Lying comfortably on his mattress, Hubert* has a smile on his face. The quadra has the impression of floating. His body expands. His arms stretch out. His negative ruminations, usually so tenacious, fade away. Nothing seems important anymore. This “trip” does not take place in his living room but in a clean room at the Pitié-Salpêtrière hospital in Paris. For forty minutes, under the watchful eye of a psychiatrist, Hubert receives an infusion of ketamine. This narcotic figure in the last recommendations of the French Association of Biological Psychiatry and Neuropsychopharmacology, which cites it among the treatments for resistant depression.
Psychedelics improve symptoms of severe depression
Like ketamine, psychedelic drugs have reinvested the field of psychiatric innovation for two decades. LSD, psilocybin, ayahuasca, MDMA, these psychotropics had already been studied in the 1950s and 1960s before being banned by the authorities following abuses in their consumption. Over the past twenty years, regulators have softened their judgment, because research in this field is very promising for certain pathologies. “Patients who have been depressed for several years are doing better since taking ketamine. Their mood is stabilizing,” notes Philippe Fossati, head of the adult psychiatry department at Pitié-Salpêtrière. “Psychedelics cause an altered state of consciousness that improves their symptoms in just a few hours,” adds Raphaël Gaillard, director of the hospital-university psychiatry center at Sainte-Anne hospital in Paris.
“This opens up a major field for pharmacology, that of fast-acting antidepressants,” enthuses psychiatrist Hugo Bottemanne. A Copernican revolution for a profession that hasn’t released any substantial innovation since the middle of the last century. It has remained focused for too long on antidepressants which target, for example, serotonin and dopamine, neurotransmitters involved in the regulation of emotions. “The mechanisms have not changed for seventy years. The molecules are better and better tolerated, but not more effective”, continues Raphaël Gaillard.
There was an urgent need to find new remedies. Depression is a real scourge that affects nearly 300 million people, on the way to becoming the leading cause of disability in 2030, according to the World Health Organization. 1 in 5 individuals will experience a depressive episode in their lifetime requiring treatment. Worse, the first treatment only works in 30% of cases. About a third of patients do not respond at all to conventional antidepressants.
Ketamine which acts on glutamate receptors can accelerate remission
The study of alternative substances has something to give them hope. The first molecule of this kind to have been marketed today is ketamine – an anesthetic whose antidepressant effect was accidentally discovered by American researchers. Administered intravenously in minimal doses, this substance “generates a cascade of effects in the brain which leads to well-being” explains Liane Schmidt, doctor in cognitive neuroscience and researcher at Inserm. Coupled with an antidepressant, the molecule, which acts on glutamate receptors, can accelerate remission. It is indicated for severe and resistant depression but also, given its rapidity of action, for suicidal crises.
The mechanisms at work remain largely mysterious, but science is progressing step by step. In October, a team of researchers from the brain institute published in the review Jamaica Psychiatry a study showing that taking ketamine caused patients with resistant depression to have less pessimistic beliefs about themselves and the world. The effects were measurable four hours after administration… whereas conventional antidepressants take four to six weeks to work. The dissociation of the individual with his own body, experienced during the infusion, could contribute to the therapeutic effects.
A substance used intravenously in the hospital
Pharmaceutical companies closely follow the work on psychotropics – even if they remain discreet. The pioneer Janssen, a subsidiary of the American giant Johnson & Johnson, has patented a nasal spray based on esketamine, a derivative of ketamine. The product, called Spravato, was approved by the American regulator in 2019, and by Europe in the process. “We use it a lot in Sainte-Anne. The depressant effect works as well as ketamine by infusion, but nasal administration is simpler”, says Professor Raphaël Gaillard. Before adding: “This allows us to treat five times more patients than intravenously.” Doses are given twice a week for a month, then spaced out.
However, the use of Spravato remains limited in French hospitals because of its cost. In his book Healing Our Wounded Souls – The Therapies Revolution (Marabout, 2023), David Gourion, expert with the High Authority for Health, pleads for the possibility of administering ketamine in the office, as “in other European countries”. An accompaniment is in any case essential because of potential adverse effects, like hallucinations qualified as Alice in Wonderland syndrome. “These therapies must be associated with psychotherapeutic support. The psychedelic experience is often rich in meaning for the patient, but can prove to be destabilizing”, insists Hugo Bottemanne.
Extracts of hallucinogenic mushrooms developed in synthetic version
In addition to ketamine, a large number of molecules derived from psychotropic drugs are under development. The most studied and promising, psilocybin, is extracted from hallucinogenic mushrooms. Australia has just legalized it to treat acute depression, following the path of Oregon in the United States, in 2019. The very influential FDA, the American drug agency, had granted this psychoactive substance the status in 2017. of “therapeutic breakthrough”.
A British start-up, Compass Pathways, has developed a synthetic version of psilocybin and conducted a large clinical trial involving 233 people in 10 countries. The results were published in the prestigious New England Journal of Medicine. After three weeks, 29% of patients who received a 25 milligram dose were in remission. An unprecedented performance. The French hospitals Sainte-Anne and La Pitié-Salpêtrière are participating in phase 3 trials which start this year and will extend until 2025. “The studies report very significant reductions in depression scores, both immediately and lastingly. “, confides the researcher in cognitive neuroscience Lucie Berkovitch. The trip, which lasts four to eight hours, is like an intensive therapy session. The patient frequently experiences a mystical state and transcendental revelations. Two therapists accompany him to reassure him, help him let go of control and verbalize what he is going through.
Treatments with powerful side effects
A sacred Native American plant, ayahuasca, also fuels the hopes of researchers. Powerful psychedelic traditionally used by Amazonian shamans, it contains dimethyltryptamine. The effects of this molecule on depression are currently being studied by BioMind, a canadian biotechnology company. “The trip is relatively short, fifteen minutes to an hour, but can cause nausea,” tempers Lucie Berkovitch.
With the improvement of treatments, could these substances one day supplant current antidepressants? “I fear that there is an unreasonable expectation on psychedelics. Their intake must be done in a very precise framework because the side effects can be powerful”, tempers Raphaël Gaillard. Given their mode of administration, the adoption of these new drugs will indeed require substantial human resources.But in a very constrained budgetary context, the French hospital crisis is the biggest obstacle to better treatment of severe depression.
* The first name has been changed