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L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania - Psychiatric Times

L-methylfolate is commonly presented as a safe augmenting agent to patients with antidepressant non-response in unipolar depression with virtually no side effects. Although this is likely to be true most of the time, as with any treatment, there are risks that can be significant albeit rare. Currently, there is a paucity of published literature of double-blind placebo-controlled randomized clinical trials of the efficacy and tolerability of L-methylfolate in both unipolar and bipolar depression. This article discusses the rationale and history of L-methylfolate use in such patients, and then shares three cases that collectively suggest L-methylfolate may contribute to agitation and mania.


In humans, folate (ie, Vitamin B9) is one of 13 essential vitamins. Low serum folate and low red blood cell (RBC) folate levels are independent risk factors for major depressive disorder (MDD); they also are associated with more severe depressive episodes and poor response to antidepressant treatment.1,2 Maternal folate deficiency prior to conception and throughout pregnancy has been shown to increase the risk of neural tube defects and congenital abnormalities in the developing fetus, as well as peripheral neuropathy and anemia in the mother.3

Ongoing studies in psychiatry and obstetrics support the use of oral dosing with the bioactive form of folate, L-methylfolate. L-methylfolate is FDA approved as a medicinal supplement for antidepressant augmentation.4 The use of L-methylfolate allows the clinician to bypass a critical metabolic step in folate’s transformation to L-methylfolate, specifically the reduction of methylenetetrahydrofolate to L-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR). MTHFR is the rate limiting step in this process, and significantly, MTHFR enzymatic activity has a wide range of function depending on its genetic polymorphisms at three nucleic acid sites, the most significant being: C677C (good activity), C677T (decreased activity), and T677T (poor activity).

L-methylfolate is the only form of folate that can cross the blood-brain barrier, where it plays an essential role in the one carbon cycle metabolic pathway that is required for the production of the monoamines serotonin, dopamine, and norepinephrine.5

Evidence for efficacy and tolerability

Papakostas and colleagues6 undertook a randomized study of L-methylfolate as adjunctive therapy in patients with MDD who had a partial response or no response to selective serotonin reuptake inhibitors. A population of 75 patients were treated for 60 days with 15 mg L-methylfolate daily. The findings indicate that L-methylfolate was significantly more effective as compared with placebo. The response rates were 32.3% in the SSRI plus 15 mg L-methylfolate group compared with 14.6% in the SSRI plus placebo group.

The number needed to treat to achieve response with the addition of 15 mg L-methylfolate to an SSRI was 6. Overall L-methylfolate was well tolerated with minimal adverse effects; manic symptoms developed in one patient in the L-methylfolate/SSRI group, which resulted in patient discontinuation.

A subset of the original acute treatment cohort was followed in a 12-month open-label continuation study during which outpatients were treated with 15 mg L-methylfolate and an SSRI.7 The researchers reported “high rates of response, remission, and recovery,” as well as overall safety, tolerability, and a good rate of retention.

Bipolar depression

Unfortunately, there is a paucity of research into the use of L-methylfolate to treat bipolar I depression (BD-I). To address this unmet need, Nierenberg and colleagues8 created an open label registry of patients with bipolar depression. The patients received treatment as usual as well as 15 mg L-methylfolate daily for 6 weeks. Pre-study medications included lithium, lamotrigine, quetiapine, valproate, lurasidone, levothyroxine, Dexedrine, and extended release methylphenidate. At week 6, there was a 50% or greater improvement on the Montgomery Asberg Depression Rating Scale, with a pre-treatment mean score of 23.4 and a post-treatment score of 13.9 in six of the 10 patients studied. Significantly, the researchers noted that one patient had “an exacerbation in YMRS (Young Mania Rating Scale) and a possible manic episode.”

With that in mind, we present three case vignettes of women with affective disorders, two with MDD and one with BD-I. All three had acute symptoms of agitation shortly after augmenting their divergent psychotropic medication regimen with 15 mg of L-methylfolate. In all 3 cases, the agitation rapidly improved upon discontinuation of L-methylfolate.

Case Vignette 1

“Jesse” was a 63-year-old married white woman who was on disability for Multiple Sclerosis. She struggled with treatment-resistant MDD for several years, with no evidence of a bipolar diathesis. She received numerous antidepressant medication trials, including therapeutic doses of phenelzine, fluoxetine, sertraline, nortriptyline, escitalopram, mirtazapine, venlafaxine, vilazodone, vortioxetine, and duloxetine; all of which failed.

Pharmacogenomic testing of the MTHFR gene was consistent with decreased activity of this enzyme (C677T). It was decided to augment duloxetine with 15 mg L-methylfolate daily.

After several days on this regimen, her husband called to report that she had become uncharacteristically irritable and agitated. No identifiable situational stressors, substance use, new medication, or medical illness could be identified. Her long-term medical history was significant for Multiple Sclerosis, hyperlipidemia, osteoporosis, neurogenic bladder, and hypertension.

Shortly after discontinuing the L-methylfolate, the irritability and agitation resolved. Upon obtaining further history, the patient reported a hypomanic-like adverse effect from previous prednisone treatment. There was no other history of bipolar spectrum symptoms.


MS Robinson is Psychiatric-Mental Health Nurse Practitioner, Seacoast Mental Health Center, Portsmouth, NH; and Clinical Assistant Professor, Department of Nursing, University of New Hampshire, Durham, NH; Dr Miller is Medical Director, Brain Health, Exeter, NH; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; and Consulting Psychiatrist, Insight Meditation Society, Barre, MA. MS. Robinson and Dr Miller indicate they have nothing to disclose regarding the subject of this article.


1. Papakostas GI, Cassiello CF, Iovieno N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry. 2012;57:406-413.

2. Alpert JE, Mischoulon D, Nierenberg AA, Fava M. Nutrition and depression: focus on folate. Nutrition. 2000;16:544-546.

3. Greenberg JA, Bell SJ, Guan Y, Yu Y. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4:52-59.

4. Mathew SJ. Treatment-resistant depression: recent developments and future directions. Depress Anxiety. 2008;25:989-992.

5. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12:739-744.

6. Papakostas GI, Shelton RC, Zajecka JM, 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;169:1267-1274.

7. Zajecka JM, Fava M, Shelton RC, et al. Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study. J Clin Psychiatry. 2016;77:654-660.

8. Nierenberg AA, Montana R, Kinrys G, et al. L-Methylfolate for bipolar I depressive episodes: an open trial proof-of-concept registry. J Affect Disord. 2017;207:429-433.

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Sunday, 05 July 2020

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