Depression and cardiovascular disease Penninx (2016)

Literature lecture 4

Depression and cardiovascular disease

Many studies illustrated the adverse impact of depression on somatic health.

There is convincing evidence linking depression and cardiovascular disease (CVD):

Meta-analyses show that depression:

• Results in an 80-90% increased risk of CVD onset.

• Increases the risk of cardiovascular mortality when the disease has already emerged.

• Is bidirectionally linked to CVD: depression and CVD mutually reinforce each other.

Mechanism linking depression to CVD risk

1. residual confounding hypothesis

2. unhealthy lifestyle: smoking, excessive alcohol use, unhealthy diet, lower treatment compliance and worse medical care

3. Iatrogenic effects: The pharmacological impact of antidepressants increases cardiovascular risk

4. third underlying factors: childhood stressors, personality, genetic pleiotropy

Residual confounding hypothesis

even in extensively adjusted epidemiological models, residual confounding may still exist, accounting for some of the links between CVD and depression.

However, it is unlikely that residual confounding completely explains the increased CVD risk.

Unhealthy lifestyle

People suffering from depression might have more unhealthy lifestyles than those who are not depressed.

Unhealthy lifestyle indicators were found to be significantly more common in current and remitted major depressive disorder (MDD) patients.

However, after controlling for lifestyle differences, effect sizes were only slightly lower, suggesting that increased risks are not only due to lifestyle differences !

Iatrogenic effects

The use of antidepressants may contribute to increased cardiovascular risk among depressed individuals.

However, subjects using antidepressants are likely to have different course of depression from those that do not: it is generally more severe, chronic, or subjects have specific other reasons to use them.

Third underlying factors

= factors that increase the risk of both depression and CVD and thus link the two.

• Childhood maltreatment: a strong risk factor for the onset of depression, but also associated with cardiovascular processes and increased event risk.

• Personality: some traits (neuroticism) are linked to the development of depression as well as cardiovascular events.

• Genetic vulnerability: genetic pleiotropy may occur

  • Genetic pleiotropy = when two conditions share similar genetic risk variants, leading people with those high-risk genes to potentially develop both conditions.

Autonomic dysregulation

Depression is hypothesized to involve an autonomic nervous system (ANS) that has more sympathetic and less parasympathetic activation.

Assessment of heart rate variability (HRV) is often used as a measure of autonomic activity.

• Heart rate variability = an individual’s capacity for parasympathetic inhibition of autonomic arousal. → When HRV is low, there is less parasympathetic activation and more sympathetic activation: the parasympathetic system is not able to inhibit the sympathetic responses.

• Depressed patients show reduced HRV in some studies, but this is not the case in other studies: more research is needed.

The role of antidepressants is also important to consider in this regard.

• A meta-analysis found that TCAs (antidepressants) had a strong decreasing effect on HRV. It seems that SNRIs and SSRIs have a lesser, but still harmful impact on autonomic activity.

• So, HRV is strongly influenced by antidepressants and it is not yet clear if depression has any effect on HRV at all.

HPA axis dysregulation

Hyperactivity of the HPA axis in depression results in high cortisol levels and chronic activation can even result in atrophy of hippocampal cells.

Salivary, serum or urine measures are often used to assess cortisol levels.

It is not clear to what extent HPA axis dysregulation contributes to CVD development, because not enough longitudinal evidence is present.

Vulnerability indication:

Studies found increased cortisol responses in current as well as remitted depressed cases.

Also, HPA axis hyperactivity was observed among non-affect offspring of depressed patients, suggesting that it may partly reflect a genetic vulnerability marker of depression.

Metabolic dysregulation

Depression is linked with metabolic dysregulations, which are often assessed in the context of metabolic syndrome ( a clustering of general metabolic risk factors like abdominal obesity, and elevated blood pressure)

Metabolic syndrome and depression were found to be modestly associated

Immuno-inflammatory dysregulation

Evidence indicates that depression is associated with dysregulated inflammation (an immune response) and that this link is likely bidirectional: depression can increase inflammation by elevating pro-inflammatory cytokines, while higher levels of proteins active in inflammation can predict depressive symptoms.

Chronic elevations of pro-inflammatory cytokines (IL-6), caused by depression, have been shown to increase the onset of cardiovascular morbidity and mortality.

Depression subtypes

2 distinct depression subtypes can be identified, which helps identification of pathophysiology:

1. melancholic depression: higher prevalence of HPA axis dysregulations

2. atypical depression: higher prevalence of immune-inflammatory and metabolic dysregulations