Methylfolate as Adjunctive Treatment in Major Depression

To the Editor: As the principal investigator of the only previous placebo-controlled trial of methylfolate as an adjunctive treatment in major depression 22 years ago (1), I appreciated the new trial by Papakostas et al. (2) in the December 2012 issue confirming the efficacy of the vitamin in some resistant depression.

Important differences between the two trials raise interesting questions. Our study was for depressed patients with borderline or definite folate deficiency (red blood cell folate levels <200 pg/mL), but Papakostas et al. did not mention the folate status of their patients. I presume that many would not have been folate deficient. We also used 15 mg of methylfolate, but our trial was for 6 months and demonstrated increasing efficacy at 3 and 6 months in contrast to the 60-day study by Papakostas et al.

I first reported in 1967 the beneficial effect of the vitamin on mood and some aspects of cognitive and social function in an open trial of folic acid, 5 mg/day for 1 to 3 years, in folate-deficient patients with epilepsy (3). At the Medical Research Council Neuropsychiatry Research Unit, we then showed not only that folate deficiency was common in depression, as had been reported by Carney (4), but that the deficiency was associated with a poor response to antidepressant therapy (5). I subsequently collaborated with Carney and colleagues in demonstrating that depression was the most common reversible neuropsychiatric manifestation of folate-deficient megaloblastic anemia; in confirming that S-adenosylmethionine had antidepressant properties, thus implying that methylation is a key to understanding mood (6); and in identifying a subgroup of patients with depression, high plasma homocysteine levels, folate deficiency, and impaired neurotransmitter metabolism. This culminated in our positive trial of methylfolate, the transport form of folate into the nervous system, as adjunctive therapy in depression (1).

A crucial question for the future is to what extent the antidepressant properties of methylfolate depend on the folate status of the patient. Our own pilot observations suggest that methylfolate may have antidepressant properties as monotherapy, irrespective of folate status, but that responders show a greater rise in red cell folate levels than nonresponders (7). An important clue is the mood-elevating properties of nitrous oxide. This euphoriant effect is probably related to the instantaneous inactivation of methionine synthase, leading to an acute rise in methylfolate in the brain (7). Finally, methylation in the nervous system is a key not just to the biology of mood but to other aspects of cognitive function, including dementia. After 45 years, it is time for academic departments of psychiatry to invest more in this nonpharmaceutical approach to mental illness.