Depression is a common psychiatric disorder and one of the leading causes of disability worldwide. Antidepressants are the first-line treatment for moderate to severe major depressive episodes. Despite their effectiveness, only 40% of patients respond to the first antidepressant they try. A recent paper in Nature Communication strongly suggests that a particular protein, GPR56, is involved in the biology of depression and the effect of antidepressants. The research team believe that this protein could offer a novel target for new antidepressant drugs.

In this study, an international consortium of researchers and clinicians investigated changes in the activity of genes in the blood in over 400 patients who were being treated with antidepressants. The results showed clearly that there were significant changes in the levels of GPR56 in patients who responded favorably to antidepressants, but not in non-responders, or patients receiving placebo. This discovery is particularly interesting, as GPR56 may represent an easy-to-measure biomarker for response to antidepressants.

The researchers confirmed that GPR56, which can be detected through a simple blood test, was associated with biological changes in the central nervous system by doing experiments with mice, and by studying human brain tissue obtained from the Douglas Bell-Canada Brain Bank.

In mice, they show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways.

In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide.

"Identifying new therapeutic strategies is a major challenge, and GPR56 is an excellent target for the development of new treatments of depression," said the author. "We are hopeful that this will provide an avenue to alleviate the suffering of patients who face this important, and often chronic, mental illness which is also strongly associated with the risk of addiction and an increased risk of suicide."

https://www.mcgill.ca/newsroom/channels/news/promising-advance-depression-research-321494

https://www.nature.com/articles/s41467-020-15423-5

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fgpr56-adgrg1-is&filter=22