in community dwelling elderly increased not only cardiovascular mortality but also
non-cardiovascular mortality 16 17 18
.
Because it remains unclear by which means depression increases mortality in the elderly, we
studied the effect of depression on cardiovascular and non-cardiovascular mortality in the
Leiden 85-plus Study, a population-based prospective study of the oldest old.
Methods
Subjects
The Leiden 85-plus Study is a prospective population-based study of all 85-year old
inhabitants of Leiden, The Netherlands. The study and characteristics of the cohort were
described in detail previously19
. In short, between September 1997 and September 1999 all
members of the 1912 to 1914-birth cohort were asked to participate in the month after their
85th
birthday. There were no selection criteria for health or demographic characteristics. Of
the 705 eligible subjects, 14 died before they could be enrolled and 92 refused to participate.
In total, 599 subjects were enrolled (response 87%). All subjects gave informed consent. For
cognitively impaired subjects informed consent was obtained from a guardian. The Medical
Ethical Committee of the Leiden University Medical Center approved the study. Subjects
were visited annually at home for face-to-face interviews, collection of blood samples, and
recording of an electrocardiogram.
Depressive symptoms
Depressive symptoms were annually assessed with the 15-item Geriatric Depression Scale
(GDS-15), a questionnaire especially developed as a screening instrument for depression in
the elderly20
. Cognitive functioning was measured with the Mini Mental State Examination21
.
In order to obtain reliable results of the GDS-15 in the presence of impaired cognitive
function, the GDS-15 was administered only in those with a Mini-Mental State Examination
score above 18 points.
Depression was considered present when the GDS-15 score was at least 4 points, because this
cut-off point yielded the most efficient distribution of sensitivity and specificity in our
population22
. Depression was assumed to be present or absent during the year after the annual
assessment of the GDS-15.
Does depression in old age increase cardiovascular mortality ?
43
Mortality
All subjects were followed up for mortality until 1 September 2002. Survival time was
defined as the period from the 85th
birthday until 1 September 2002 (censoring date) or the
day of death as obtained from the civic registry. Shortly after the civic registry reported the
death of a subject, the treating physician (general practitioner or nursing home physician) was
interviewed to obtain the cause of death using a standardized questionnaire. Two senior
specialists of internal medicine, who were unaware of the presence of depression in the
participants, determined the causes of death by consensus according to the tenth version of the
International Classification of Diseases (ICD-10)23
. Causes of death were divided into two
groups: cardiovascular mortality (ICD-codes I00-I99, I20-I25 and I60-I69) and non-
cardiovascular mortality (all other ICD-codes). Cardiovascular mortality was defined as
myocardial infarction (I20-I25), stroke (I60-I69), and other cardiovascular causes (I00-I99).
Non-cardiovascular mortality was defined as infection (A00-B99), cancer (C00-D48), and
other non-cardiovascular causes (all other ICD-codes).
Possible confounders
All subjects’ treating physicians were interviewed annually to assess the presence of
cardiovascular disease. In addition, electrocardiograms of all subjects were recorded each year
on a Siemens Siccard 440 and transmitted by telephone to the ECG Core Lab in Glasgow for
automated Minnesota coding24
. As described earlier25
, subjects were classified as having
cardiovascular disease in case of a positive history of arterial surgery, stroke, intermittent
claudication, myocardial infarction or angina pectoris. Subjects with an ECG revealing
myocardial infarction or ischemia were also classified as having cardiovascular disease.
Socio-demographic characteristics and living arrangements were obtained for all subjects.
Level of education was dichotomised on a maximum of six years of schooling. Alcohol
consumption was considered high when more than two drinks were consumed daily. Smoking
history was classified as no smoking, smoking in the past and current smoking. The treating
physician of each participant was interviewed annually using structured questionnaires to
assess the presence of diabetes mellitus, chronic obstructive pulmonary disease (COPD),
arthritis, malignancy, dementia and Parkinson Disease. Moreover, we checked the
computerised pharmacy registries for the use of medication which are specific for the
presence of diabetes mellitus, COPD or Parkinson Disease. Diabetes mellitus was also
considered present in case of a glucose level of 11.0 mmol/L or higher in obtained blood
samples. Chronic diseases were defined as cardiovascular disease, diabetes mellitus, COPD,
arthritis, malignancy, dementia and Parkinson s̀ disease26
. Independency in daily living was
defined as being able to do all nine basic activities of daily living independently as measured
using the Groningen Activity Restriction Scale (GARS)27
.
Statistical Analysis
Cardiovascular and non-cardiovascular mortality were calculated per 1000 observed person-
years at risk for person years with depression and without depression separately.
Cardiovascular and non-cardiovascular mortality risks (RRs) and 95 % confidence intervals
(95% CIs) were estimated in a Cox proportional-hazards model using the annual categorical
assessment of depression as a time-dependent covariate. This model incorporates the course
of depression during follow-up. Adjustments were made for potential distorting variables,
including gender, smoking, alcohol consumption, and the cumulative number of chronic
diseases. Additionally, cardiovascular and non-cardiovascular mortality risks were analysed
in strata of subjects with and without cardiovascular disease at baseline.
Chapter 5
44
Results
From the 599 participants at baseline, all 500 subjects with a MMSE score of more than 18
points completed the GDS-15 at baseline (table 5.1). At baseline, 119 subjects (24 % of the
study sample) were depressed as measured by a GDS-15 score of at least 4 points.
During follow-up, 1654 person-years were observed (mean per person, 3.2 years), 424
person-years (26%) with depression (GDS-15 4 points) and 1230 person-years (74%)
without depression (GDS-15 3 points). In total, 116 subjects (23 % of the study sample)
died. The all cause mortality was 57 per 1000 person years without depression (70 events
during 1230 person-years at risk) and 108 per 1000 person-years with depression (46 events
during 424 person-years at risk). When depresssion was present, the all cause mortality risk
was twofold increased (RR 1.83, 95 % CI 1.24 - 2.69) after adjustment for gender, smoking,
alcohol consumption, and chronic disease.
To further explore whether the increased all cause mortality in depressed participants was due
to comorbid conditions, we repeated the analyses in healthy persons only. In subjects with a
baseline MMSE score of at least 24 points (n = 415), the all cause mortality was still
increased in depressed participants (RR 2.02, 95% CI 1.31 - 3.12), as it was in subjects who
were independent in their activities of daily living (n = 456; RR 1.69, 95% CI 1.09 - 2.62),
and in subjects without chronic diseases (n = 77; RR 9.96, 95% CI 1.02 - 98.99).
Table 5.1 Baseline demographic and clinical characteristics of the 85-year old participants of the
Leiden 85-plus Study with a MMSE score of more than 18 points (n = 500).
Men 184 (37 %)
Independent living 444 (89 %)
Widowed 277 (55 %)
Low level of education 303 (61 %)
High alcohol consumptiona 51 (10%)
Current smoker 82 (16 %)
Chronic disease presentb 423 (85 %)
Depression presentc 119 (24 %) a Alcohol consumption was considered high when more than 2 drinks per day were consumed. b Chronic diseases included cardiovascular disease, diabetes mellitus, COPD, arthritis, malignancy,
dementia and Parkinson`s disease. c Depression was considered present when GDS-15 score was 4 points or more.
Does depression in old age increase cardiovascular mortality ?
45
From the 116 deceased subjects, 46 subjects (40%) died from cardiovascular causes and 70
subjects (60%) from non-cardiovascular causes. Cardiovascular mortality consisted of 25
subjects (54 %) who died from myocardial infarction, 11 subjects (24 %) who died from
stroke, and 10 subjects (22 %) who died from other cardiovascular causes. Non-
cardiovascular mortality consisted of 16 subjects (23 %) who died from infection, 26 subjects
(37 %) who died from cancer, and 28 subjects (40 %) who died from other non-cardiovascular
causes. No deaths from suicide were reported. Figure 5.1 shows the cardiovascular and non-
cardiovascular mortality per 1000 person-years in subjects with and without depression,
illustrating an increase of both cardiovascular and non-cardiovascular mortality when
depression was present. Cardiovascular as well as non-cardiovascular mortality were
significantly 1.95-fold and 1.75-fold increased in participants with depression (Table 5.2).
Figure 5.1 Cardiovascular and non-cardiovascular mortality depending on the presence of depression.
Depression was measured annually and considered present when GDS-15 score was 4 points or more.
0
10
20
30
40
50
60
70
Cardiovascular Non-cardiovascular
Mortality
Events per1000 personyears
No depression
Depression
Chapter 5
46
Table 5.2 Cardiovascular and non-cardiovascular mortality risks dependent on depressiona.
Depressionb
Noc Yes
All cause mortality
Crude 1 2.07 (1.35 - 3.17)e
Adjustedd 1 1.83 (1.24 - 2.69)e
Cardiovascular mortality
Crude 1 2.10 (1.07 - 4.13)e
Adjustedd 1 1.95 (1.07 - 3.56)e
Non-cardiovascular mortality
Crude 1 2.05 (1.18 - 3.56)e
Adjustedd 1 1.75 (1.05 - 2.91)e
a Mortality risks were estimated with Cox proportional-hazards models with the annual assessment of
depression as a time-dependent covariate. b Depression was considered present when GDS-15 score was 4 points or more. c Reference category. d Adjusted for gender, smoking, alcohol consumption, and number of chronic diseases. e p < 0.05.
The relation between depression and mortality was also studied separately in subjects with
and without cardiovascular disease at baseline. In participants with cardiovascular disease at
baseline, the risk of cardiovascular mortality was 2.25-fold (95% CI 1.14 - 4.47) increased for
subjects with depression compared to those without depression (Table 5.3). On the other
hand, the risk of non-cardiovascular mortality was 3.17 times (95% 1.10 – 9.18) increased
among depressed subjects without a history of cardiovascular disease. The risk of non-
cardiovascular mortality remained increased when subjects (n=73) who developed
cardiovascular diseases during follow-up were excluded from this group (RR 2.63, 95% CI
0.79 – 8.77).
Table 5.3 Mortality risks dependent on depression stratified for the presence of cardiovascular
disease at baselinea.
Depressionb
Noc Yes
Cardiovascular disease at baseline (n=306)
All cause mortality 1 1.76 (1.13 - 2.75)d
Cardiovascular mortality 1 2.25 (1.14 - 4.47)d
Non-cardiovascular mortality 1 1.50 (0.83 - 2.71)
No cardiovascular disease at baseline (n=192)
All cause mortality 1 2.21 (0.98 - 4.97)
Cardiovascular mortality 1 1.34 (0.34 - 5.20)
Non-cardiovascular mortality 1 3.17 (1.10 - 9.18)d
a Mortality risks were estimated with Cox proportional-hazards models with the annual assessment of
depression as a time-dependent covariate, adjusted for gender, smoking, alcohol consumption, and
number of chronic diseases not including cardiovascular disease. Presence of cardiovascular disease
missing for two subjects. b Depression was considered present when GDS-15 score was 4 points or more. c Reference category. d p < 0.05.
Does depression in old age increase cardiovascular mortality ?
47
Conclusion
In the oldest old depression is associated with a two-fold increased all cause mortality. Both
cardiovascular mortality and non-cardiovascular mortality contribute equally to this excess of
mortality. Our finding that depression in the oldest old is associated with increased all cause
mortality is in line with the increased all cause mortality as described in depressed elderly of
younger age groups 1 2 28
. As earlier reported by other studies studies 8 9 10 11 12
, we also found
that depression was associated with an increased cardiovascular mortality. However, the non-
cardiovascular mortality in depressed elderly of the Leiden 85-plus Study was increased to the
same extent. Some other authors reported the same findings in younger elderly16 17 18
but this
has not yet been reported for older people. Thus, in the oldest old depression does increase the
all cause mortality, but not specifically the cardiovascular mortality.
The landmark study of Frasure-Smith et al in 1993 raised attention to the specifically
increased cardiovascular mortality in depressed patients who had suffered from myocardial
infarction29
. In line with their observations, we also found cardiovascular mortality to be more
pronounced in depressed subjects with a history of cardiovascular disease. However, in
subjects without a history of cardiovascular disease, we found a more pronounced increase of
non-cardiovascular mortality. The fact that Frasure-Smith et al studied only subjects with a
history of severe cardiovascular disease, and consequently mainly cardiovascular deaths, may
explain their conclusion that depression specifically increases cardiovascular mortality30 31
.
Within the Leiden 85-plus Study we performed repeated annual measurements of depressive
symptoms in a representative sample of community dwelling elderly subjects. Although the
GDS-15 was validated to screen for depression in the oldest old22
, the fact that depression
was not formally diagnosed could be seen as a limitation of this study. Nevertheless, it
becomes increasingly clear that both depressive symptoms and depressive disorders, pointed
out as minor and major depression respectively, have the same serious consequences in the
elderly32
. So, depression may better be interpreted as a continuum of depressive symptoms
than the mere presence or absence of a depressive disorder.
How does depression in old age increase mortality ? Within the Leiden 85-plus Study, we
found an increased mortality risk for depressed elderly even after adjustments for comorbid
conditions. In line, the mortality risks of depressed participants remained increased in
participants who were independent in activities of daily living, in participants with good
cognitive function, and in those without chronic diseases. These results demonstrate that the
excess of mortality is not only caused by co-morbidity and frailty, as was already mentioned
by other authors authors3 28
. Furthermore, antidepressive pharmacotherapy was almost
nonexistent in our population33
, which makes it unlikely that treatment effects of depression
increase mortality. Earlier, we found that the prognosis of depression in terms of mortality is
especially poor when accompanied by feelings of loneliness34
. Depressed subjects who
suffered from feelings of loneliness were at a 2.1 higher mortality risk, whereas depressed
subjects who did not suffer from feelings of loneliness were at 1.2 higher increased mortality
risk. Following this observation, social isolation could underlie the excess mortality in
depression. Subjects who ”give up” are likely to disengage from health promoting behaviour
leading to decreased mobility, nutritional deficiency, reduced compliance to prescribed
medication, and finally to earlier death7. Thus, motivational depletion may play an important
role in the increased mortality in depressed elderly.
Chapter 5
48
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