The European Commission has awarded 7.5 M Euros to an international research project, led by a team at the Medical Research Council’s Social, Genetic, and Developmental Psychiatry Centre (SGDP), which aims to find a way to use information about patients’ genes to help doctors decide which antidepressant treatment will work best for which patient, with the least side-effects.
One in five people at some point in their lives suffer from an episode of depression severe enough to warrant antidepressant treatment. But, at present, choosing one antidepressant over another is largely a matter of an educated guess. This means that patients may not get better on the first drug they try, or they may get lots of side-effects.
Scientists and clinicians from 10 countries, led by Prof Peter McGuffin and Dr Kathy Aitchison at the MRC SGDP Centre at the Institute of Psychiatry, King’s College London, have begun a 3-year research project in which they will be studying 1000 depressed people, and conducting related basic science studies. The people with depression be treated with one of two antidepressants which represent the two major mechanisms of action of all antidepressants currently on the market: one is a drug like prozac (affects serotonin in the brain), and the other has a different type of action (affects another chemical messenger in the brain, noradrenaline). The depressed people will have blood tests, which will be used for genetic studies, including looking at which genes are turned on by which antidepressant, and will be followed up over 6 months of taking the antidepressant, so that their response and any side-effects can be measured. In this way, the project aims to link a person’s genetic profile with how they respond to the medication that they have been taking in the study, which will provide us with information about what genetic markers are associated with response to antidepressants that affect serotonin, and with response to antidepressants that affect noradrenaline, or both. Parallel elements of the research conducted in basic science (including studies in cultured cells), will enhance the ability of the project to make reliable predictions. It is hoped that these predictions will lead to the making of a genetic test to assist clinicians in choosing the right antidepressants for their patients.
The relevant ethical issues are also being investigated in the project, including the views of patients and the general public on the potential impact of having genetically tailored treatments. In addition, the project hopes to make discoveries regarding the biological mechanisms responsible for an antidepressant being effective, which might lead to the development of new and better treatments for depression.
IMPORTANT UPDATE REGARDING GENDEP STUDY
Recruitment for the GENDEP study will be concluded in June 2008. Analysis results are expected over the years 2008-2009 and will be put on the GENDEP website as they be becoming available. To date we have recruited and treated over 800 people with depression. The preliminary results show that most of them have improved over the course of the study, although many incompletely. We have identified at least one gene that seems to influence response to one of the antidepressants, but we will only report this when it is confirmed in the final analysis. The only results published to date are on the measurement of depression and is an important building block for the future analyses. It shows that symptoms of depression cluster into three groups: mood, dissatisfaction and physical symptoms including disturbed sleep and appetite. We are now exploring whether these groups of symptoms are affected by the antidepressant drugs and genes in different ways.
GENDEP (Genome-based therapeutic drugs for depression)
The multicentre, comprehensively prospectively rated clinical trial using two antidepressants representative of the two major classes of antidepressants in current clinical use has been successfully completed. All other areas of GENDEP have also successfully delivered (http://gendep.iop.kcl.ac.uk/results.php). Novel analytical approaches applied to the clinical data from GENDEP have yielded highly interested results, of relevance to the conduct and analysis of all clinical trials (Uher et al, 2009a; Uher et al, 2009b). Analysis of the clinical and genetic data from the trial has generated information regarding clinical and genetic predictors of response to the antidepressants studied (Uher et al., in press (a); Uher et al., in press (b); Uher et al., in press (c); Gupta & Keers et al., in press; Huezo-Diaz & et al., under review), and of the adverse drug reactions experienced during the trial (Uher et al., in press (d)). Data on neurogenesis (Petersén et al., 2008), proteins differentially regulated in rat models of depression treated with the same antidepressants as in the clinical trial have been provided, as well as functional proteomic data (Ryan et al., 2008). Data has also been provided for transcripts and proteins differentially regulated in treatment of in vitro cell cultures (Sugden et al., 2008) and of inbred mouse lines. Progress in integrative analysis has been made. An increased understanding of the views of service users and organisations representing them on pharmacogenomics testing has been gained (Rose et al., 2007; Barr & Rose, 2008). A uniquely well-characterised resource for further studies including whole genome association analysis and (via the lymphocyte pellets) further in vitro functional studies has been created. cell cultures (Sugden et al., 2008) and of inbred mouse lines. Progress in integrative analysis has been made. An increased understanding of the views of service users and organisations representing them on pharmacogenomics testing has been gained (Rose et al., 2007; Barr & Rose, 2008). A uniquely well-characterised resource for further studies including whole genome association analysis and (via the lymphocyte pellets) further functional studies has been created.
Go to GENDEP website.
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