P.0106 Pharmacogenetic gene variants in treatment-resistant depression: preliminary results of a pilot study

Introduction Major depressive disorder (MDD) is the most common psychiatric disease and a leading cause of disability worldwide. Despite the wide number of available antidepressant drugs (ADs), only about 30% of patients respond adequately to the first treatment and approximately 15-30% develop treatment-resistant depression (TRD). Clinical predictors of non-response to ADs include higher disease severity, earlier age of onset, comorbidity with anxiety and personality disorders, presence of psychotic symptoms. To date the mechanisms underlying the inter-individual variability in AD response/resistance have not been fully elucidated. However, various studies indicated the existence of a genetic vulnerability to non-response to ADs and to TRD. Objectives: The aim of this study consisted in the identification, through a pharmacogenetic-based approach, of genetic variants putatively associated with TRD phenotype or with its related negative clinical predictors. Methods: We selected all genetic variants with high, moderate and low clinical evidence of association with AD response (Clinical Annotation Levels 1, 2 and 3) in European MDD patient populations from the PharmGKB database. We identified 56 variants in 23 genes that were analysed in a cohort made of 70 non-TRD and 169 TRD patients. SNP genotyping was performed with the Openarray technology on the QuantStudio 12K Flex System, whereas the CNV of CYP2D6 and the 5-HTTLPR were evaluated using a TaqMan Copy Number Assay and a PCR analysis, respectively. The haplotype determination of CYP2D6 and CYP2C19 was carried out through the AlleleTyper Software based on the translation tables available on PharmGKB. SNP association analyses, Pearson’s Chi-Square Test for comparing non-TRD vs TRD as well as the False Discovery Rate correction were carried out with SNPassoc and R Studio software (version 4.0.4). The association of genes, which variants resulted positively associated with response/resistance phenotype, were also investigated through a gene based-association analysis. This analysis was performed by using MAGMA v1.6 software implemented in FUMAGWAS web tool, starting from GWAS summary statistics obtained in a larger cohort made of 460 TRD patients. Results: The analyses on the 56 variants comparing non- TRD vs TRD revealed significant associations with TRD for 5 SNPs in three different genes: FKBP5 (rs4713916, rs1360780, rs3800373), RFK (rs11144870) and GLDC (rs10975641). After FDR correction, all the SNPs in the FKBP5 gene maintained their significance when considering the recessive model (p = 0.014, p = 0.014 and p = 0.022, respectively). Gene-based analyses revealed significant associations between the FKBP5 gene and age of onset (p = 0.025), presence of psychotic symptoms (p = 0.026) and comorbidity with anxiety disorders (p = 6.4x10 −5 ). The RFK and GLDC genes did not show any significant association with the variables tested. This project is ongoing; new analyses on larger cohorts will be included in the poster that will be presented at the congress. Conclusion: In the present study, significant associations of FKBP5 , a gene involved in immunoregulation and in basic cellular processes, with TRD as well as with clinical predictors of non-response were identified. This evidence suggests a putative role of FKBP5 gene in the resistance to AD treatment by impacting on specific features related to TRD condition.