Skip to main content
Full access
Communications and Updates
Published Online: 1 May 2013

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.

References

1.
Godfrey PSA, Toone BK, Carney MWP, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH: Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990; 336:392–395
2.
Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M: l-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012; 169:1267–1274
3.
Reynolds EH: Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet 1967; 1:1086–1088
4.
Carney MWP: Serum folate values in 423 psychiatric patients. Br Med J 1967; 4:512–516
5.
Reynolds EH, Preece JM, Bailey J, Coppen A: Folate deficiency in depressive illness. Br J Psychiatry 1970; 117:287–292
6.
Reynolds EH, Carney MWP, Toone BK: Methylation and mood. Lancet 1984; 2:196–198
7.
Reynolds EH: Vitamin B12, folic acid, and the nervous system. Lancet Neurol 2006; 5:949–960

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 560
PubMed: 23632839

History

Accepted: February 2013
Published online: 1 May 2013
Published in print: May 2013

Authors

Details

Edward H. Reynolds, M.D., F.R.C.Psych.
From the Department of Clinical Neurosciences, King’s College, University of London.

Funding Information

The author reports no financial relationships with commercial interests.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share