Penninx (2016). Depression and cardiovascular disease: Epidemiological evidence on their linking mechanisms – Article summary

Major depressive disorder increases the risk of cardiovascular morbidity and mortality. This impact can partially be explained by mediating mechanisms (e.g. unhealthy lifestyle and unfavourable pathophysiological disturbances).

Cardiovascular disease refers to those conditions that affect the heart and blood vessels. Depressed individuals are at increased risk for peripheral atherosclerosis. Depression increases the risk for the onset of cardiovascular disease and mortality when the disease has already emerged. Cardiovascular disease can also increase the risk of developing depressive symptoms. Depression increases onset and prognosis of multiple diseases.

There are several potential causal mediating mechanisms for the effect of depression on the risk of cardiovascular disease:

1. Unhealthy lifestyle (e.g. smoking)
2. Pathophysiology (e.g. metabolic dysregulation)
3. Residual confounding (i.e. depression is a prodrome of not yet discovered clinical conditions).
4. Iatrogenic effects (i.e. pharmacological impact of antidepressants).
5. Third factors (e.g. personality; childhood stressors).

People with depression are usually older (1), female (2), have a low SES (3) and have poor general health (4). This means that socio-demographics and baseline health conditions rather than depression could be responsible for the risk of cardiovascular disease. However, controlling for these variables does not explain all variance. The residual confounding hypothesis states that there are factors that influence the risk of cardiovascular disease after controlling for the previously mentioned variables.

Increased behavioural risk profiles in depressed people may contribute to the higher risk of cardiovascular diseases. This includes unhealthy lifestyles (e.g. smoking).

Depression-related biological dysregulations that also constitute risk factors for somatic illnesses could explain part of the increased risk for cardiovascular disease in depressed individuals.

Acute stress results in immediate activation of sympathetic nerves and reduction of parasympathetic nerves in order to prepare the body for fight or flight. Depression involves an autonomic nervous system that is in a relative state of more sympathetic and less parasympathetic activation. Autonomic dysregulation is involved in cardiovascular somatic symptoms.

There are inconsistent findings regarding the association between depression and lower heartrate variability. Depressed people show less parasympathetic and sympathetic activity when under stress. Antidepressants act through changing both parasympathetic and sympathetic activity which could explain the increased risk for cardiovascular disease. Antidepressants could have a detrimental role on autonomic activity which could explain the increased risk for cardiovascular disease.

There is hyperactivity of the HPA-axis in depressed individuals. Chronic stress is perceived by the cortex of the brain and transmitted to the hypothalamus where corticotropin releasing hormone (CRP) is released upon pituitary receptors. This leads to the release of cortisol in the blood. The chronic activation of the stress response may result in an atrophy of hippocampal cells (1), reduced neurogenesis and synaptic plasticity (2) and altered monoaminergic signalling (3). This can all lead to a more depressive state. Depressed individuals display increased cortisol levels. HPA-axis dysregulation is not restricted to major depressive disorder. HPA-axis hyperactivity represents a vulnerability rather than a state indicator. However, it is not clear to what extent the HPA-axis contributes to the development of cardiovascular disease.

Metabolic syndrome refers to a clustering of general metabolic risk factors (e.g. abdominal obesity). This is a pre-clinical state. Depression and metabolic syndrome is related. However, the strongest association exists between depression and obesity-related factors. Once a depression and a metabolic syndrome are both present, abdominal obesity may give rise to multiple metabolic dysregulations which might be responsible for remaining in a depressed state.

White adipose tissue is an active endocrine organ producing inflammatory cytokines and hormones. This is especially the case in the abdominal area. This is thus a major contributor to pathogenic immune-metabolic responses in the central nervous system and the rest of the body. It affects hippocampal and cortical structure through its actions on neurogenesis (1), axon growth (2), synaptogenesis (3) and dendritic morphology regulation (4). Cerebrovascular damage may link metabolic dysregulation and depression. There is a strong relation between metabolic abnormalities and inflammation as abdominal fat tissue produces cytokines and these increase metabolic syndrome development.

Dysregulated inflammation refers to an immune response that derives from activation of the innate immune system. This is associated with depression. It consists of pro-inflammatory cytokines. Chronic, low-grade systematic elevations of these molecules increase the onset of cardiovascular morbidity and mortality. The link between inflammation and depression is likely bi-directional. Cytokines could affect neurogenesis in emotion-regulating brain structures and damage the hippocampal neurons. Depression may facilitate weight gain which promotes inflammation that may reinforce depression.

There are two stable subtypes of depression. They do not differ in prevalence of core symptoms of depression (1), in overall severity or duration of depression (2) and in disability or psychiatric comorbidity patterns (3).

There is increased cardiovascular risks among people using antidepressants. Antidepressants might affect pathophysiological dysregulations. TCAs and SNRIs may increase cardiac vagal control. However, it may also lead to reduction of other specific pathophysiological disturbances (e.g. cortisol or inflammation levels). SSRIs appear to reduce cytokine levels.

There are several potential third variables that could explain the link between depression and cardiovascular disease. This includes childhood maltreatment (1), personality traits (2) and genetic vulnerability (3). Genetic pleiotropy refers to a shared genetics effect. Genetic influences could make a person more vulnerable for biological dysregulations which could result in both depression and cardiovascular disease.