New insights into major depressive disorder and treatment response

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Psychiatric and mood disorders are some of the hardest to treat, probably because they are also some of the hardest to understand in terms of underlying disease mechanisms. Though the treatment for many of these disorders has certainly improved, there remains room for further improvement. For instance, when it comes to the treatment of major depressive disorder (MDD), a disorder characterized by the loss of pleasure, decreased mood, and feelings of decreased self-worth, there is a wide range of responders to available treatments, with some patients responding much better than others.

In the most recent issue of Nature Medicine, researchers at McGill University and University of British Columbia identify, through the use of human postmortem brain tissue, a micro-RNA (miRNA) whose expression is decreased in the brains of depressed patients and predictive of responses to antidepressants.

Micro-RNAs are small pieces of RNA (genetic material) that do not code for protein. In other words, these RNA pieces remain strands of RNA. On the other hand, messenger-RNAs (mRNA), another type of RNA, sit around and are used by cells as instructions to build new proteins. The cool thing about miRNA is that the codes carried by these strands are complementary to different mRNA molecules. In this way, miRNAs can pair with the coding RNAs and prevent the cell from using them to make additional proteins. This process allows miRNAs to control different cellular functions by controlling the levels of specific proteins.

In this paper, Lopez et al. shows that miR-1202, a miRNA, is decreased in the brains of depressed individuals. Interestingly, when the authors  investigated the conservation of this molecule in different species, they found that miR-1202 was only expressed in human and primate samples. Specifically, miR-1202 was most expressed in the brain compared to other tissues. The authors also tested rat, mouse, and chicken brains, where they did not detect any expression.

Interestingly, the authors also tested the levels of miR-1202 targets, identifying 5 genes that were changed in the brains of depressed patients. One of these genes, GRM4, was negatively correlated to the expression of miR-1202, showing increased levels when levels of miR1202 are low. This is an important finding as GRM4 is a glutamate receptor gene, a gene that codes for a protein known to be involved in the signaling of a variety of neurotransmitters including glutamate, dopamine, GABA, and serotonin. This data suggests that miR-1202 probably plays an important role in controlling neurotransmitter signaling in the brain, a process that could underlie the symptoms associated with MDD.

Perhaps that most important finding of the study was that miR-1202 expression was linked to the response to antidepressant treatment. In the final experiment the researchers treated patients with the antidepressant citalopram and looked at the levels of miR-1202 in blood samples from patients with MDD and control subjects, where as already described, they found decreased miR-1202 in the depressed samples. Next, the levels of miR-1202 were compared after the depressed patients were classified into “remitter” and “nonresponder” groups. This comparison revealed that the lower expression levels were actually specific to the remitter patients, while miR-1202 levels were no different between the nonresponders and control subjects, linking levels of miR-1202 to the ability of patients to respond to an antidepressant drug.

Doctors everywhere wish that they could predict how well their patients would respond to their prescribed treatments, an ability that would allow them to create effective treatment plans based on these predictions. This has been a hot topic in biomedical research as scientists have been scrambling to identify “biomarkers” that can detect disease onset or predict treatment outcomes. This paper presents an important step in potentially predicting treatment responses in individuals with MDD. Could miR-1202 be used as a biomarker? Are other miRNAs involved in depression or other psychiatric disorders? Can these be used as biomarkers as well? This paper not only presents important findings for the future of MDD treatment, it also brings up new questions to be considered when it comes to the treatment of all psychiatric disorders. Personalized medicine may well be on its way.

Lopez, J. P., Lim, R., Cruceanu, C., Crapper, L., Fasano, C., Labonte, B., et al. (2014). miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nature Medicine, 1–7.

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