5-methyltetrahydrofolate and Depressive-Disorder--Major

  Partial response to pharmacotherapy is common in major depressive disorder (MDD) and many patients require alternative pharmacotherapy or augmentation, including adjunctive L-methylfolate. Given that L-methylfolate augmentation is rarely included in major clinical practice guidelines, we sought to systematically review evidence for L-methylfolate augmentation in adults with MDD and to examine its efficacy meta-analytically..  We systematically searched PubMed for articles up to December 31, 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Included studies were published in peer-reviewed, English-language journals and examined L-methylfolate adjunctive therapy in depressive disorders or its effect on antidepressant response. A fixed- and random-effects meta-analysis and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted..   Qualitative assessment of nine articles (N=6,707 patients) suggests that adjunctive L-methylfolate improved antidepressant response. In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies,.   Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Humans; Tetrahydrofolates

Depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to standard antidepressants. Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the central nervous system, as well as folate metabolism. Additional factors such as stress and metabolic disorders also may contribute. Multiple inflammatory, metabolic, and genetic markers have been identified and may provide critical information to help clinicians individualize treatments for patients to achieve optimal outcomes. Recent advancements in research have clarified underlying causes of depression and have led to possible new avenues for adjunctive treatment. Among these is L-methylfolate, a medical food that is thought to enhance synthesis of monoamines (serotonin, norepinephrine, and dopamine), suppress inflammation, and promote neural health. Clinical studies that assessed supplemental use of L-methylfolate in patients with usual care-resistant depression found that it resulted in improved outcomes. Patients with selective serotonin reuptake inhibitor-resistant depression, and particularly subgroups with biomarkers of inflammation or metabolic disorders or folate metabolism-related genetic polymorphisms (or ≥2 of these factors), had the best responses. Considering this, the goals of this review are to 1) highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers and 2) establish the profiles of patients with depression who could benefit most from supplemental use of L-methylfolate.

Topics: Antidepressive Agents; Depressive Disorder, Major; Humans; Tetrahydrofolates

The use of two antidepressants from the initiation of treatment in major depressive disorder has been investigated in several recent studies and forms a paradigm shift in the pharmacotherapy of the condition. Several, but not all, trials have claimed improved response and remission rates with the combinations as opposed to monotherapy. The use of folate preparations (folic and folinic acid and l-meth-ylfolate) have shown effective augmentation of antidepressant response in a variety of controlled and open-label settings in patients with normo- and hypofolatemic status. Several recent trials using L-methylfolate, the active and more bioavailable form of folic acid, have shown promising adjunctive use with a well-tolerated adverse event profile.

Topics: Antidepressive Agents; Depressive Disorder, Major; Drug Therapy, Combination; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Tetrahydrofolates; Treatment Outcome

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

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and L-methylfolate), and folinic acid. Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B(12) deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks. Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.

Topics: Aged; Chemistry, Pharmaceutical; Clinical Trials as Topic; Dementia; Depressive Disorder, Major; Dietary Supplements; Dosage Forms; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Tetrahydrofolates; Treatment Outcome

Topics: Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Folic Acid; Humans; Hypnotics and Sedatives; Secondary Prevention; Tetrahydrofolates; Treatment Outcome

Topics: Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Clinical Trials as Topic; Combined Modality Therapy; Deep Brain Stimulation; Depressive Disorder, Major; Drug Resistance; Electroconvulsive Therapy; Humans; Piperazines; Prognosis; Quinolones; Tetrahydrofolates; Transcranial Magnetic Stimulation; Treatment Outcome; Vagus Nerve Stimulation

L-methylfolate is a compelling candidate to treat bipolar I major depressive episodes. While approved as an adjunct for unipolar major depressive disorder, no studies have been done to assess the tolerability, safety, and efficacy of L-methylfolate for bipolar depression. As a first step, we developed a registry of bipolar patients treated with L-methylfolate to examine tolerability and outcomes.. Subjects (N=10) received treatment as usual plus daily L-methylfolate 15mg for 6 weeks in this open-label registry. Depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and manic symptoms with the Young Mania Rating Scale (YMRS). Effect size was measured with Cohen's d to provide an estimate of potential efficacy.. The pre-treatment mean (SD) MADRS score was 23.4 (4.34); the post-treatment score was 13.9 (8.24). Cohen's d was 1.19. At post-treatment, 6/10 patients had at least 50% MADRS improvement, and 4/10 patients exhibited remission with MADRS≤10. The pre-treatment YMRS score was 3.2 (3.0); the post-treatment score was 2.7 (5.2). Cohen's d was 0.17.. This registry was a small open-label clinical trial for a fluctuating disorder. We cannot rule out that our results are due to regression to the mean. A controlled trial is warranted.. This first proof-of-concept open registry suggests that L-methylfolate in combination with treatment as usual has potential to treat bipolar depression.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Registries; Tetrahydrofolates; Treatment Outcome

To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg.. Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks. Subjects were enrolled between September 2006 and February 2010. Efficacy outcomes included predefined criteria for response, remission, recovery, relapse, and recurrence. Subjects treated with adjunctive L-methylfolate 15 mg were included in the efficacy analysis.. Of 68 subjects who met criteria for the 12-month open-label phase, 38% (n = 26) achieved full recovery, and none experienced a recurrence of MDD. For subjects entering the open-label phase in remission (n = 11), 91% (n = 10) achieved full recovery with L-methylfolate 15 mg, and none experienced a relapse or recurrence. Among 57 subjects who entered the open-label phase as nonremitted, 61% (n = 35) achieved remission. Of subjects who entered the open-label phase with a response without remission (n = 4), 50% (n = 2) had full recovery, and of subjects entering the open-label phase with no response (n = 53), 26% (n = 14) met recovery criteria.. Adjunctive L-methylfolate 15 mg/d may be an early option in patients who fail to adequately respond to antidepressant monotherapy, with preliminary evidence demonstrating sustained remission and sustained recovery.. ClinicalTrials.gov identifier: NCT00321152.

Topics: Adult; Aged; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Prospective Studies; Recurrence; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates; Treatment Outcome; Young Adult

To characterize the impact of S-adenosyl methionine (SAMe) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe, S-adenosyl homocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MTHF) in 35 of 73 patients from a 6-week randomized double-blind, placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010.. Subjects were randomized from June 4, 2004, until August 8, 2008, to adjunctive placebo or SAMe 800-1600 mg/d for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t test) and between treatment arms (by independent samples t test). Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels, examined by linear regression (for change in Hamilton Depression Rating Scale scores) and logistic regression (for response or remission).. We found significant differences in pretreatment plasma levels of tHCY (P = .03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (P = .002) and SAH (P < .0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Posttreatment plasma SAMe (P = .0035), SAH (P < .0001), and tHCY (P = .0016) levels differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission.. Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution.. ClinicalTrials.gov identifier: NCT00093847.

Topics: Biological Availability; Depressive Disorder, Major; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Homocysteine; Humans; Male; Methionine; Middle Aged; Psychiatric Status Rating Scales; S-Adenosylhomocysteine; S-Adenosylmethionine; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates

The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs).. In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods.. In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo.. Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

Topics: Chemotherapy, Adjuvant; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates; Treatment Outcome

Women often seek antidepressant alternatives for major depressive disorder (MDD) in anticipation of or during pregnancy. In this preliminary study, EnBrace HR, a prenatal supplement containing methylfolate, was investigated for depressive relapse prevention and for acute treatment of MDD in women planning pregnancy or during pregnancy.. This 12-week open-label study included women with histories of MDD who were planning pregnancy or pregnant < 28 weeks. At enrollment, Group 1 participants were well (not depressed) and planned to discontinue antidepressants for pregnancy. Group 2 participants were depressed. Primary outcome variables by group included MDD relapse and depressive symptoms, verified with the Mini-International Neuropsychiatric Interview and the Montgomery-Åsberg Depression Rating Scale (MADRS), respectively. Biomarkers of inflammation and the folate cycle were collected.. Group 1 participants (N = 11) experienced lower rates of depressive relapse (27.3%. Results suggest EnBrace HR is a well-tolerated intervention with potential efficacy for prevention and treatment of perinatal depression. Larger controlled trials are necessary.

Topics: Adult; Depressive Disorder, Major; Dietary Supplements; Female; Humans; Pregnancy; Prenatal Care; Psychiatric Status Rating Scales; Secondary Prevention; Tetrahydrofolates

Topics: Antidepressive Agents; Depressive Disorder, Major; Drug Therapy, Combination; Humans; Nurse Practitioners; Tetrahydrofolates

Topics: Depressive Disorder, Major; Female; Humans; Male; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates

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

The sequential parallel clinical trial is a novel clinical trial design being used in psychiatric diseases that are known to have potentially high placebo response rates. The design consists of an initial parallel trial of placebo versus drug augmented by a second parallel trial of placebo versus drug in the placebo non-responders from the initial trial. Statistical research on the design has focused on hypothesis tests. However, an equally important output from any clinical trial is the estimate of treatment effect and variability around that estimate. In the sequential parallel trial, the most important treatment effect is the effect in the overall population. This effect can be estimated by considering only the first phase of the trial, but this ignores useful information from the second phase of the trial. We develop estimates of treatment effect that incorporate data from both phases of the trial. Our simulations and a real data example suggest that there can be substantial gains in precision by incorporating data from both phases. The potential gains appear to be greatest in moderate-sized trials, which would typically be the case in phase II trials.

Topics: Bias; Biostatistics; Depressive Disorder, Major; Humans; Likelihood Functions; Linear Models; Mental Disorders; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Tetrahydrofolates; Treatment Outcome