The aim of this study is to identify genetic, physical (brain) and psychological (cognitive) markers (or combinations of them) that predict specific response to a range of antidepressants treatment (Escitalopram, Venlafaxine, Sertraline) in patients diagnosed with major depressive disorder. This study is focused on outcomes which may impact on how "personalised medicine" is implemented in depression.

This is an open-label, randomised (effectiveness) study (ie. comparison of active treatments) to identify genetic markers, brain function, brain structure, and psychological and cognitive indicators (or a combination of markers) in MDD subjects versus healthy controls. Approximately 2,016 subjects with major depressive disorder (MDD) across multiple international sites (USA, Canada, UK, South Africa, New Zealand, The Netherlands and Australia) will be randomised to one of three approved and effective treatment arms:

Treatment A Escitalopram. Treatment B Sertraline. Treatment C Venlafaxine XR.

A group of matched healthy controls (n = 672) will also be enrolled.

Subjects will be asked to attend the testing facility on two separate occasions; for Pre-treatment (Pre-Tx) and at 8 weeks post initiation of treatment. The assessments/procedures at Pre-Tx and Week 8 include: Baseline a clinical work-up, blood collection for genetic analyses, cognitive testing and electrical brain functioning (EEG/ERP). Structural and functional data MRI data will be collected in ten percent (10%) of participants.

On Day 4 and Weeks 2, 4, 6, 12, 16, 24 and 52 Subjects will be contacted by phone and asked to complete 2 questionnaires via the internet.

• Drug: Escitalopram
• Drug: Sertraline
• Drug: Venlafaxine XR

• Active Comparator: Escitalopram
• Active Comparator: Sertraline
• Active Comparator: Venlafaxine
• No Intervention: Healthy matched controls

Inclusion Criteria:

• Meet DSM-IV criteria for primary diagnosis of MDD.
• HAM-D21 score of ≥ 16.
• 18-65 years age-range
• Subjects with English or Dutch literacy and fluency.
• Written, informed consent.

Exclusion Criteria:

• Presence of suicidal ideations/tendency (as determined by a score >= 8 in Section C of the MINI Plus, bipolar I-III, psychosis or primary eating disorders, post-traumatic Stress disorder, Obsessive Compulsive Disorder as well as any Axis II personality disorders.
• Pregnancy and women of child bearing potential who are not taking a medically accepted form of contraception and are at risk of becoming pregnant during the study.
• Breastfeeding.
• Known contra-indication to the use of Escitalopram, Sertraline or Venlafaxine XR as defined in the product package insert for each drug (including previous treatment failure at the highest recommended dose).
• Use of any antidepressant or CNS drug which can not be washed out prior to participation.
• Use of any medication which is known to be contraindicated with Escitalopram, Sertraline, or Venlafaxine XR (refer to the product package insert for each drug).
• Known medical condition, disease or neurological disorder which might, in the opinion of investigator/s, interfere with the assessments to be made in the study or put subjects at increased risk when exposed to optimal doses of the drug treatment (including, but not limited to, a cardiac rhythm disorder, prior myocardial infarction, angina, congestive heart failure, hypertension, stroke, active peptic ulcer, renal insufficiency, liver disease, neoplastic disease, inflammatory disease, diabetes, blood clotting disorder).
• Personal history of physical brain injury or blow to the head that resulted in loss of consciousness of greater than five minutes.
• Recent/current substance dependence.
• Participation in an investigational study within four months of the baseline visit (excluding follow-up studies in which the test drug/device has been registered in a major market) in which subjects have received an experimental drug/device that could affect the primary end points of this study.
• Subjects who, in the opinion of the investigator, have a severe impediment to vision, hearing and/or hand movement, which is likely to interfere with their ability to complete the testing batteries.
• Subjects who, in the opinion of the investigator, are unable and/or unlikely to comprehend and follow the study procedures and instructions.