Researchers have updated the role of the GPR56 gene in the response to antidepressants and the pathophysiological mechanisms of depression. This discovery is “a source of hope because it represents a possibility of developing new leads”, explains doctor Raoul Belzeaux, first author of the study, to Why doctor.
Every year, depression affects more than 2 million people in France. It is often treated with antidepressant treatments. Unfortunately, these do not work for one in five patients. The reasons for this lack of response are still poorly understood today. A new study could, however, change the situation. A consortium of researchers and clinicians coordinated by Professor Gustavo Turecki (Douglas Mental Health University Institute and McGill University, in Canada) and supported in France by the Fundamental Foundation, discovered the role of the GPR56 gene in the response to antidepressants and the pathophysiological mechanisms of depression. Why doctor questioned the first author of the study, which appeared in the journal NatureCommunications. According to Raoul Belzeauxpsychiatrist at the Assistance Publique Hôpitaux de Marseille and researcher at the Timone Neuroscience Institute (Aix-Marseille University/CNRS), these results are “a source of hope because they represent a possibility of developing new avenues”.
“Identifying new therapeutic strategies is a major challenge for a large number of patients. When we prescribe an antidepressant treatment, we do it a little by experience, by habit, and above all, unfortunately, by chance. In fact, we are never sure of attributing the right treatment to the right person because we know little about the different mechanisms of action of one drug to another.he explains first. PohTo understand and discover new leads on how they work, we started with clinical studies of patients who received a placebo or different types of antidepressants. We used genomic techniques to try to identify genes that varied, without havinga priori. This is how we discovered GPR56”continues the researcher.
GPR56 is a particularly complex receptor involved in many biological processes including neurogenesis (formation of neurons) and brain maturation, astrocyte maturation but also the activation of the immune system. If it is a known gene, it is not yet known in the field of psychiatry.
The region of the cerebral frontal cortex particularly affected
“It has been seen in three different studies, including a total of 400 patients, that many antidepressants activate GPR6 in treatment-responsive patients”. On the other hand, when the molecule was not activated, nothing changed in the patients, develops Doctor Belzeaux. GPR56 also did not activate in those given a placebo.
However, until then, these were only observations: no causal link had been proven. “However, with animal models, we have been able to modify the activity of the gene. Result: if we increase the GPR56 in the frontal cortex, with pharmacological agents or genetic modifications, we obtain an antidepressant effect. On the other hand, if it is reduced or inhibited, a depressogenic effect is observed in rodents”explains the psychiatrist, referring to the work carried out by Eleni Tzavara, doctor and director of research at Inserm, who contributed greatly to this project. Thereby, “hyporesponsiveness of GPR56 could therefore well be a potential mechanism of drug resistance”.
“The involvement of the frontal cortex is interesting, because this area is very important in decision-making, the regulation of emotional reactions or even cognition, that is to say the ability to analyze and filter one’s emotions.says Raoul Belzeaux.
“GPR56 is an easy-to-measure blood biomarker”
While it seems that all antidepressants act via this mechanism, this has yet to be proven. “There are about forty antidepressants available in France, it’s very vast. The effect of GPR56 does not seem to be an ultra-specific mechanism, which is rather interesting”, welcomes the psychiatrist. Also, even ifit is not every day that we manage to describe in a sufficiently robust way a possible pharmacological mechanism to find a molecule”there is still a long way to go before arriving at the infallible treatment for today’s antidepressant-resistant patients.
From now on, the roadmap is composed of three stages. The first should be the fastest and could be completed within a few years. “The main interest of our discovery lies in particular in the fact that GPR56 is also an easy-to-measure blood biomarker.explains Dr. Belzeaux. As we can measure GPR56 in the blood, perhaps it can be used to biologically monitor the response of patients to antidepressants.
“We could therefore determine the possible interest of blood tests. We obtained international funding with our Canadian and Spanish collaborators (ANTARES project, ERA-NET Neuron, led by E Tzavara) to measure biological variations in the first days following the start of antidepressant treatment. These appear long before the clinical variations, which sometimes appear several weeks later. A certain number of hypotheses will therefore be tested, including GPR56. This will allow the patient to be told: ‘In one week you haven’t had a gene variation, it’s a bad prognosis. We must therefore change our strategy‘”, explains the psychiatrist.
At the same time, researchers may therefore be able to understand why some patients are unable to activate the GPR56 gene when they take antidepressants. “It can be genetic or epigenetic causes: has the gene, modified by negative life experiences, become too ‘rigid’ to be stimulated despite antidepressants?“says Raoul Belzeaux.
A new drug target
The second step should take a little longer since it is a question of pharmacologically targeting GPR56. A first strategy would be that of repositioning drugs that are already known. “One can analyze many drugs available on the market today and look for those that might stimulate GPR56. If we find some that do not already belong to the family of antidepressants, this could make it possible to introduce new drugs into the pharmacopoeia of depression. In a few years, we could develop the use of a drug already known for something else and try it quickly in the clinic without going through the stages of development of a new molecule. If we already know a drug, we know its effective dose, its risks and its interactions”continues the researcher.
The third stage, on the other hand, will probably take well over ten years since it will involve developing new molecules. “The industry generates many molecules that have never been tested on humans. However, it is not because a molecule works well in vitro that its effects will be well tolerated in humans and that it will be usable”explains Raoul Belzeaux.
Thus, this discovery about GPR56 not only unveils a previously unknown mechanism of antidepressants, but it also offers a new drug target. “If we discover pharmacological compounds that act on this receptor, this could lead to the creation of new antidepressants. For now, the available molecules act mainly on the serotonin transporter. But molecules targeting GPR56 could perhaps work very well in the treatment of depression”concludes the researcher, full of hope.
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