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Major depression, also known as clinical depression, and formally as major depressive disorder (MDD), is a mental illness so severe that many patients continue to be prescribed antidepressant drugs after the initial course of treatment (first episode).

Continuation treatment aims to prevent further episodes of depression, but there is a challenge:

At present, doctors have no way of predicting their patients’ individual repeat risk of major depression. This is why some patients are prescribed preventive medicine without actually needing it, while others who are not currently given preventive antidepressants after their first episode might benefit from this precautionary treatment.

This may be about to change, however, as a new method makes it possible to delve deep into the DNA of depression. The aim is to reveal details behind the genetically determined vulnerability that in combination with external factors such as the individual’s personal circumstances and environment trigger major depressive disorder.

This new method is described in a research article just published in The American Journal of Human Genetics by an international team of 20 researchers led by Morten Dybdahl Krebs, MD, PhD and principal investigator Andrew Schork, PhD. Both are affiliated with the Institute of Biological Psychiatry, Mental Health Services – Sct Hans, Rigshospitalet – Copenhagen University Hospital and The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH).

“The method we have jointly developed tells us, for example, that people diagnosed with major depressive disorder in purely genetic terms typically also have a greater risk of developing a number of other mental illnesses such as schizophrenia, bipolar disorder, ADHD and autism,” explains Krebs, first author of the scientific article.

Meanwhile, with the aid of the new method, the researchers can now demonstrate for the first time a significant difference in the genetic risk of developing major depression, Krebs explains: “We can see that on average, patients treated for the second time for this mental illness have a higher genetically determined risk of developing the illness than patients treated for the first time.” 

Does this mean that the method can be used by doctors for assessing if someone should be put on preventive medication after a first episode of major depression?

“We’re not that far along yet,” says Krebs, who is training as a psychiatrist. “But the more light we can shed on the genetics underlying major depression, the closer we will hopefully be to that situation. You could say that our method points in the direction of a more individualised treatment for major depression. If we do achieve that, we should also be able to offer valid pointers to how long a preventive course of treatment should be prescribed for a given patient after their first episode, meaning, for one year, two years or three?”

Millions of family members

When scientists investigate the links between genetics and mental illness, they try to identify special constellations in the DNA. These are genetic patterns that are typically present in patients with the illness in question, and which are present in a different way and with a different frequency than is the case for people unaffected by the illness.

This provides insights into the genetic ‘architecture’, which combined with the individual’s personal circumstances and environment, trigger the mental illness. But as the genetic ‘architecture’ is typically very complex and not yet fully understood, experiments are currently ongoing to include health information from relatives.

The hypothesis is that if various mental illnesses occur in someone’s family, then that in itself is very likely to increase their genetic risk of developing a mental disorder like major depression.

The process of testing this hypothesis is precisely what led to development of the new method described in The American Journal of Human Genetics. And the study was in no way small in scale!

Krebs and his associates used the iPSYCH registry to look at anonymised genetic data from 31,000 Danes diagnosed with major depressive disorder.

Next, by consulting the Danish National Patient Register, the researchers could then link – still in anonymised form – each one of the 31,000 to 100 of his or her relatives: grandparents, parents, siblings, half-siblings, uncles, aunts, cousins – and in some cases more distant relatives, too. Up to a total of almost 2 million people!

“We didn't have access to DNA information on all these relatives. But through the Danish National Patient Register we could see the psychiatric diagnoses these 2 million people had been given over the course of their lives,” Krebs explains. And after adding up all the data, the researchers were able to conclude that the genetic risk of developing major depression increases if there is a a high incidence of mental illness in the family.

“The study also underlines that although it is becoming increasingly easy to study DNA sequences, information about relatives – family trees – still plays a major role in research into disease genetics,” stresses Schork, the last (lead) author of the scientific article.

Krebs will be continuing to work on this type of study over the next five years with a research grant of DKK 2.5 million from the Lundbeck Foundation. Meanwhile, the aim is for the method to be trialled on other illnesses with a genetic component:

“Examples would be cardiovascular disease and diabetes. We’ll be looking into that in collaboration with researchers from Rigshospitalet – Copenhagen University Hospital,” says Krebs.