Depression is a common presenting condition in primary care, yet approximately two-thirds of people with depression do not achieve complete remission with a first antidepressant trial.1
Atypical antipsychotics have recently gained attention for antidepressant augmentation, but they present a potential for side effects such as weight gain and dyslipidemia. With obesity and metabolic syndrome on the rise, atypical antipsychotics often are not a safe augmentation strategy. L-methylfolate is a well-tolerated augmentation agent that addresses underlying conditions to increase the likelihood of achieving and maintaining the benefits of antidepressant therapy. It can be especially beneficial in obese patients (body mass index of 30 or higher).2
Research also shows that patients with depression that is resistant to selective serotonin reuptake inhibitors can benefit from augmentation therapy with L-methylfolate.2 The most recent study, published in 2012, documented good safety, response and tolerability of L-methylfolate in patients with major depressive disorder (MDD). L-methylfolate is available by prescription in the United States under the brand name Deplin.
Research About L-Methylfolate
L-methylfolate is the only form of folate that crosses the blood-brain barrier and acts centrally. One-third to one-half of people are unable to enzymatically convert folate from the diet into centrally active L-methylfolate.
L-methylfolate was approved as a medical food by the Food and Drug Administration in 2006. The decision to move forward with drug development is being evaluated by Nestle Health Science, and an investigational new drug application has been filed. Deplin is dosed once daily as a 15-mg capsule.
The article published in 2012 reported on two multicenter sequential parallel comparison design trials. Seventy-five patients with SSRI-resistant MDD were randomized to receive L-methylfolate 15 mg or a placebo. Twice as many patients responded to therapy with SSRI plus L-methylfolate 15 mg in 30 days compared to SSRI plus placebo (P = 0.02). In a 12-month continuation phase, more than half of patients taking SSRI plus L-methylfolate 15 mg maintained remission, and no one relapsed. In a double-blind analysis, adjunctive L-methylfolate 15 mg demonstrated superiority among patients stratified by the presence of certain biomarkers and genotypes.2
L-methylfolate is immediately available for neurotransmitter synthesis.3,4 It modulates the synthesis of all three monoamines in a two-step process involving tetrahydrobiopterin (BH4), which is critical for the synthesis of monoamines, and activation of tyrosine hydroxylase and tryptophan hydroxylase (for the synthesis of serotonin, norepinephrine and dopamine). Thus, L-methylfolate is a trimonoamine modulator and indirect regulator of trimonoamine neurotransmitter synthesis and monoamine concentrations. L-methylfolate represents a therapeutic option in the management of depression by enhancing BH4 to increase monoamine synthesis.5
History of Use
Thousands of providers have prescribed L-methylfolate to help patients achieve and maintain the benefits of antidepressant therapy. The drug is well tolerated for long-term use and is not associated with weight gain or sexual dysfunction, two of the most common side effects of antidepressant therapy.
When discussing L-methylfolate as an option for patients, break down the information into simple terms. L-methylfolate is a refined B vitamin that helps produce monoamine neurotransmitters in the brain. While taking L-methylfolate, patients should discontinue the use of any other supplemental folic acid or B-complex that contains folic acid, since it may lessen L-methylfolate's efficacy.
One concern when treating depression is adequate - and frequent - patient monitoring. Often patients aren't seen again in the office soon enough or are not treated aggressively enough to achieve remission. If a patient receives a low starting dose of a medication and is told to return in 3 months, the medication is not likely to be effective and the patient will likely discontinue it. Adult patients with MDD need to be seen no more than 3 weeks after starting a medication or making a dose adjustment.
Education is important for adherence and outcomes. Patients need to be informed that most antidepressants do not reach effectiveness for at least 3 weeks and that it can take 6 to 8 weeks for a full response. They need to be informed that most adverse events resolve within a few days to 2 weeks after starting a medication. They should be encouraged to ride out these transient events if possible or to call the office to discuss the issue.
Patients also should be informed that the majority of antidepressants require tapering. Missed doses or stopping abruptly can produce nausea, headache, unsteadiness or worsening depressive symptoms.
When treating MDD, achieving complete remission is the goal. Patients with residual symptoms of MDD are more likely to relapse.6 When treating depression, it is important to examine the patient's medication list. Anticonvulsants, antibiotics, corticosteroids, nonsteroidal anti-inflammatories, methotrexate, lithium, metformin, H2 blockers, potassium-sparing diuretics and oral contraceptives can deplete folate. In my mental health practice, all patients with depression who take any of the above medications and who are not in complete remission receive a prescription for Deplin to add to their antidepressant therapy.
1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-659.
2. Papakostas GI, et al. L-Methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
3. Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(7):1103-1112.
4. Stahl SM. L-methylfolate: A vitamin for your monoamines. J Clin Psychiatry. 2008;69(9):1352-1353.
5. Ginsberg LD, et al. L-methylfolate plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive episode. Innov Clin Neurosci. 2011;8(1):19-28.
6. Judd LL, et al. Major depressive disorder: A prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord. 1998;50(2-3):97-108.
Ian Mackey is a physician assistant at Psychiatric Medicine Associates in Skokie, Ill. He has completed a disclosure statement and reports that he is a scientific consultant to Nestle Health Science-Pamlab.