A Critical Review:

Is there a causal relationship between Depression and Cardiovascular Disease?

S. Frankland
Student #: 16220086
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S. Frankland (2563 words)

INTRODUCTION

Cardiovascular disease and depression are two of the most common causes of disability in
high-income countries today, and for years, it has been common knowledge that there is a
relationship between depression and cardiovascular disease (CVD). Over a quarter of
cardiovascular patients suffer from depression and there is evidence to support that people
with depression develop heart disease. Despite it being an important and well-researched
area, it still lacks definitive explanations of a true causal relationship. Depression and CVD
is a complex relationship – raising many questions. Is depression a causal factor for heart
disease? Is heart disease a cause of depression, or a bi-directional relationship? Is depression
a result of trauma due to cardiac surgery? 350 million people suffer from depression
worldwide and 17.3 million of them die of heart disease (WHO) so the need for an answer is
of vital importance.

There is a substantial body of evidence showing that individuals with a depressive disorder
have a 64% greater risk of developing coronary artery disease (CAD), and patients with
established CAD and suffering depression are 59% more likely to have another adverse
cardiovascular incident. With better diagnostic tools and increased research and awareness, it
has been possible to establish a connection between depression and heart disease leaving only
to determine if there is a causal link. What this paper attempts to understand is whether the
psychosocial factor depression causes cardiovascular disease through the review of findings
from several journal articles.

SUMMARY

Previous literature regarding psychosocial and cardiovascular disease, has been limited by a

number of considerations, such as subject selection or publication bias and many studies are

highly confounded, possibly due to the interaction of other psychosocial factors (Sharpe,

2003). Measurement methods are often poorly standardised and their generalisability and

validity across different social structures and cultures are questionable, making data

comparison difficult. To establish true cause and effect and a link to heart disease there

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needs to be evidence from randomised studies, showing that treatment or reduction of

depressive episodes reduces the risk of future heart disease (Pozuelo et al., 2009).

Studies have examined the impact of depression on heart disease in both healthy individuals,

and in patients with established cardiovascular disease who develop depression. Findings

showed that people with major (moderate to severe) depression, were four times more likely

than the norm, to have a myocardial infarction (MI) and individuals who experienced only 2

weeks of sadness had twice the risk (Pozuelo et al., 2009). A United Kingdom cohort study

of individuals with no initial heart disease, found major depression to be associated with

higher death rate from ischemic heart disease. Patients with existing depression at the time or

development within 12m of an MI, had 2.7 times greater risk of dying than those who had

never had depression or had had it longer than 12m prior. (Pozuelo et al., 2009). Carney et

al, found that patients with major depression were more likely to have another adverse

cardiac event in the 12m following cardiac surgery, than those without depression; Frasure-

Smith et al, showed that patients who were depressed 1 week after a myocardial infarction

were 3-4 times more likely to die in the 6m following the MI than non depressed individuals.

In longer studies, of nearly 20 years of follow-up, depression was associated with higher

death rates from cardiac issues. Lesperance et al, found that the more severe the depression

at admission the higher the 5 year death rate; Barth et al found the risk of dying within 2

years after initial assessment to be twice the likelihood in depressed patients than in non-

depressed patients. (Pozuelo et al., 2009) supporting evidence for an association between

depression and cardiovascular disease, but still not showing a cause and effect relationship.

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Smoking, cholesterol, hypertension and other factors trigger arterial inflammation. It is

common knowledge, that depression is characterised by a sustained inflammatory state and

an increase of inflammatory markers (Nemeroff, 2012). Arterial inflammation ceases when

the physiological repair process is triggered, however if the inflammation continues it causes

more damage. Elevated C-protein levels has been reported in patients with depression

(Nemeroff, 2012).

Khandaker et al., 2019, studied subjects aged 40-69, recruited throughout the United

Kingdom, over a four year period, from 22 assessment centres. Each subject received geno-

typing at outset as well as the documenting of self-reported health behaviour, linked with

electronic health records. Depression was identified using self-reports by answering

questions related to depression at moderate-severe levels (Nemeroff, 2019); individuals were

questioned about family history of depression and cardiovascular disease. Using the

Mendelian randomisation measurement, a method that measures genes for causal effect of a

modifiable exposure on disease, they found a definite association between a history of heart

disease and depression but a weak association between genetic risk and depression. Almas et

al’s study used existing data from a longitudinal cohort study to assess both depression and

anxious distress disorders and the possible link to cardiovascular disease. Participants were

aged 20-64 years and a sample size of 10 443 was used. Psychiatric rating scales and DSM-5

were used to assess the level of depression in the subjects and register-based and self-reports

were used to assess cardiovascular disease. What this study showed was that moderate

depression had higher odds ratios (OR) than severe depression finding that the severity level

of depression appears to be significant for increased risk of cardiovascular disease among

depressed patients and found even higher risk for those who presented with symptoms of

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anxious distress and depression (Almas et al, 2019). Mary Whooley (2006) studied a single

patient in his 50’s, with a history of coronary disease and a myriad of other lifestyle and

medical dispositions, with no initial depression but whom developed depression within 2m of

cardiac surgery. This study looked at depression as a cause of cardiovascular disease and

subsequent coronary issues.

The studies in this review investigated depression as a possible cause for cardiovascular

disease using cohort studies and one focusing on a particular, single subject. The

methodologies used were systematic and accounted for confounding variables, genetics and

history. The findings all produced similar results.

CRITIQUE

Depression is a growing public health problem worldwide and a concern on its own.

Compounded with other related conditions such as PTSD and general anxiety disorder it

adversely affects the cardiovascular system and increases risk of cardiovascular disease.

There is definite evidence to support a connection between depression and CVD and that

treatment for depression improves cardiovascular outcomes, but the actual relationship

remains unexplained, as so many other factors could be involved, such as age; lifestyle habits

or depressive-associated behaviours (not taking medication due to lethargy or disinterest in

life). It is a known fact that depression has physiological impact and elevates inflammation,

which erodes and destroys the function of arterial walls, contributing to atherosclerosis, yet

information is still limited in understanding the mechanisms of depression. Patients with

depression and individuals with cardiovascular risk have been found to have common

physiological manifestations, such as hypothyroidism that impair tissue repair processes and

possibly cause arterial damage. However, this could simply be the result of aging which

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itself reduces the repair process, causing inflammation and possible arterial wall damage

(Nemeroff, 2012).

Lack of variability in heart rate reflects an imbalance in sympathetic and vagal stimulation, a

risk factor for cardio issues such as arrhythmias. Carney et al reported that patients with

depression and coronary artery disease had less heart rate variability than non-depressed

cardiac patients; implying low heart rate variability mediated adverse effects of depression on

MI survival. Gehi et al, in The Heart and Soul study, found no distinct relationship between

heart rate variability and depression but de Jong et al in the same study found specific

somatic symptoms of depression to be associated with lower heart rate variability.

Depressed patients have been found to have exaggerated platelet reactivity (Pozuelo et al.,

2009) which can lead to thrombosis and this platelet activation is higher in depressed patients

with ischemic heart disease, than non-depressed patients. They have also been found to have

impaired flow-dialation of the brachial artery, indicating endothelial dysfunction. Another

plausible mechanism for worse clinical outcomes in depressed cardiac patients is that they

have more activation of the hypothalamic-pituitary-adrenocortical (HPA) and sympathetic

adrenal medullary systems (Pozuelo et a.l, 2019, p 62). Findings have also shown that

sudden emotional stress can cause transient left ventricular dysfunction even in people

without coronary disease. Other risk factors for cardiovascular disease are things such as

smoking, high cholesterol, diabetes and hypertension and these tend to manifest in depressed

people confounding studies that aim to place depression as a cause of heart disease.

Mary Whooley, 2019 studied a 58-year-old patient with existing and historic coronary issues

and surgeries, diabetes mellitus, hypertension and several unhealthy lifestyle habits. At 2m

follow-up the patient presented with symptoms of depression and on investigation it was

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found he had been suffering depression since the initial heart surgery 5 years prior (Jama,

2006), leading to a diagnosis of major depressive disorder. In this patient, depression was

brought on by cardiovascular traumatic events however the depression was linked to further

coronary issues. Anti-depressant medication was prescribed for the patient. Although no

randomised trial has shown that antidepressant medication decreases the risk of future

cardiovascular events, this patient experienced a resolution of his depressive symptoms over

a period of 1-2 months and was free of depression after 3m. A 2-year follow up showed that

he had continued his use of anti-depressant medication and had no depressive or cardiac

events since. Although this study clearly showed an association between depression and

adverse cardiac events it could not be established if giving the patient anti-depressant

medication 5 years earlier, before his MI would have prevented it (Jama, 2006). This patient

also had several confounding factors, all of which could have contributed to his cardiac

events both initial and subsequent.

Almas et al (2015) used data from a longitudinal cohort study of adults 20-64 years of age

residing in Sweden. He used an A-B-A design over a period of 12 years, measuring at

intervals of 2 years, 3 years and 7 years. This population based study aimed to determine an

association between depression and risk for cardiovascular disease. Measurement methods

used identical questionnaires at each interval, depression was assessed using the Major

Depression Inventory (MDI) and anxious distress as per the DSM-V criteria, cardiovascular

measurement was from self-report health questions. This study also identified any possible

confounders such as age, socio-economic status (SES), Socio-economic position (SEP) and

history of heart disease. T- and chi-square tests were used for statistical analysis to compare

depressed and non-depressed participants and logistic regression to calculate the odds ratio

(OR) and confidence intervals (CI) at 95%. The results of this study showed that depression

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was definintely associated with risk for CVD (OR of 1.9%) but weakened when confounding

factors were considered (OR 1.7%) yet remained for the final model after adjusting for

confounders at an OR of 1.5%. This study also indicated that not only depression but the

level of depression is a risk factor for cardiovascular disease, the highest odds ratio for

moderate depression, as the association for mild or severe depression could be explained by

the confounders whereas for moderate depression the OR remained the same with association

to CVD. (Almas et al., 2015). These findings are in line with previous findings even where

differences in age and population existed and different assessment methods and instruments

were utilised. A further two meta-analyses of 80 000 and 500 000 subjects concluded

depression is a risk factor for cardiovascular disease, stroke and further CVD events or stroke

(Almas et al., 2015, p 6/12).

Studies by Pozuela et al, had similar findings, using both healthy patients; those with

depression who develop heart disease and accounting for lifestyle and other psychosocial

factors, as did studies by Khandaker et al (2019) who used data from a cohort study;

recognised methodologies and measurement tools. The study also looked at shared

mechanisms between depression and heart disease but suggested family history of

cardiovascular disease is strongly associated with moderate/severe depression but not with

genetic risk score. Their findings indicated that comorbidity between the two was more from

shared environmental factors. Nemeroff (2012) found evidence to support that depression

adversely affects the cardiovascular system and increases the risk of cardiac disease.

The Enhancing Recovery in Coronary Heart Disease (ENRICHD) study was designed to

ascertain whether psychosocial interventions would decrease death in depressed cardiac

patients but despite the intervention having a positive influence depression, it did not increase

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the rate of event free survival. The MIND-IT (Myocardial Infarction Depression Intervention

Trial tested to see whether a specific anti-depressant would improve long term depression and

cardiac outcomes in post MI patients. It did not. Khandaker et al, (2019), found that a

previous Mendalian randomisation study did not find evidence for a causal association

between depression and C-reactive protein but found potential causal relationships with

depression for LDL cholesterol and triglycerides. There is evidence that inflammation leads

to changes in lipid metabolism including decreased HDL and increased triglycerides levels,

both associated with increased risk of depression (Khandaker et al., 2019).

There have been extensive studies on how inflammation causes depression and

cardiovascular problems and its effects on myocardial function. Evidence indicates that

peripheral inflammation influences the central nervous system (CNS) and brain responses to

inflammation involve neural systems for motivational and homoeostatic control which are

expressed through mood state and autonomic cardiovascular regulation changes (Khandaker

et al., 2019). According to a Swedish twin study, environmental factors played a large role in

depression-coronary heart disease comorbidity, that could be linked to early lifestyle factors

that influence inflammatory regulation, such as impaired foetal development or maltreatment

in childhood. These findings are consistent with the foetal programming hypothesis by David

Barker – low birth weight and childhood maltreatment are both associated with increased

levels of circulatory inflammatory markers and depression and adult coronary heart disease

(Khandaker et al., 2019).

CONCLUSION

We know that sustained inflammation can cause physiological damage and these findings

point to a common factor in both depression and cardiovascular problems presenting in

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increased levels of inflammatory markers. What is interesting is the importance of the level

of depression and the connection to cardiovascular disease. Moderately depressed patients

have greater risk for CVD than mild or severely depressed individuals and those with

concomitant anxious disorders are at even greater risk for cardiovascular disease (Almas et

al., 2015).

So does depression cause cardiac disease? There is no definitive evidence to support a causal

relationship between depression and cardiovascular disease even when accounting for

confounding factors; however, there is significant evidence to support an association between

depression and heart disease although treating the depression has not seen a decrease in

cardiac related deaths (Pozuela et al., 2009). Current research is focusing on measuring the

aspects of depression associated with cardiovascular disease such as somatic and effective

mood symptoms to try to determine the depression subtype which carries a worse cardiac

prognosis as well as emotional vitality (energy for living) which has been shown to protect

against coronary heart disease and holds much promise (Pozuelo et al., 2009).

Although there is strong evidence to support an association between depression and

cardiovascular disease and new data supports treatment of depression could improve CVD, a

precise relationship remains uncertain, as so many other factors such as aging, could be

responsible. More research is needed to understand the complex relationship between

depression and cardiovascular disease before it can be claimed there is a causal relationship

(Nemeroff C, 2012).

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REFERENCES

Almas, A., Forsell, Y., Iqbal, R., Janszky, I., & Moller, J. (2015). Severity of Depression,
Anxious Distress and the Risk of Cardiovascular Disease in a Swedish Population-Based
Cohort. PLOS ONE, 10(10), e0140742. doi: 10.1371/journal.pone.0140742

Khandaker, G., Zuber, V., Rees, J., Carvalho, L., Mason, A., & Foley, C. et al. (2020).
Correction: Shared mechanisms between coronary heart disease and depression: findings
from a large UK general population-based cohort. Molecular Psychiatry. doi:
10.1038/s41380-020-0857-7

Nemeroff, C., & Goldschmidt-Clermont, P. (2012). Heartache and heartbreak—the link

between depression and cardiovascular disease. Nature Reviews Cardiology, 9(9), 526-
539. doi: 10.1038/nrcardio.2012.91

Pozuelo, L., Zhang, J., Franco, K., Tesar, G., Penn, M., & Jiang, W. (2009). Depression and
heart disease: What do we know, and where are we headed?. Cleveland Clinic Journal Of
Medicine, 76(1), 59-70. doi: 10.3949/ccjm.75a.08011

Sharpe, N. (2003). Depression and cardiovascular disease: a complex relationship. European

Heart Journal, 24(22), 1997-1998. doi: 10.1016/j.ehj.2003.09.014

Whooley, M. (2006). Depression and Cardiovascular Disease. JAMA, 295(24), 2874. doi:

10.1001/jama.295.24.2874

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