Methylfolate as Monotherapy in Depression. A Pilot Randomised Controlled Trial

Background: The commonest neuropsychiatric complication of severe folate deficiency is depression. Placebo controlled trials of folates as adjunctive therapy in major depression have confirmed that they enhance the response to standard antidepressant medication, even in the absence of folate deficiency. We have undertaken a pilot randomised controlled trial of 5-methyltetrahydrofolate (5- MTHF) monotherapy against Amitriptyline in out-patients with mild to moderate depression. Methods: 31 patients, aged 20 ? 69 years with DSM-111-R criteria for a depressive episode of mild to moderate severity and a Montgomery Asberg Depression Score (MADS) of at least 14 were randomly allocated to 5-MTHF 50 mgs (25 mgs biologically active) or Amitriptyline 150 mgs for 6 weeks. Clinical response was defined as a fall in MADS of 25% or more. Non-responders to initial therapy were crossed over to the alternative active therapy for a further six weeks. Haemoglobin, mean cell volume, serum and red cell folate and serum vitamin B12 were measured at entry to the study, after six weeks of initial and crossover treatment and at six months. Results: Of 19 patients randomised (n = 16) or crossed over (n = 3) to treatment with 5-MTHF for six weeks, eight (42%) responded. Of 20 patients randomised (n = 15) or crossed over (n = 5) to Amitriptyline, seven (35%) responded. Only 3 patients (10%) had low or borderline red cell folate values at randomisation. Response to 5-MTHF was associated with a significantly greater rise in red cell folate. Conclusions: Placebo controlled trials of 5-MTHF as monotherapy in depression would be justifiable. Our observations together with studies of S-adenosylmethionine (SAM) and nitrous oxide (N2O) are consistent with the hypothesis that 5-MTHF has intrinsic mood elevating properties in some patients.