What happens in the body when antidepressants work. An international group of researchers, led by Professor Gustavo Turecki of McGill University and the Douglas Mental Health University Institute, examined changes in the activity of genes (measured using mRNA) in the blood in over 400 patients who were being treated with antidepressants.
They identified one gene that was significantly more active in patients who had an antidepressant response to either citalopram or duloxetine. The gene is known as ADGRG1 and the gene product (a G receptor protein) is known as GPR56.
GPR56 is an adhesion G protein-coupled receptors (adhesion GPCRs) and has many roles in cell guidance and cell adhesion as shown by its roles in tumour inhibition and neuron development. In addition, GPR56 is associated with several processes implicated in depression, including neurogenesis, development of oligodendrocytes, progenitor cell migration, and myelin repair.
The researchers examined GPR56 regulation in three groups of patients treated for depression. A group of patients treated with duloxetine 60 mg a day, a group of patients treated with citalopram 10 to 60 mg a day, and a group of patients treated in a naturalistic way with a number of antidepressants. In all three groups of patients GPR56 increased in a way that clearly distinguished treatment responders and nonresponders. In the initial study of duloxetine patients the researchers were able to show that placebo responders did not show an increase in GPR56, so the increased production of GPR56 was not a marker for depression improvement in general, but a specific marker for the effectiveness of antidepressant medications.
The researchers also showed that GPR56 was down regulated in an animal model of uncontrolled stress and in the prefrontal cortex of people who committed suicide.
In other words, this finding is not just a fortuitous correlation of two events. Upregulation of GPR56 is associated in many ways with depression and its effects in the body. This suggests that research into medications that affect GPR56 may lead to new treatments for depression.
“Identifying new therapeutic strategies is a major challenge, and GPR56 is an excellent target for the development of new treatments of depression.”Gustavo Turecki in an interview posted on the McGill University website.
In fact, researchers at the University of Chicago, led by Gabriel Salzman, have already begun to characterize the activity of GPR56. They have shown that there are two ways that the receptor can be activated. In one, a large part of the protein that extends into the extracellular region is clipped off and then the receptor is activated. This type of activation (Stachel mediated activation) is irreversible and may play a role in neuronal development and other functions in human development.
Another type of activation is more familiar to us in psychiatry. There are compounds that interact with the receptor in a reversible way and increase activity.
Identifying these compounds and synthesizing analogs may be one way this finding might lead to new treatments.
One challenge faced by researchers may be the diversity of roles for GPR56 throughout the body. It is involved in muscle development, regulation of T-cell activity in the immune system, and it seems to play a key role in the body’s response to several types of cancer.
Strokes N, Piao X (2010). Adhesion-GPCRs in the CNS. Advances in Experimental Medicine and Biology. 706. pp. 87–97. doi:10.1007/978-1-4419-7913-1_7. ISBN 978-1-4419-7912-4. PMID 21618828.
Belzeaux R et al. GPR56/ADGRG1 is associated with response to antidepressant treatment. Nat Commun 2020 Apr 2; 11:1635. (https://doi.org/10.1038/s41467-020-15423-5)
PNAS September 19, 2017 114 (38) 10095-10100; first published September 5, 2017 https://doi.org/10.1073/pnas.1708810114