Depression affects millions of people worldwide. Antidepressant medications are available, but their beneficial effects often appear only after several weeks and their efficacy varies across patients. Moreover, the mechanisms underlying responses to antidepressant treatments remain poorly understood.
In recent years, ketamine—an NMDA receptor antagonist initially used as an anesthetic in both veterinary and human medicine—has profoundly changed the management of depression. When administered at low doses, it can relieve symptoms within just a few hours. Until now, however, the cellular and molecular bases of this rapid antidepressant effect had remained inaccessible
in vivo.
The BioMaps teams (a unit located at SHFJ, CEA/Inserm/CNRS/Université Paris-Saclay) and MOODS (CESP-Inserm, Université Paris-Saclay[1]) used a state-of-the-art molecular imaging technology: positron emission tomography (PET) with the radiotracer [¹¹C]UCB-J, which targets the SV2A protein, a direct marker of synaptic density.
Using SV2A-PET imaging, the researchers observed a global decrease in synaptic density in well-characterized mouse models of depression (induced by corticosterone exposure) from a behavioral standpoint. This finding reflects a measurable loss of neuronal connections associated with a depressive state.
Administration of a single dose of ketamine led to rapid behavioral improvement without an immediate change in synaptic density. In contrast, repeated treatment resulted, three weeks later, in an increase in synaptic density that was correlated with normalization of social and emotional behavior tests.
Ex vivo analyses confirmed these observations, showing a positive correlation between the cerebral PET signal and the actual expression of the SV2A protein or PSD-95, an alternative synaptic marker. The delayed increase in synaptic density induced by ketamine in the depression model was not observed in mice that had not been exposed to corticosterone.
This unique translational approach makes it possible to link ketamine-induced changes in synaptic density to their behavioral manifestations and to study their temporal relationship. It demonstrates the relevance of SV2A-PET for investigating the effects of antidepressant treatments such as ketamine on synaptogenesis, which is impaired in depression, an approach that could be extended to other psychiatric disorders.
Towards CliNICS
This approach is currently being implemented as part of a clinical study aimed at exploring the dynamics of synaptic plasticity in response to antidepressant treatments in patients (ANR SYNAPTOMOOD project[2]).
The ambition of this innovative approach is to enable earlier objective assessment or prediction of therapeutic response, to identify non-responding patients, and to optimize the effectiveness of treatment protocols.
Thus, SV2A-PET should make it possible to link the molecular, functional, and behavioral dimensions of depression. It offers a unique tool to bridge preclinical research and fundamental neuroscience with clinical practice. Like precision medicine developed in oncology, this approach lays the groundwork for biomarker-guided psychiatric care based on molecular imaging
Contact Frédéric-Joliot Institute for Life sciences:
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[1]Centre de recherche en Epidémiologie et Santé des Populations (Inserm, Université Paris-Saclay, UVSQ)
[2]ANR SynaptoMOOD (coordinateur : Pr Romain Colle) : ANR-22-CE17-0015