ANTIDEPRESSANT AUGMENTATION STRATEGIES TARGETING SIGNAL TRANSDUCTION PROOF OF CONCEPT IN ANIMAL MODELS

Abstract Background Antidepressant (AD) resistant depression is a major cause of disability. We have recently identified a novel AD target, the transcription factor ELK-1. ELK-1 operates inside the cell rather than the synapse, where « classical » ADs act. Aims & Objectives We hypothesized that an add-on strategy (classical + ELK-1 modulator) would lead to rapid AD action and/or better efficacy. Methods Mice were subjected to social defeat (SD, males) or vicarious social defeat (vSD, females) for 10 days and then, screened in the social interaction test (SI). Susceptible mice (SI<1) were further used in two different sets of experiments. (i) To determine the augmentation effect in the delay of onset of action, mice were treated for 6 days with either desipramine (DES; 15mg/kg), fluoxetine (FLX; 10mg/kg), the ELK-1 modulator (TDE; 2 mg/kg) or in combination (DES + TDE ; FLX + TDE). (ii) To determine the augmentation effect on treatment response, mice were treated for 14 days with desipramine; then stratified for each sex into responders (R=35) and non-responders (NR=19) in the SI. NR were divided into two groups, one treated for an additional week with DES alone (n=10) and one treated with DESI+TDE (n=9). At 21 days mice were rescreened at the SI. Same design was repeated to stratify for each sex mice treated with FLX and subsequently non-responders with FLX alone or FLX+TDE. Results The combination of the DESI+TDE resulted in the augmented AD effect, namely (i) a faster onset of action (6 days instead of 14 days) and (ii) a greater proportion of AD-R mice treated with the combination (6/9) as compared to DESI alone (2/10). However, using the same methodoogy, this effect was not found with the SSRI FLX+TDE combination. The augmentation effect and te selectivity for DESI was similar for both sexes. The TDE effect was prevented by the mGluR5 antagonist MPEP. Conclusion ELK-1 modulation could represent a promising novel augmentation strategy, most likely via glutamate rigid modulation. However, this effect does not apply to all AD classes, in particular SSRIs.