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

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

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.

Concepts Keywords
4 L Sertraline
Adjunctive Therapy Mood disorder
Affective Disorders Pharmacogenomic
Anemia Depression
Antidepressant Psychiatric diagnosis
Bioactive Levomefolic acid
Bipolar Methylenetetrahydrofolate reductase
Bipolar Depression Antidepressants
Bipolar Spectrum Organic compounds
Blood Chemical compounds
Blood Brain Barrier RTT
Carbon Cycle Psychoactive drugs
Cohort Bypass
Congenital Abnormalities Adjunctive therapy
Cross Maternal folate deficiency
Dexedrine
Diathesis
Disability
Dopamine
Double Blind
Duloxetine
Enzymatic
Enzyme
Escitalopram
FDA
Fetus
Fluoxetine
Folate
Folate Deficiency
Genetic Polymorphisms
Hyperlipidemia
Hypertension
Hypomanic
Irritability
Lamotrigine
Levothyroxine
Lithium
Major Depressive Disorder
Mania
Manic
Manic Episode
Metabolic Pathway
Methylenetetrahydrofolate Reductase
Methylphenidate
Mirtazapine
Monoamines
Montgomery
MTHFR
Multiple Sclerosis
Neural Tube Defects
Norepinephrine
Nortriptyline
Nucleic Acid
Obstetrics
Osteoporosis
Peripheral Neuropathy
Pharmacogenomic
Phenelzine
Placebo
Poor Activity
Prednisone
Pregnancy
Psychiatry
Psychotropic Medication
Quetiapine
Randomized Clinical Trials
Remission
Serotonin
Sertraline
Serum
SSRI
Tolerability
Unipolar Depression
Valproate
Venlafaxine
Vignettes
Vitamin B9

Semantics

Type Source Name
drug DRUGBANK Prednisone
disease MESH hypertension
disease MESH neurogenic bladder
disease MESH osteoporosis
disease MESH hyperlipidemia
drug DRUGBANK Duloxetine
drug DRUGBANK Vortioxetine
drug DRUGBANK Vilazodone
drug DRUGBANK Venlafaxine
drug DRUGBANK Mirtazapine
drug DRUGBANK Escitalopram
drug DRUGBANK Nortriptyline
drug DRUGBANK Sertraline
drug DRUGBANK Fluoxetine
drug DRUGBANK Phenelzine
disease MESH multiple sclerosis
disease MESH affective disorders
drug DRUGBANK Methylphenidate
drug DRUGBANK Levothyroxine
drug DRUGBANK Lurasidone
disease MESH major depressive disorder
disease MESH risk factors
drug DRUGBANK Folic Acid
disease MESH unipolar depression
disease MESH Mania
drug DRUGBANK Levomefolic acid
drug DRUGBANK Norepinephrine
drug DRUGBANK Dopamine
drug DRUGBANK Serotonin
drug DRUGBANK Activated charcoal
disease MESH anemia
disease MESH peripheral neuropathy
disease MESH neural tube defects
disease MESH congenital abnormalities
disease MESH fetus
drug DRUGBANK Valproic Acid
drug DRUGBANK Quetiapine
drug DRUGBANK Lamotrigine
disease MESH depression

Original Article

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