He is one of the most recognized figures in French neurobiology. Tuesday, November 21, Jocelyne Caboche, research director at the CNRS, recipient of the Legion of Honor, CNRS medalist, received the Marcel Dassault Prize – Fundamental Foundation for her promising work on new molecules to combat severe depression, while current treatments suffer a high failure rate. Interview.
L’Express: Depression still remains poorly addressed in our societies. However, we go to the pharmacy at the slightest cold. How do you explain this paradox?
Jocelyne Caboche: It is a difficult disease to diagnose, including by the patient. What is the difference between low mood, low mood, depression? Often, we consider it a sign of weakness, so we tend not to talk about it. Especially since there is a large lack of knowledge of treatments, modes of action, and time limits for effectiveness. All this harms care.
The doctor may also have difficulty recognizing depression. The symptoms, as defined, described, in the DSM, the reference work, are complex and diverse: it can be a loss of pleasure, anxiety, metabolic disorders, weight loss, libido. At least two of these symptoms must be detected, and they must be constant, every day for a week, to detect depression. Difficult to navigate.
How widespread are these depressions?
Major depressive disorders affect psychological functions and reduce quality of life. Around 350 million people are affected worldwide. The number of cases has jumped by 25% since the health crisis. It will be the leading cause of socio-economic and medical disability by 2030. It is a condition particularly diagnosed in developed countries, but this is mainly explained by access to screening, which is much simpler and common in these areas of the world.
What treatments are currently available?
Antidepressants systematically act on the levels of monoamines, these natural substances, such as serotonin, dopamine or norepinephrine, which the brain sends into the synapse between two neurons to regulate their activity. To regulate itself and gauge how much of these neurotransmitters is needed, the brain recaptures some of them.
First generation antidepressants prevent this reuptake mechanism. This causes the brain to produce more monoamines. Those of the second generation suppress mono-amine oxidase, enzymes responsible for cleaning up, degrading serotonin or norepinephrine. Here again the goal is to increase rates. The third generation mixes the two actions.
But these molecules are not ideal. Their response times are very long. It takes at least four weeks for antidepressants to take effect. Around 40% of patients do not respond to these molecules. And there are significant side effects, which lead to premature termination of care. In reality, few people see their quality of life improve as a result of these prescriptions.
New molecules appear, such as S-Ketamine. It acts as an intranasal injection, and has an immediate antidepressant effect. But it is a hallucinogenic dissociative agent. You must therefore be under medical supervision to be treated. There also remains electroshock, still used to stimulate brain activity in areas affected by depression. But again, it is a very restrictive process because it is invasive: a surgical procedure is necessary.
With the research we are carrying outInstitute of Biology Paris Seine – Sorbonne, and with the start-up that we created, MElkin Pharmaceuticals, we are trying to understand the intimate, cellular, molecular mechanisms that govern psychological illnesses within the brain. Instead of influencing hormonal levels, we want to act directly on the neurons, inside the cell. Thus, we hope that the action will be more targeted, and therefore more effective and sustainable.
By performing autopsies, we discovered that depressed people produce more ELK-1* proteins. We developed a peptide, PElk, capable of blocking these functions in mice, then tested these effects in these animals voluntarily subjected to a depressive state, via chronic stress. After several injections, their condition improved. And in combination with PElk, antidepressants have a faster effect.
Acting on the concentration of this substance in the neuron therefore constitutes a promising, and truly innovative, avenue which could reduce the time it takes for treatments to take effect. Especially since during the tests, no toxicity appeared. We have filed patents. But there are still many steps before a potential treatment. We will have to find stabilized molecules, with a method of administration guaranteeing that they are not too degraded by the body…
*Antidepressant effects of targeting ELK-1 signal transduction, Nature Medicine2018.
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