Major depression leaves a metabolic signature

24 Apr

Researchers have made a surprise discovery that major depression leaves a metabolic mark, giving them new insight into the nature of this disorder.

Sad woman.
The researchers unexpectedly discovered higher levels of mitochondrial DNA in samples taken from women with histories of stress-related major depression.

This unexpected finding, published in Current Biology, was made when Prof. Jonathan Flint and colleagues were researching genes that could increase the risk of depression.

“Our most notable finding is that the amount of mitochondrial DNA changes in response to stress,” states Prof. Flint, a professor of molecular psychiatry at the University of Oxford, UK.

Mitochondria are sometimes known as the powerhouses of cells, generating the energy that is required for cells to fulfill their roles. An increase in mitochondrial DNA (mtDNA), Prof. Flint explains, may indicate a change in mitochondria and cellular energetics.

“We see an unexpected link between cellular energetics and major depression, which has always been seen as a mood disorder,” he continues.

The discovery was made by chance when the researchers were investigating the genes of thousands of women with recurrent major depression, comparing them with the genes of healthy control participants.

In the DNA samples taken from women with histories of stress-related depression – often related to forms of childhood adversity such sexual abuse – the researchers found that there were more mitochondrial DNA present compared with samples from other study participants.

“We were surprised at the observation that there was a difference in mitochondrial DNA – so surprised it took us a long time to convince ourselves it was real, and not an artifact,” Prof. Flint recounts.

Depression can occur as a result of chemicals in the brain, genetics and life situations. In particular, situations that are consistently stressful can increase the risk of depression developing. If stress is not dealt with properly, it can wear individuals down and have a marked influence on their health.

Study offers a ‘snapshot of the relationship between molecular markers and depression’

Prof. Flint and his team set about investigating another molecular process that previous studies have associated with depression. Researchers have demonstrated that changes in metabolism can change the rate of aging, indicated by the shortening of telomeres – sequences that cap the ends of chromosomes to protect them from deterioration.

The team wondered whether the way in which telomeres erode would change alongside changes to amounts of mitochondrial DNA. Using whole-genome sequencing, the team discovered that this was indeed the case.

To assess whether these molecular changes were caused by stress, the team examined laboratory rats that were made to endure stress for 4 weeks. Not only did this investigation demonstrate that the molecular changes were caused by stress, but these changes were reversible to a degree and elicited by corticosterone, a stress hormone.

These molecular changes may indicate how the body copes with major environmental stressors, Prof. Flint states.

Perception of a threat such as a history of abuse could lead to a series of metabolic changes as a form of protection. “Depression might in some sense be considered a metabolic reaction to perceived stress,” Prof. Flint suggests.

The team hopes that these changes could be used as biomarkers of stress and associated conditions. Levels of mitochondrial DNA, for example, could be assessed after a course of treatment in order to find out how successful the treatment was.

“We have only a snapshot of the relationship between the molecular markers and depression,” Prof. Flint admits, indicating that further research is required. “We want to know how they change over time – before, during, and after a depressive illness. That information will tell us much about their clinical utility.”

Recently, Medical News Today reported on an editorial article published in The BMJ, in which a professor of psychiatry argues the idea that depression is caused by low levels of the neurotransmitter serotonin is a myth.