does depression in old age increase cardiovascular mortality?

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.

Chapter 5

40


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.


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.


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.


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

References

1 Saz P, Deway ME. Depression, depressive symptoms and mortality in persons aged 65 and over

living in the community: a systematic review of the literature. Int J Geriatr Psychiatry 2001; 16: 622-

30.2 Schulz R, Drayer RA, Rollman BL. Depression as risk factor for non-suicide mortality in the elderly.

Biol Psychiatry 2002; 52: 205-25. 3 Wulsin LR. Does depression kill ? Arch Intern Med 2000; 160: 1731-32. 4 Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci 2003; 58:

249-65. 5 Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with

physical disability: a review of the literature and prospectus for future research. Am J Geriatr

Psychiatry 2001; 9: 113-35. 6 Ganguli M, Dodge HH, Mulsant BH. Rates and predictors of mortality in an aging, rural,

community-based cohort: the role of depression. Arch Gen Psychiatry 2002; 59: 1046-52. 7 Schulz R, Beach SR, Ives DG, et al. Association between depression and mortality in older adults.

Arch Intern Med 2000; 160: 1761-68. 8 Wassertheil-Smoller S, Applegate WB, Berge K, et al. Change in depression as a precursor of

cardiovascular events. Arch Intern Med 1996; 156: 553-61. 9 Mendes de Leon CF, Krumholz HM, Seeman, TS, et al. Depression and risk of coronary heart

disease in elderly men and women. Arch Intern Med 1998; 158: 2341-48. 10 Penninx BWJH, Guralnik JM, Mendes de Leon CF, et al. Cardiovascular events and mortality in

newly and chronically depressed persons > 70 years of age. Am J Cardiol 1998; 81: 988-94. 11 Sesso HD, Kawachi I, Vokonas PS, et al. Depression and the risk of coronary heart disease in the

normative aging study. Am J Cardiol 1998; 82: 851-56. 12 Penninx BWJH, Beekman, ATF, Honig A, et al. Depression and cardiac mortality. Results from a

community-based longitudinal study. Arch Gen Psychiatry 2001; 58: 221-27. 13 Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry

1998; 155: 4-11. 14 Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease.

Arch Gen Psychiatry 1998; 55: 580-92. 15 Nemeroff CB, Musselman DL. Are platelets the link between depression and ischemic heart

disease? Am Heart J 2000;.140: 57-62. 16 Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in

a community sample. Circulation 1996; 93: 1976-80. 17 Whooley MA, Browner WS. Association between depressive symptoms and mortality in older

women. Arch Intern Med 1998; 158: 2129-35. 18 Penninx BWJH, Geerlings SW, Deeg DJH, et al. Minor and major depression and the risk of death

in older persons. Arch Gen Psychiatry 1999; 56: 889-95. 19 Bootsma-van der Wiel A, van Exel E, de Craen AJM, et al. A high response is not essential to

prevent selection bias: results from the Leiden 85-plus Study. J Clin Epidemiol 2002; 55: 1119-25. 20 Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression

screening scale: a preliminary report. J Psychiatr Research 1982; 1: 37-49. 21 Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the

cognitive state of patients for the clinician. J Psychiatr Research 1975; 12: 189-98. 22 de Craen AJM, Heeren TJ, Gussekloo J. Accuracy of the 15-item Geriatric Depression Scale (GDS-

15) in a community sample of the oldest old. Int J Geriatr Psychiatry 2003; 18: 63-66.


49

23 World Health Organisation. International Statistical Classification of Diseases and Related Health

Problems (ICD-10). 1994. Geneva: WHO. 24 Rautaharju P. Electrocardiography in Epidemiology and Clinical Trials. 1219-66. In:

Comprehensive Electrocardiology. Macfarlane PW, Lawrie TDV (eds). 1989. Oxford: Pergamon

Press.25 van Exel E, Gussekloo J, Houx P, et al. Atherosclerosis and cognitive impairment are linked in the

elderly. The Leiden 85-plus Study. Atherosclerosis 2002; 165: 353-59. 26 Bootsma-van der Wiel A, Gussekloo J, de Craen AJM, et al. Common chronic diseases and general

impairments as determinants of walking disability in the oldest-old population. J Am Geriatr Soc

2002; 50: 1405-10. 27 Suurmeijer TP, Doeglas DM, Moum T, et al. The Groningen Activity Restriction Scale for

measuring disability: Its utility in international comparisons. Am J Public Health 1994; 84: 1270-73. 28 Takeshita J, Masaki K, Ahmed I, et al. Are depressive symptoms a risk factor for mortality in

elderly Japanese American men ?: The Honolulu-Asia Aging Study. Am J Psychiatry 2002; 159:

1127-32. 29 Frasure-Smith N, Lespérance F, Talajic M, et al. Depression following myocardial infarction.

Impact on 6-month survival. JAMA 1993; 270: 1819-25. 30 Lespérance F, Frasure-Smith N, Talajic M, et al. Five-year risk of cardiac mortality in relation to

initial severity and one-year changes in depressive symptoms after myocardial infarction. Circulation

2002; 105: 1049-53. 31 Vinkers DJ, Gusskloo J, Stek ML, van der Mast RC, Westendorp RG. Does depression specifically

increase cardiovascular mortality? Arch Intern Med 2005; 165: 119. 32 Geerlings SW, Beekman AT, Deeg DJ, et al. Duration and severity of depression predict mortality

in older adults in the community. Psychol Med 2002; 32: 609-18. 33 Stek ML, Gussekloo J, Beekman AT, van Tilburg W, Westendorp RG. Prevalence, correlates and

recogntion of depression in the oldest old: the Leiden 85-plus Study. J Affect Disord 2004; 78: 193-

200.34 Stek ML, Vinkers DJ, Gussekloo J, Beekman AT, van der Mast RC, Westendorp RG. Is depression

in old age fatal only when people feel lonely ? Am J Psychiatry 2005; 162: 178-80.

does depression in old age increase cardiovascular mortality?

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