Synaptogenesis as a readout of antidepressant response in major depression: a translational approach. – SYNAPTOMOOD

Major depressive disorder (MDD) is the leading cause of incapacity worldwide. The varying degrees of efficacy of antidepressant drugs justifies further investigation of the mechanism of action of antidepressants. Accumulating evidence suggests that synaptic plasticity is involved in the pathological changes of major depressive episodes (MDE). Synaptogenesis, i.e. the formation of new synapses between neurons, is a major mechanism of cerebral plasticity and may explain different levels of antidepressants’ efficacy and onset of action. Interestingly, the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET), rapidly induces synaptogenesis in rodents and produces rapid (within hours) antidepressant response in treatment-resistant depression. Synaptic plasticity may therefore explain antidepressant efficacy and onset of action between antidepressant drugs. Quantify synaptic density in the living human brain may therefore represents the translational lever to better understand, predict, monitor and optimize therapeutic efficacy of antidepressants. Thus, [11C]UCB-J is an innovative radiopharmaceutical for quantitative Positron Emission Tomography (PET) imaging of synaptic vesicle protein 2A (SV2A), a transmembrane protein specifically located in secretory presynaptic vesicles of functionally active synapses. [11C]UCB-J PET has emerged as a translational biomarker of synaptic density for investigating synaptic loss in psychiatric disorders. Indeed, a lower synapse density has been recently evidenced in MDE patients with [11C]UCB-J PET in both the hippocampus, a key hub within the limbic system, and two connected areas from the limbic system, i.e. the prefrontal cortex and anterior cingulate cortex. Furthermore, preliminary data from our group show that a depression-like phenotype in mice is associated with a decrease in both hippocampal area volume and [11C]UCB-J uptake, both of which may be related to a deficit in synaptic density.
[11C]UCB-J PET imaging could provide an appealing tool to study how synaptic plasticity relates to clinical improvement in the brain of MDE patients.
The current project proposes a translational program to provide in-depth monitoring of synaptogenesis associated with efficacy of the monoaminergic antidepressant venlafaxine (VENLA) alone or associated with KET as a booster of efficacy.
The preclinical work-package 1 will investigate whether brain SV2A density measured with [11C]UCB-J PET represents synaptic density in mouse model of depression and define a synaptic proteomic signature of a KET booster to VENLA, a conventional antidepressant drug.
The clinical work-package 2 will investigate a putative “growth” in synaptogenesis after antidepressant treatment, in limbic areas of patients hospitalized with a severe MDE, by measuring changes in [11C]UCB-J PET before and 14 days after initiation of VENLA+PLACEBO or VENLA+KET in a treatment randomized, controlled, double-blind, mono-center, parallel group study.
The reverse translational preclinical work-package 3, combining multimodal in vivo and post-mortem approaches in a mouse model of depression will decipher how synaptogenesis modulating structural and functional activities in limbic areas, including the hippocampus, is involved in antidepressant onset of action of VENLA alone or in combination with a boost of KET.
This study paves the way for translational program to thoroughly characterize the differential impact on synaptogenesis of a KET boost versus a conventional antidepressant and the contribution of these impacts on antidepressant efficacy in depressed patients. Finally, PET imaging offers the missing link and translational lever to explore synaptogenesis as a determinant of therapeutic response in MDD patients. It would undoubtedly foster further collaborative research using innovative radiopharmaceuticals for neuroimaging in translational psychiatry.