Denis David: fighting depression with new therapeutic goals

Denis David is a professor of Pharmacology at Université Paris-Saclay and a member of the Moods team at the Centre for Epidemiology and Population Health (CESP - Univ. Paris-Saclay, Inserm, UVSQ). He is committed to pushing the boundaries of research in order to improve care for patients suffering from depression.

After completing a General Academic Studies Degree (DEUG) in Life Sciences and a Bachelor's degree in Physiology in 1998 at the Institut Catholique de Vendée, Denis David continued with a Master's degree in Physiology/Pharmacology. "I did a voluntary internship in the Neuropharmacology laboratory at the Faculty of Medicine in Nantes during my undergraduate studies, and I liked it so much that I did it again during my Master's degree." In 2000, he completed an MPhil in Experimental and Clinical Pharmacology at Université Paris-Sud (now Université Paris-Saclay), while continuing his research internship in the Neuropharmacology laboratory. In 2003, he completed his thesis while at the laboratory, in partnership with the Serotonin and Neuropharmacology team from Université Paris-Sud (absorbed into the CESP in 2020 and renamed Moods) to add a neurochemical component to it. His topic was the study of variability and size of the effect of antidepressants in behavioural and neurobiological models.
Combining behavioural studies with neuroscience

Thanks to a grant awarded by the professional organisation Les Entreprises du Médicament (LEEM), Denis David did a post-doctoral fellowship at Columbia University, New York in 2003. This was an opportunity for him to learn new skills in immunohistochemistry - a technique that uses antibodies to identify antigenic proteins in the cells of a tissue section. "I wanted to gain a better understanding of the role of neurons produced in the hippocampus of the adult brain, a region involved in emotion regulation and learning."

The study of adult hippocampal neurogenesis

In September 2004, he returned to France and was recruited as a lecturer in the Serotonin and Neuropharmacology team. From there, he directed his work towards hippocampal neurogenesis in adults and its implication in the response to antidepressants. Hippocampal neurogenesis is a phenomenon present in almost all mammals. It takes place all through life in the dentate gyrus area, located in the hippocampus in the brain. The neural stem cells undergo an asymmetric division, which generates new cells (or young neurons) that are then included in the neural network. This process is modified in depressive states and under the action of antidepressants. "Even though the hippocampus is not the only region activated by antidepressants, our work showed that these young neurons are actively involved in the remission of depressive symptoms."

The Cort model: a considerable advance for the scientific community

In order to test antidepressants on rodents, the rodents must be in a depressive-like state. Thanks to the National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator award granted by the American Brain & Behavior Research Foundation, Denis David developed, in partnership with Columbia University, the Cort pharmacological animal model. It mimics, via an exogenous contribution of corticosterone in drinking water, the consequences of chronic stress. Thanks to the contribution of this metabolic hormone secreted by the adrenal gland, it reproduces certain aspects of the depression characterised. Denis David studied the behavioural changes induced, namely a loss of preference for sucrose, a decrease in grooming, apathy, anhedonia (the inability to feel pleasure), cognitive disorders and hypersomnia (excessive sleep). In 2009, he published the results of this work in the journal Neuron. "The paper has had nearly 1,300 citations to date, and the Cort model is now used in laboratories all over the world".

The development of therapeutic molecules for human beings

The model also makes it possible to observe identical mechanisms in rodents and humans, such as neuroplasticity. Antidepressants that are effective in humans are therefore also effective in the Cort model, as they are able to restore all the neurobiological changes induced by corticosterone. Identifying the pathophysiology and pharmacological response is useful for the development of new molecules, and Denis David and his team enjoy numerous partnerships with the pharmaceutical industry. "Starting in 2006, we took part in the behavioural and neurobiological characterisation that was validated by the National Agency for the Safety of Medicines and Health Products (ANSM in French) in 2013. It is now available from chemists in France, Japan and the United States." The Moods team is one of the few translational teams in France, i.e. where it is possible to go from the mouse to the human being and vice versa.

Minimising relapses and recurrences

This translational approach is fertile and Denis David is now interested in the role of adult hippocampal neurogenesis in the prevention of relapse and recurrence in depression. During antidepression treatment, a maintenance phase follows the acute phase, during which the therapeutic response is observed: the treatment is then prolonged for a few weeks in order to minimise the risks of recurrence. And yet "there is no data in the scientific literature in preclinical studies on this subject," says Denis David who therefore set out to model these relapses in rodents and observed that adult hippocampal neurogenesis was also involved in reducing the risk of relapse in these animals.

Further work thanks to the Schaefer Award

Denis David has authored over a hundred scientific articles in renowned journals, and is never short of projects. He is working, in collaboration with the CEA and thanks to the Schaefer Award from Columbia University in 2022, on imaging hippocampal neuroplasticity with translational radioactive markers. This funding also gives him the opportunity to develop alternatives to benzodiazepines, i.e. symptomatic treatments for anxiety disorders. "They have many serious side effects, such as the risks of addiction, sedation and amnesia." In partnership with Columbia University, he is also interested in the serotonin 5HT4 receptor, which has rapid anxiolytic properties.

A passion for sharing knowledge

Passionate about his teaching mission at the Faculty of Pharmacy of Université Paris-Saclay, Denis David has been authorised to direct research since 2008 and has been a university Professor since 2015. He is Associate Director of Research at the Graduate School of Health and Drug Sciences of Université Paris-Saclay. He is also co-director of the University's Master's degree in Medicine and Health Product Sciences. "I really enjoy handing down my passion for research to students, and teaching them how our discipline has a very real impact on the therapeutic management of patients."