This project will address the emerging healthcare problem of Treatment Resistant Depression (TRD). Major Depressive Disorder (MDD) is a major social and clinical burden, responsible for ~15% of all days lived with disability in EU. Treatment challenges arise from the different biological dysfunctions implicated in different patients and the lack of biomarkers available to guide the choice of anti-depressants. Preliminary evidence suggests that genetic variants may be useful in making treatment choices, but further work to identify relevant variants is needed. Previous pharmacogenetic studies have focused on identifying common genetic variants associated with antidepressant response. The role of rare variants has not been well studied and few studies have investigated the genetics of TRD (patients with two or more failed treatments).
This project will combine exome sequencing and genome-wide genotyping in the unique GSRD sample of 1346 MDD patients characterized for stages of treatment resistance (number of failed treatments). This study aims to identify both rare and common variants associated with stages of resistance, the first such study to be performed. The analysis will focus on genes and pathways instead of single variants, since the cumulative effect of a number of variants is likely to disrupt the functionality of a gene or pathway. The study will assess the impact of clinical variables on genetic finding, and develop a genomic profile for TRD which can be used to guide treatment in patients. These findings will be used to design a prospective clinical trial to test the cost-effectiveness of the TRD genetic markers. I will seek funding sources to implement the trial, an essential step to translate the findings to the clinic.
This personalised medicine study should facilitate the development of new evidence-based treatments and substantially reduce the time to identify the best treatment strategy in MDD.
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