Depression is associated with an increased risk of somatic disease (e.g. diabetes, cardiovascular disease, cancer). There are several factors that could explain the increased somatic comorbidity in people with depression:

• Poor lifestyle (e.g. smoking).
• Poor self-care.
• Poor general treatment adherence.

An unhealthy lifestyle (1), pathophysiology (2), residual confounding (3), third factors (4) and iatrogenic effects (5) can be mediating factors for the effect of depression on the risk for cardiovascular disease. Iatrogenic effects refer to, for example, the pharmacological impact of antidepressants.

Antidepressants could explain the effects of depression on the risk of cardiovascular disease because antidepressants influence both sympathetic and parasympathetic activity.

Depression can be seen as a brain disease. There are differences on different levels in the brain:

1. Structural
   The volume of the hippocampus, amygdala and prefrontal cortex is lower in people with depression.
2. Connectivity
   There is an increase in default mode network, a decrease in salience networks and central executive networks and differences in the frontostriatal limbic system.
3. Functional activation
   There is an increased response to negative and decreased response to positive stimuli in the brain.

Depression is related to the immune system, the autonomic nervous system and the HPA-axis. Dysregulation in these systems increases the risk of cardiovascular disease. It could lead to somatic changes which could play a role in the development of a depressive state.

There are different depression-related biological dysregulations:

• HPA-axis
• Autonomic nervous system
• Immune system
• Oxidative stress
• Accelerated ageing

The HPA axis enables reaction to stress. It uses the mobilization of stored energy (1), suppression of immune function (2) and facilitation of many processes of the central nervous system (3).

A chronic activation of the stress response leads to atrophy of hippocampal cells 1), reduced neurogenesis (2), reduced synaptic plasticity (3) and altered monoaminergic signalling (4). Depressed individuals tend to have increased cortisol levels. Higher levels of cortisol are associated with the onset of depression.

The sympathetic nervous system prepares the body for action (i.e. fight or flight). The parasympathetic nervous system regulates the resting state of the body. Antidepressants lead to a lower heart rate variability.

Increased pro-inflammatory cytokines appear to induce sickness behaviour. In depression, there may be a chronic inflammatory response. Transmission of stress induces inflammatory signals to the brain.

The cytokines and inflammatory markers influence monoamine metabolism (1), glutamate metabolism (2) and neuroplasticity (3). There can be an increase in glutamate because of inflammatory markers. Reduced metabolism can lead to the damage of neurons.

Higher levels of CRP at baseline predict depressive symptoms. The IL-6 pathway is upregulated in depression. Adipose tissue is a big source of inflammation. People with depression exhibit higher levels of inflammatory markers and obesity prevalence is higher in people with depression. The association between obesity and depression is bidirectional.

Oxidative stress is the result of a disruption between the balance between reactive oxygen species and antioxidants. Reactive oxygen species are a normal product of aerobe metabolism with essential physiological functions. It can be damaging but the antioxidants protect against reactive oxygen species. Oxidative stress plays a role in ageing and disease.

Increased reactive oxygen species can occur through exposure to toxins (1), exposure to radiation (2) and chronic inflammatory conditions (3). Decreased antioxidants can occur through depletion of vitamins or micronutrients. Oxidative stress leads to damage by the ROS.

Telomeres are the end part of the DNA part. The end-replication problem refers to shorter telomeres each cell division. Critically short telomeres lead to DNA damage and the cell loses the ability to function well. Telomerase adds base pairs to telomeres and this delays cell dysfunction. Telomere length can be seen as a biological clock as they reduce every year.

Depression is associated with telomere shortening. It is possible that depressive and anxiety disorders leave a long-lasting cellular-scar because a short telomere length is already present in adolescents with major depressive disorder. It is also possible that there is a short telomere length before the onset of a depressive or anxiety disorder. This means that telomere length could be a risk factor for depression. Lastly, it is possible that there are shared genetic effects between telomere length and depression.

DNA methylation correlates with chronological age and this can be seen as an epigenetic clock. There is oxidative stress in depression. Depressed people have shorter telomeres and higher epigenetic age but no accelerated shortening of telomeres.

There are a lot of variations of depression. There are two subtypes of depression:

1. Atypical depression
   This includes mood reactivity (1), increased appetite and weight (2), hypersomnia (3), leaden paralysis (4) and interpersonal rejection sensitivity (5).
2. Melancholic depression
   This includes a loss of pleasure (1), a lack of mood reactivity (2), decreased appetite (3), early morning awakening (4), excessive guilt (5), distinct quality of mood (6), a worse mood in the morning (7) and psychomotor retardation and agitation (8).

BMI is increased in depression and especially in the atypical depression group. There is no hyperactivity of the HPA axis in atypical depression but the HPA axis is hyperactive in melancholic depression.

Depression moderates the effect of fat mass and obesity-related gene (FMO) on BMI. Different subtypes of depression have different biological underpinnings. This requires the reassessment of antidepressants and their inflammatory effects and increases the need for personalized care.

Once a depression and a metabolic syndrome are both present, abdominal obesity may give rise to multiple metabolic dysregulations which may be responsible for remaining in a depressed state. White adipose tissue is a major contributor to pathogenic immune-metabolic responses in the central nervous system and the rest of the body. It produces inflammatory cytokines and hormones. It affects hippocampal and cortical structure through its actions on neurogenesis (1), axon growth (2), synaptogenesis (3) and dendritic morphology regulation (4).

Dysregulated inflammation refers to an immune response that derives from activation of the innate immune system and is associated with depression. Chronic, low-grade elevation of pro-inflammatory cytokines increase the onset of cardiovascular morbidity and mortality. Cytokines could affect neurogenesis in emotion-regulating brain structures and damage the hippocampal neurons. This could contribute to depression. Depression may facilitate weight-gain which promotes inflammation, which, in turn, reinforces depression.

Giving people inflammatory medication when there is no inflammatory dysregulation can have detrimental effects.