An expert review of clinical challenges in primary care and psychiatry


This supplement is supported by Pamlab.


Dr. Shelton is the James G. Blakemore Research Professor and Vice Chair for Research in the Department of Psychiatry at the Vanderbilt University School of Medicine.

Disclosures: Dr. Shelton serves as consultant to Eli Lilly, Pamlab, Pfizer, and Sierra; serves on the speakers bureau of Abbott, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Sierra, and Wyeth; and receives research support from Abbott, Eli Lilly, GlaxoSmithKline, Janssen, Pamlab, Pfizer, and Wyeth.



Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.


Recent research, particularly the data coming out of the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,1 have highlighted the reality that depression is a difficult condition to treat to remission and even more troublesome to maintain in a remitted state. Several problems with currently available modalities emerged from that landmark study. The STAR*D program provided high quality, multi-level treatment using the best evidence-based treatments, including both medications and cognitive behavioral psychotherapy.2 Only a small proportion of patients remitted with any of the treatments at any level. A very low proportion of patients responded to treatment after Level 3 (ie, three treatment trials). At all levels, relapse rates were high even after achieving remission.

These data suggest several conclusions. Despite notions to the contrary, depression is a very difficult condition to treat to sustained remission. In addition, there appear to be significant problems with current treatment modalities; although most produce a degree of improvement, there appear to be countervailing influences that either prevent remission in the first place or that “defeat” wellness in the long run. This may be explainable by a fundamental biological substrate that resists correction to a normal baseline mood.

The accompanying article by Farah reviews the evidence for the possible effectiveness of L-methylfolate as a novel alternative to achieve remission in treatment resistant depression. Folic acid is a normal dietary constituent; unlike the past, deficiency is uncommon in the United States because of the fact that grain products are fortified with folic acid. However, simple addition of folic acid does not solve the “true folate deficiency” problem; the conversion of folic acid to its active metabolite, L-methylfolate is of low efficiency in humans, requiring four metabolic steps. Moreover, as noted by Farah, a common single nucleotide polymorphism of one of the metabolic enzymes, methyltetrahydrofolate reductase, reduces the conversion of folic acid to L-methylfolate. L-methylfolate, in turn, is involved in the synthesis of tetrahydrobiopterin, a cofactor in the synthesis of the three key neurotransmitters involved in the regulation of mood: serotonin, norepinephrine, and dopamine.

This is significant because of the fact that all of the currently available treatments require sufficient quantities of one or more of these transmitters. A synthetic deficiency of the key monoamines involved in mood regulation may, in fact, explain several of the findings noted earlier. For example, take Level 1 treatment in STAR*D: citalopram was dosed as high as 50 mg/day, which would achieve saturation levels of the serotonin transporter in most people. Clearly, sustained serotonin signaling is required to achieve and maintain the antidepressant response of serotonin selective reuptake inhibitors (SSRIs). This has been demonstrated by research that has shown that acute depletion of tryptophan, the amino acid precursor of serotonin, leads to rapid relapse in people who have achieved sustained response to an SSRI.3 Under normal conditions, serotonin is taken up presynaptically following release by the serotonin transporter, and repackaged in synaptic vesicles. However, since SSRIs block the reuptake mechanism, ongoing synthesis of serotonin is required to provide adequate levels of the transmitter to response to depolarization-dependent release. A deficiency of synthesis of serotonin, then, could be expected to either prevent remission in the first place, or increase risk of relapse.

Although there is a clear therapeutic rationale for L-methylfolate, the clinical trials data supporting its effectiveness are very limited. Five studies have evaluated the effectiveness of L-methylfolate treatment in major depression, most of which are of questionable relevance to L-methylfolate in typical treatment-resistant depression. One early report4 showed open treatment with methylfolate of patients with depression or schizophrenia with low red blood cell folate levels. Another study5 evaluated the effectiveness of 15 mg of racemic methylfolate in persons with “organic mental disorders with depression,” who also had low red blood cell folate levels. The third6 involved a monotherapy trial of 50 mg of methylfolate (roughly 25 mg of L-methylfolate) compared against an inadequate dose of trazodone (100 mg/day) in elderly depressed patients. The fourth7 was, again, a open monotherapy trial of 90 mg of methylfolate (45 mg of L-methylfolate) in depressed alcoholic patients. The closest to a real augmentation trial is the study by Alpert and colleagues8 using folinic acid, a 5-formyl derivative of folic acid that is metabolized to racemic methylfolate without the action of methyltetrahydrofolate reductase. In this project, persons who were non-responders to SSRIs were given 15-30 mg/day of folinic acid. The Hamilton Rating Scale for Depression score reduced, on average, from 19.1 to 12.8 points, a significant but modest effect. This is reflected by only 27% achieving response status—a 50% reduction in depression scores. Although suggestive of benefit, larger scale controlled clinical trials are needed before L-methylfolate can be recommended as a first-line treatment. 


1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
2. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26:457-494.
3. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 1999;46:212-220.
4. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
5. Passeri M, Cucinotta D, Abate G, et al. Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano ). 1993;5:63-71.
6. Guaraldi GP, Fava M, Mazzi F, La Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5:101-105.
7. Di Palma C, Urani R, Agricola R, Giorgetti V, Della Verde G. Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res. 1994;55:559-568.
8. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33-38.