Innovative strategies and molecular mechanisms for enhanced antidepressant action – STRATAGEM

Depression (MDD) resistant to antidepressant (AD) drugs has profound individual and societal impact. We have recently identified a novel AD target the transcription factor ELK1. Because ELK1 operates inside the cell rather than the synapse, where “classical” ADs act, this discovery could pave the road to novel therapeutics. We content that an add-on strategy (classical AD+ELK1 modulator) would lead to rapid AD action and/or better efficacy.

Our preliminary results in the animal show that indeed this is the case with the tricyclic AD desipramine. We propose now to further validate our results in both sexes and determine if they generalize in all classes of ADs.

We also aim to inform on three important aspects, lack of which has hindered the translation of novel targets to novel therapeutics in the past: (i) understanding the causal mechanism of action; (ii) finding alternatives to drug development challenges (iii) targeting the correct subpopulation of individuals as opposed to a one-fits-all approach.

To get insight in the causal mechanism we propose to functionally dissect the neuronal circuits underlying the ELK1 modulator add-on effect. We will focus on the VTA- dopamine system, which contributes to the processing of rewarding stimuli and which is compromised in depression and AD resistance.

Development of small molecule modulators for novel targets such as ELK1, has proven to be difficult. miRNA regulation of ELK1, via RNA therapeutics, could represent an alternative strategy. miRNAs would also represent ideal biomarkers to stratify those individuals that would most likely benefit from an add-on scheme. We therefore propose to bring translational evidence from clinical cohorts though transcriptomic/epigenomic datasets and subsequent orthogonal validation of selected miRNAs in behavioral and neurobiological/electrophysiological depression-relevant phenotypes.