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Diet and lifestyle

Missing link found between stress and mental illness

Anxiety and depression annually cause 1.6 million to 1.9 million days of sick leave in Denmark. Now Swedish researchers have found a possible link between the stress hormone cortisol and these two mental disorders. The individual sensitivity for developing these conditions appears to be mediated by modifications of our DNA. The new knowledge can open the door for new and alternative treatment strategies.

Nearly a quarter million Danes live with anxiety or depression and 30,000 new cases are added every year. Treatment of these disorders is actually quite complex, partly because knowledge on the physiological causes of the disorders is limited. Swedish researchers have now published their findings in Scientific Reports showing a possible link between stress and these mental disorders.

“We can see that in situations in which the endogenous level of the stress hormone cortisol is elevated, the chemical surface of our genome changes slightly. These changes, in turn, are further associated with the prevalence of fatigue, anxiety and depression,” explains first author Camilla Glad, Postdoctoral Researcher from the Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg.

Fat deposits on the face, abdomen and neck

The researchers arrived at their results by studying 48 subjects with Cushing’s syndrome – a rare disease that leads to chronically elevated levels of cortisol, an adrenocortical hormone. Cushing’s syndrome is caused by a benign tumour of the pituitary or adrenal gland and is characterized by abdominal obesity, fat deposits in the face and neck, high blood pressure and diabetes. The affected individuals also frequently experience chronic fatigue syndrome, anxiety and depression.

“As a group, people with the syndrome experienced much more fatigue, anxiety and depression than a control group matched for sex, age and educational level. Also, we looked into their epigenome, and they had lower degrees of a specific form of epigenetic marker, called DNA methylation, on their genes.”

DNA methylation is known to be important in determining how a specific gene is expressed. The researchers examined the DNA of the people with Cushing’s syndrome and discovered that they not only had lower levels of global DNA methylation but also that a large number of the identified differentially methylated regions were further associated with anxiety and depression. 

“This suggests that cortisol directly influences the DNA methylation of specific genes and that these genes, in turn, influence the development of psychopathology. We are now beginning to examine the precise molecular mechanisms.”

Lasting impact

The new results also provide a snapshot of the lasting impact of the mental problems associated with Cushing’s syndrome, even after the benign tumour has been surgically removed. This may explain why stress similarly has a long-term effect on the human psyche.

“Previous research has shown that events in our childhood can lead to long-term dysregulation that influences not only important physiological functions but also our mood and emotions.”

Even after surgery, many of the people with Cushing’s syndrome never return to work and may not even venture out into society – not even for simple everyday activities. The researchers therefore hope that they can use this new knowledge to find new ways of helping the this group of patients with Cushing’s syndrome – but perhaps also people affected by stress-related psychopathology in general.

“The results may potentially lead to new strategies for treating other stress-related conditions such as anxiety, depression and post-traumatic stress because, presumably, the same mechanisms apply to people experiencing stress as to those with Cushing’s syndrome.”

A possible cure for anxiety and depression

Although considerable additional research is required to discover the detailed mechanisms of how the subsequent DNA methylation may influence sensitivity to anxiety or depression, the researchers now have an idea about how people with these mental disorders can be treated.

“With the knowledge we have today, I do not think we will able to affect cortisol-induced DNA methylation changes themselves. Methylation depends on our inherited genes but is also influenced by the environment, diet and lifestyle. In the long term, we therefore hope to be able to counteract its effects.”

Instead, the researchers hope to discover which protein products are affected by the changes in DNA methylation. Identifying these will open the door for new treatment opportunities because drugs may be able to regulate or influence the production or biological effects of these proteins. Although much research is required, Camilla Glad is confident that it will be worthwhile.

“We are talking about changes in DNA that have the potential to persist for the remainder of life and that also can be hereditary, so if we can solve this task it will have major impact in human and societal terms.”

Anxiety in Denmark costs more than DKK 2 billion for treatment and care and DKK 12 billion for lost production.

Reduced DNA methylation and psychopathology following endogenous hypercortisolism – a genome-wide study” has been published in Scientific Reports. In 2015 and 2016, the Novo Nordisk Foundation awarded a grant to one of the article’s main authors, Gudmundur Johannsson, Professor, Sahlgrenska University Hospital, Gothenburg, Sweden for the project Biomarker Discovery in Endocrinology – Biomarkers of Glucocorticoid Action.

Gudmundur Johannsson
Professor/ chief physician
Major research interests include pituitary diseases, the importance of growth hormone in adults and adrenal insufficiency. He is a board member (president elect) of the Growth Hormone Research Society Council, and actively supports a number of journals: as Editor of the European Journal of Endocrinology and has served on the Editorial Board of the Journal of Clinical Endocrinology and Metabolism, and Growth Hormone & IGF Research. Professor Johannsson has more than 200 publications in peer-reviewed journals.