A third of patients with moderate to severe depression do not respond adequately to standard antidepressants, and this trial tests whether adding a daily 5mg folic acid tablet can improve their treatment outcomes. Depression affects one in four people at some point in their lives, yet only half respond well to active treatment. Evidence suggests many patients have a functional folate deficiency that may blunt antidepressant effectiveness—low folate is linked to worse responses, and the severity of deficiency correlates with depression severity. This trial directly tests whether folate supplementation can close that gap. If folate augmentation works, it would offer a cheap, safe, and readily available add-on to existing antidepressant regimens in primary care. The trial also examines cost-effectiveness and whether genetic differences in folate metabolism predict who benefits, which could allow GPs to target the supplement to patients most likely to respond. Blood samples will exclude those with frank folate or B12 deficiency, ensuring the trial tests augmentation in patients who are not already deficient. The results could shift routine prescribing for the 730 patients recruited across North Wales and Swansea, and potentially for millions more in primary care worldwide.
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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 trial is to estimate the effect of folate augmentation in new or continuing treatment of depressive disorder in primary, intermediate 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. 730 patients will be recruited from North East Wales, North West Wales and Swansea. Patients with moderate to severe depression will be referred to the trial by their GP or Psychiatrist. If patients consent they will be assessed for eligibility and baseline measures will be undertaken. Blood samples will be taken to exclude patients with folate and B12 deficiency. Some of the blood taken will be used to measure homocysteine levels and for genetic analysis (with additional consent). Eligible participants will be randomised to receive 5mg of folic acid or placebo. Patients with B12 deficiency or folate deficiency will be given appropriate treatment and will be monitored in the 'comprehensive cohort study'. Assessments will be at antidepressant initiation, randomisation and 3 subsequent follow-ups.
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