Publication date: Mar 18, 2020
L-methylfolate is commonly presented as a safe augmenting agent to patients with antidepressant non-response in unipolar depression with virtually no side effects.
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.
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).
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 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 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.
The patients received treatment as usual as well as 15 mg L-methylfolate daily for 6 weeks.