What has depression got to do with diabetes?

Investigating the causes of depression might seem an unusual area for CCS's Department of Diabetes epigenomic medicine group, but that’s exactly what scientists there are doing – and in an ambitious way.

Researchers led by Dr Tom Karagiannis have conducted an interdisciplinary review of the breadth of biological pathways that can lead to Major Depressive Disorder (MDD). MDD is the most severe form of depression; patients experience chronic sadness and hopelessness, find it hard to go about their normal life and can think suicidal thoughts. One in five people is estimated to experience it at least once in their lifetime. Women are twice as likely to have MDD although the suicide rate is higher in men. 

MDD can usually be treated successfully using medication, psychotherapy and by introducing changes to lifestyle.

However, while clinicians can treat the symptoms, the precise cause of the disease is not known. This is despite extensive research and a vast body of literature into the pathways leading to MDD by researchers worldwide from laboratory scientists to psychiatrists.

“What we wanted to do was look at the specific pathways that are involved in depression and amalgamate them into a model,” Dr Karagiannis said. “You need a model because depression, as we know, is complicated. There are some very primitive fight-or-flight pathways involved, which makes it very difficult to handle and to treat,” he said.

Pathways are molecular interactions in a cell that leads to changes to the cell, including the formation of new molecules, such as a fat or protein, switching genes on and off, and causing disease.

The pathways in the review, summarised in the figure above, overlap. Dr Karagiannis said that some compounds in diet affect several pathways. The key pathways discussed include neurotransmission, neuroinflammation, circadian gene machinery pathways, oxidative stress, the role of neurotrophins, stress response pathways, the endocannabinoid and endovanilloid systems, and the endogenous opioid system.

Dr Karagiannis is currently conducting research investigating the role of oxidative stress in depression. Oxidative stress occurs when there is an imbalance between unstable, potentially damaging ‘free radicals’ and antioxidants in the body.

“We have studied mouse models of diabetes and have seen elevated expression of enzymes related to monoamine oxidase enzymes which leads to behaviour that mimics depression,” Dr Karagiannis said.

The review garnered information that Dr Karagiannis and his group will use to inform investigations testing compounds that might lead to therapeutic targets for MDD. “We have an enormous library of compounds – proteins and enzymes associated with depression – that we can screen using animal modes of disease,” he said.

The review also describes the current management of MDD, and emerging novel therapies focussing on patients with treatment-resistant depression. First author was Ms Eleni Pitsillou.

Pitsillou E, Bresnehan SM, Kagarakis EA, Wijoyo SJ, Liang J, Hung A, Karagiannis TC. The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression. Mol Biol Rep. 2019 Oct 14. doi: 10.1007/s11033-019-05129-3. [Epub ahead of print] 

If you are experiencing depression: Beyond Blue (www.beyondblue.org.au)