Major depressive disorder (MDD) 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 (MDE), and although they are effective, not every patient responds to antidepressant treatment. Approximately 40% of patients respond to their first antidepressant trial, and following multiple trials, response rates increase up to 70%. Antidepressants are thought to act through modulation of mono-amines, but the precise mechanisms whereby they affect therapeutic response, as well as the underlying causes of treatment-response variability, remain poorly understood. Therefore, there is an important need to better understand molecular pathways and mechanisms involved in antidepressant response. A new paper in Nature Communication strongly suggests that a particular protein, GPR56, is involved in the biology of depression and the effect of antidepressants. Professor Gustavo Turecki of McGill University and the Douglas Mental Health University Institute, an international consortium of researchers and clinicians, led the investigation. The McGill led research team believe that this protein could offer a novel target for new antidepressant drugs.
In this study, scientists 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. GPR56 is involved in a number of biological functions relevant to the pathophysiology of depression, including neurogenesis, oligodendrocyte development and progenitor cell migration in brain, as well as myelin repair, in parallel to its important role in immune cell functioning. GPR56 ligands comprise two general subtypes: (1) proteins from the surface of neighboring cells, and (2) extracellular matrix proteins. Known extracellular ligands of GPR56 include collagen III, the enzyme transglutaminase 2 and heparin. Very recently, the aminoacid L-phenylalanine, the basic precursor for antidepressant norepinephrine and dopamine, was discovered to behave as a metabolic activator of GPR56 as well, strenghtening the its link with depressive disorders.
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.They focused on four regions of interest: the dorsal and ventral hippocampal areas, the prefrontal cortex (PFC) and the Nucleus Accumbens (NAcc), all previously implicated in stress and depression, albeit in a different manner. They found that GPR56 was changed in depression, and that it was modified, both in the blood and the brain, when antidepressants were administered. These changes were particularly evident in the prefrontal cortex, an important area of the brain for the regulation of emotions and cognition. In the PFC, it was observed a bimodal regulation of Gpr56 mRNA by chronic mild stress and antidepressant treatment. Chronic mild stress exposure led to reduced Gpr56 mRNA expression, which was normalized by antidepressant administration in responder mice, but not in non-responder mice, a pattern remarkably similar to that seen in the mouse and human blood samples. Following activation of the GPR56 receptor by its ligands, the extracellular and transmembrane domains of GPR56 dissociate to reveal a tethered-peptide-agonist.
Based on this mechanism, the team made synthetic peptides P7 (TYFAVLM-NH2) and P19 (TYFAVLMQLSPALVPAELL-NH2), able to activate the receptor itself. Good activity was seen especially on the prefrontal cortex though GPR56 is expressed in all known human brain areas. Finally, using coltured neuroblastoma cells, raw experiments and RNA sequencing found that GPR56 agonists enhanced the Akt-GSK3-eIF4 axis, a cellular pathway mechanisms previously associated with depression and antidepressants action. Professor Gustavo Turecki of McGill University commented positively: “While further efforts are needed to develop compounds with optimised pharmacokinetic properties for in vivo administration, our findings identify a previously unsuspected GPCR as a possible target for antidepressants. Identifying new therapeutic strategies is a major challenge, and GPR56 is an excellent target for the development of new treatments of depression. 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”.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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