Epigenetic modifications determining variability in antidepressant response: beyond genetic association studies

The identification of genetics factors that might assist in the prediction of an individuals antidepressant response has attracted lot of attention during the last years. However, despite the tremendous effort in identifying predictive genes in genome-wide association studies most recently, the results are fairly modest, suggesting that alternative pharmacogenetic strategies need to be established. It still remains a mystery why a patient does not respond to the same antidepressant drug in the current depressive episode that was convincingly effective years ago. Here, additional factors like epigenetic modifications are likely to be decisive. We use a genetically homogeneous inbred mouse strain (DBA/2OlaHsd) known to be antidepressant responsive and treat a large number of animals chronically with paroxetine. Due to the large number of animals, we hypothesize that we will be able to identify subgroups of animals which are good and poor treatment responders according to their performance in specific behavioural tests. Tissue from hippocampal and prefrontal cortical regions will be dissected. Comparative gene expression profiling followed by DNA methylation analysis using a two-step protocol involving next-generation sequencing and custom-design methylation arrays will be employed to identify differences in the methylation pattern between good and poor responders which, in turn, point to a potential involvement of these genes in individual drug response.

This study was supported by Phenoquest AG, Munich, Germany