To determine whether giving folic acid to people with depression will help their antidepressants work better. If folate does help antidepressants to work better, then it will provide a safe, simple and cheap way of improving the treatment of depression.

Clinical depression is common, debilitating and treatable; one in four people experience it during their lives. The majority of sufferers are treated in primary care and only half respond well to active treatment. Evidence suggests that folate may be a useful adjunct to antidepressant treatment: 1) patients with depression often have a functional folate deficiency; 2) the severity of such deficiency, indicated by elevated homocysteine, correlates with depression severity, 3) low folate is associated with poor antidepressant response, and 4) folate is required for the synthesis of neurotransmitters implicated in the pathogenesis and treatment of depression.

The primary objective of this multi-centred placebo-controlled randomised trial is to estimate the effect of folate augmentation in new or continuing treatment of depressive disorder in primary and secondary care. Secondary objectives are to evaluate the cost-effectiveness of folate augmentation of antidepressant treatment, investigate how the response to antidepressant treatment depends on genetic polymorphisms relevant to folate metabolism and antidepressant response, and explore whether baseline folate status can predict response to antidepressant treatment.

Comparisons: Eligible patients with moderate to severe depression will be randomised to receive 5mg of folic acid or placebo as an adjunct to their antidepressant treatment.

Inclusion Criteria:

• Only patients aged 18 or over
• ICD-10 diagnosis of moderate to severe depression
• Able to give informed consent (not delirious, actively psychotic or with severe communication or learning disability)
• Able to complete the research assessments

Exclusion Criteria:

• are folate deficient
• are B12 deficient
• have knowingly taken supplements containing folic acid within 2 months
• suffer from psychosis
• are already participating in another research project
• are pregnant or planning to become pregnant
• are taking anticonvulsants
• have a serious, advanced or terminal illness with a life expectancy of less than 1 year
• have recently started treatment for a medical condition which has not yet been stabilised
• are taking lithium
• have had a diagnosis or treatment for any malignant disease or any related condition such as intestinal polyposis