The depression jigsaw: genetic predisposition, inflammation, and specific depression profiles

The depression jigsaw: genetic predisposition, inflammation, and specific depression profiles

Philipp Frank, Olesya Ajnakina, Andrew Steptoe and Dorina Cadar

Depression is a growing public health concern and a major cause of disability, with over 300 million people experiencing the disorder worldwide. It is typically characterised by a range of cognitive, psychological, and somatic symptoms, including difficulties concentrating, anhedonia, depressed mood, sleep problems, and changes in appetite. Depression is also associated with a number of negative health outcomes such as an increased risk of morbidity, cognitive decline, and mortality.

In the past decades, research has attempted to uncover plausible biopsychosocial pathways contributing to the development of depression. However, it is still unclear why some people develop depression, while others remain healthy. Notably, approximately one third of patients with depression fail to respond to conventional anti-depressant medication, highlighting the complexity of the disorder.

This also raises the question of whether there are other, potentially unexplored, factors contributing to the development of depression. New evidence points to the importance of genetic variation and inflammatory processes in the manifestation of specific depression profiles.

A recent study carried out at UCL’s Department of Behavioural Science and Health found that increased genetic susceptibility to depressive symptomatology was associated with both subsequent cognitive-affective and somatic symptoms of depression in a nationally representative sample of English adults aged 50 years and older. In this study, depression was measured by asking participants if they had experienced a number of common depressive symptoms during the past seven days. Furthermore, all participants were genotyped to explore genetic variants related to depressive symptomatology.

Next, the researchers derived a polygenic score, summarising genetic risk for depression into a single score. Inflammatory activity was assessed two years prior to measuring depression by examining participants’ blood levels of C-reactive protein – a biological marker typically used in medicine to determine inflammation levels. Interestingly, the study found that increased inflammation acted as an inherent mechanism driving the development of somatic (e.g. sleep problems, lack of energy, or difficulties to motivate yourself) but not cognitive-affective symptoms (e.g. feeling sad, lonely, or depressed) in individuals with a higher genetic risk for depression.

Depression is a highly heterogenous disorder with varying types of symptom expressions. For example, some people may be more likely to experience primarily somatic symptom, whereas indications of sadness or loneliness may be dominant in others. This variability can make treatment difficult and might explain why a considerable proportion of people does not get significantly better after antidepressant treatment.

The UCL study found that genetic variation may play an important role in the development of cognitive-affective and somatic depressive symptoms. This means that certain genes may predispose some individuals to develop depressive symptoms later in life. Notably, the findings also suggest that inflammation seems to be particularly important for the manifestation of somatic symptoms. This is in line with the sickness behaviour theory, which posits that inflammation and subsequent neuroendocrine responses can affect those parts of the brain involved in mood regulation, triggering a cascade of largely somatic symptoms.

Indeed, research has shown that inflammatory agents in our circulatory system are capable of crossing the blood-brain barrier, initiating neuroendocrine responses that lead can lead to the development of depressive-like symptoms or sickness behaviour. Inflammatory processes of the body are mainly known for their function as the body’s first line of defence against tissue damage and microbial infection. Sickness behaviour is usually an adaptive response to acute illness or infection – something most of us experience when we get sick. This includes behaviours such as social withdrawal, fatigue, or reduced motor activity.

However, in most cases, these initially adaptive behaviours tend to fade once the individual recovers from the illness. Importantly, the UCL researchers excluded people with acute infections (for example people with the flu or inflammatory diseases) and focused on individuals with just slightly higher levels of inflammation – something that is known as low-grade inflammation. Low-grade inflammation is typically chronic, and there are many reasons for why this condition occurs. For example, it has been related to older age – a process researchers often refer to as ‘inflammageing.’

Moreover, low-grade inflammation is often found in people with low levels of physical activity, high alcohol consumption, unhealthy diets, and in smokers. Hence, the findings may also suggest that individuals with poorer lifestyle behaviours are at a particularly high risk of developing somatic rather cognitive-affective symptoms of depression. However, further research is needed to untangle these relationships.

Inflammatory processes in the human body may also be a probable explanation for why we often see higher levels of depression in people with distinct inflammation-related illnesses. For example, people with cardiovascular diseases, inflammatory bowel disease, and cancer are significantly more likely to experience depression as compared to their healthy counterparts. In addition, evidence from experimental studies shows that treatment with drugs that increase inflammation can initiate to the development of depressive symptoms.

Piecing together the puzzle of depression is likely to continue for many more years. Understanding that inflammatory processes could exacerbate the genetic predisposition in the manifestation of somatic rather than cognitive symptoms represents an important avenue that needs to be considered in future studies. Ultimately, this will inform healthcare professionals to design more targeted treatments for individuals with a somatic depression profile. This may include anti-inflammatory drug treatment as well as behavioural interventions.

In fact, the first clinical trials have been already launched to investigate the efficacy of anti-inflammatory drugs in people with depression. The first results show that the administration of drugs lowering inflammatory processes in the body alleviated depressive symptoms in a subset of patients with severe medical illnesses such as cancer or rheumatoid arthritis, as well as in some people diagnosed with depressive disorders. Behavioural interventions may also be a promising approach to alleviate symptoms in people with a somatic depression profile. For example, a traditional Mediterranean diet (vegetables, olive oil, low intake of saturated fats) has been found to downregulate inflammatory activity.

Moreover, even mild or moderate levels of regular physical activity (walking, dancing, stretching exercises) can have substantial short- and long-term anti-inflammatory and anti-depressant effects. Further, sleep is a fundamental driver of both health and disease. Establishing healthy sleep patterns may have similar anti-inflammatory effects. Although research exploring the link between inflammation and depression is still in its infancy, it has the potential to shed further light on the causes and treatments of specific depression profiles.

Frank, P., Ajnakina, O., Steptoe, A., & Cadar, D. (2020). Genetic susceptibility, inflammation and specific types of depressive symptoms: evidence from the English Longitudinal Study of Ageing. Translational Psychiatry10(1), 1-9.


Philipp Frank is an ESRC/BBSRC funded PhD student in the Department of Behavioural Science and Health at UCL. Olesya Ajnakina is a Research Fellow in Psychosis at KCL’s Institute of Psychiatry, Psychology and Neuroscience. Andrew Steptoe is the director of the English Longitudinal Study of Ageing and the Head of the Research Department of Behavioural Science and Health at UCL. Dorina Cadar is a Senior Research Fellow in the Department of Behavioural Science and Health at UCL.

Image Credit: Sasha Freemind from Unsplash