ESTREA · Exome Sequencing in stages of Treatment REsistance to Antidepressants
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-10-01 → 2020-03-31
- EU contribution
- €137,591
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Exome Sequencing in stages of Treatment REsistance to Antidepressants
Depression is the second-largest contributor to disability or health loss and a leading underlying cause for the 128,000 suicide deaths that occur each year in the European Region. The number of people with depressive disorders in the Region amounted to 40 million in 2015 (World Health Organization 2017). More than 40 antidepressant drugs are available, however response rates to antidepressants are often unsatisfactory (complete symptom remission to the first treatment in about 1/3 of patients). No reliable predictors of response are available and both treatment choice and monitoring are guided by clinical observation only. Previous evidence suggests that antidepressant response has a genetic basis, therefore, the present project aimed to identify genetic variants associated with non-response and resistance to pharmacological treatments in patients with depression in order to provide an objective tool to identify patients at risk since the baseline evaluation. This is indeed the first step for the personalisation of treatments in depression and improvement of response rates. Compared to previous studies, this project investigated the role of not only common genetic variants (generally defined as those observed in > 1% of the population), but also rare variants in coding regions, which are those regions of our genome coding for proteins and therefore hypothetically critical in controlling the functioning of biological processes. In detail, this project aimed to address the following research questions: 1) Is it possible to identify genetic predictors of non-response and resistance (failure of more than two treatments) to antidepressant medications? 2) Are these genetic predictors concentrated in some genes or groups of genes functionally related among each other? 3) How these genetic predictors interact with clinical risk factors of treatment resistance? 4) How can genetic predictors of antidepressant resistance be translated into clinical recommendations for the personalisation of treatment prescription?
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- KING'S COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union