Predictive testing for adverse psychiatric side effects

The EDITOX test method is an in vitro cell assay designed to predict the risk of depression and/or suicidal adverse effects of a given drug in a patient. This test method quantitatively analyses variations of the relative proportion of the 32 mRNA editing isoforms of the serotonin receptor (5-HT2cR) (biomarkers) using a next generation sequencing (NGS) approach in SH-SY5Y cell line (human neuroblastoma). It is confirmed in the literature that anomalies of serotonin biology in brain appear to be a characteristic trait underlying depression and/or suicidal behavior (Dracheva et al., 2008). By analysing postmortem brain tissue of suicide victims, Alcediag and others have observed distinct epigenetic alterations of the RNA editing profile of the 5-HT2cR pre-mRNA, known to greatly impair its pharmacological properties (Weissmann et al. 2016; Dracheva et al., 2008; Burns et al. 1997), including significant decrease in its response to serotonin. Apparently, similar RNA editing profile of the 5-HT2cR is reproduced by an exposure to human IFNa (positive control) using SH-SY5Y cell line. IFNa is known to induce, in some patients treated for chronic type C hepatitis, full blown depression and suicidal behaviour (Cavarec et al. 2013). Based on this observation, the Submitter has developed a proprietary algorithm to assess whether the editing profile of tested drugs is close to the one induced by human IFNa, allowing categorisation of tested compounds into "hIFNa-like" vs "non-hIFNa-like" profiles. Furthermore, EDITOX test method is proposed to be used for classification of drugs into the following categories of “High risk”, “Low risk” or “Moderate risk” to induce adverse side effects, such as depression and/or suicide in pre-clinical drug development phase, and also in regulatory toxicological safety assessment.