5-methyltetrahydrofolate and Depressive-Disorder--Treatment-Resistant

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Evidence-Based Medicine; Humans; One-Carbon Group Transferases; Pteroylpolyglutamic Acids; Randomized Controlled Trials as Topic; S-Adenosylmethionine; Tetrahydrofolates

Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs).. The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011.. Seventy-five patients were enrolled. Patients with specific biological (body mass index ≥ 30 kg/m², elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo.. Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed.. ClinicalTrials.gov identifier: NCT00955955.

Topics: Adolescent; Adult; Aged; Aldehydes; Biomarkers; C-Reactive Protein; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Female; Genotype; Humans; Male; Middle Aged; S-Adenosylhomocysteine; S-Adenosylmethionine; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates; Young Adult

Individuals diagnosed with major depressive disorder not responding to at least two adequate treatments are defined as treatment-refractory major depressive disorder (TR-MDD). Some TR-MDD patients have altered metabolic phenotypes that may be pharmacologically reversed. The characterization of these phenotypes and their underlying etiologies is paramount, particularly their genetic components. In this study, TR-MDD patients (n = 124) were recruited and metabolites were quantified in their cerebrospinal fluid (CSF) and peripheral blood. Three sub-categories of deficiencies were examined, namely 5-methyltetrahydrofolte (in CSF; n = 13), tetrahydrobiopterin (in CSF; n = 11), and abnormal acylcarnitine profiles (in peripheral blood; n = 8). Whole exome sequencing was performed on genomic DNA from the entire TR-MDD cohort and exonic variant allele frequencies for cases were compared to a control cohort (1:5 matching on ancestry). Low frequency, damaging alleles were identified and used for in silico pathway analyses. Three association signals for TR-MDD approached genome-wide significance on chromosomes 22, 7, and 3. Three risk-associated variants from a prior depression study were replicated. Relevant biological pathways were identified that contained an enrichment of rare, damaging variants in central nervous system (CNS)-specific pathways, including neurotransmitter receptors, potassium channels, and synapse transmission. Some TR-MDD patients had rare variants in genes that were previously associated with other psychiatric disorders, psychiatric endophenotypes, CNS structural defects, and CNS-related cellular and molecular functions. Exome analysis of metabolically phenotyped TR-MDD patients has identified potentially functional gene pathways and low frequency, deleterious gene variants for further investigation. Further studies in larger cohorts of biochemically phenotyped TR-MDD patients are desirable to extend and confirm these findings.

Topics: Adolescent; Adult; Alleles; Biopterins; Carnitine; Computer Simulation; Depressive Disorder, Treatment-Resistant; Exome Sequencing; Female; Genetic Predisposition to Disease; Humans; Male; Phenotype; Polymorphism, Single Nucleotide; Tetrahydrofolates; Young Adult

Despite antidepressant treatment, some patients continue to experience significant symptoms of depression. Literature has demonstrated modest benefit of folate supplementation in treatment-resistant depression among adults, though evidence is lacking in the pediatric population. This case series describes 10 adolescents (mean age 14.4 ± 2.8 years) with treatment-resistant depression prescribed adjunctive l-methylfolate (LM). The patient population was predominantly female (80%), Caucasian (90%), with an average of three comorbid psychiatric diagnoses, and failures of three psychotropic medications before starting LM. The majority of patients (80%) had a single mutation among the two methylene tetrahydrofolate reductase (

Topics: Adolescent; Aminohydrolases; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Female; Formate-Tetrahydrofolate Ligase; Humans; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Multienzyme Complexes; Mutation; Retrospective Studies; Tetrahydrofolates

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism. Many studies have demonstrated an association between MTHFR C677 T variant with depression, schizophrenia and bipolar disorder as one of them being comorbid to other. This has justified the use of folate supplement in psychiatric disorders mainly depression but still not in various other comorbid complex psychiatric disorders. Here we have tried to show how the l-methylfolate in conjunction with the conventional psychotropic drugs can be useful in a state of such complex psychiatric phenomenon and comorbid diagnosis with genetic polymorphism of MTHFR C677 T mutation.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Fluoxetine; Humans; Lithium Compounds; Male; Methylenetetrahydrofolate Reductase (NADPH2); Obsessive-Compulsive Disorder; Polymorphism, Genetic; Tetrahydrofolates; Vitamin B Complex

For patients with depression, antidepressant response rates are generally low and residual symptoms can increase the risk of relapse. Poor response may be linked to increased inflammatory cytokines and obesity. Specifically targeting inflammation with adjunct l-methylfolate treatment may help patients with depression finally achieve remission. In this Webcast, experts examine the multi-directional relationship between obesity, inflammation, and depression, consider preliminary data on genetic alleles, and review evidence using l-methylfolate as a targeted therapy.

Topics: Adult; Alleles; Antidepressive Agents; Brain; Coenzymes; Controlled Clinical Trials as Topic; Cytokines; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; DNA Mutational Analysis; Drug Therapy, Combination; Genetic Predisposition to Disease; Humans; Inflammation Mediators; Lithium; Magnetic Resonance Imaging; Methylenetetrahydrofolate Reductase (NADPH2); Nerve Growth Factors; Obesity; Obesity, Abdominal; Polymorphism, Genetic; Risk Factors; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates; Waist Circumference