What is GENDEP?

GENDEP 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.The European Commission awarded 7.5 M Euros to fund the GENDEP project, led by a team at the Medical Research Council's Social, Genetic, and Developmental Psychiatry Centre (SGDP).

Although there is abundant evidence for efficacy of antidepressants, a substantial minority of patients show an unsatisfactory response, and cessation of medication because of adverse effects is common. The choice of what drug to prescribe for optimal response with minimum unwanted effects is largely a matter of taking an educated guess. Pharmacogenetics offers considerable potential to provide tools to aid targeted, rational prescribing. GENDEP has three closely interconnected major themes aimed to address these issues. The first is a large-scale multi-centre human pharmacogenomics study focussed on the prediction of therapeutic response to antidepressants and adverse effects. The second is a set of basic science studies using animal models and in vitro experiments, and the third is a programme of work to address the relevant ethical, social, and legal issues. This project will include an integrative analysis of the results of the transcriptomics and proteomics on the samples from the human, the rodent, and the in vitro studies, in order to identify biomarkers consistently identified across all of these experimental methodologies. This integrated project should lead to validated pharmacogenomic methods for symptom improvement, the prediction of response to psychiatric drug treatment and the reduction of adverse effects. We may also be able to make a beginning on identifying new targets for drug discovery. GENDEP will examine such associated issues as the views of service users regarding consent in human pharmacogenomics studies, a cost-benefit analysis of introducing pharmacogenomic theranostics, and the investigation of the potential impact of a new generation of pharmacogenomically tailored treatments on patients' and consumers' views and attitudes. A key feature of the entire project is the active research involvement of stakeholders, including psychiatric service users, practising clinicians and industrial partners.

Why is GENDEP important?

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.

Professor Peter McGuffin, Director of the MRC SGDP Centre, said: "This study has the potential to revolutionise the treatment of depression. Its main aim is to make it easier for doctors to decide which antidepressant will be most likely to work for a given depressed person, with the least side effects, but the research will also help us understand depression better, and may lead to the development of new and improved treatments in the future."