Nutraceutical Augmentation Strategies for Depression: A Narrative Review.

Context: Depression is one of the most commonly diagnosed psychiatric disorders, but antidepressant pharmacotherapy often fails to achieve remission, leading health care professionals and researchers to consider various augmentation strategies to improve clinical outcomes. Objective: To assess the safety, tolerability, and efficacy of nutraceutical augmentation for depression. Methods: Nutraceutical-focused systematic reviews and clinical practice guidelines identified the more commonly studied augmentation strategies for depression. Results: S-adenosylmethionine, l-methylfolate, omega-3 fatty acids, and hydroxyvitamin D have sufficient scientific evidence to support their clinical consideration in the stepped care approach to the management of depression. Conclusions: Clinical remission is the goal in the management of depression, and nutraceuticals may be part of an overall treatment approach to achieve that outcome.

L-Methylfolate Calcium Supplementation in Adolescents and Children: A Retrospective Analysis.

Previous studies have shown l-methylfolate to be a safe and beneficial therapy for neuropsychiatric conditions, including major depressive disorder and schizophrenia in adults. The purpose of this study was to assess safety and describe patient experience using l-methylfolate calcium in a real-world pediatric and adolescent population. A retrospective chart review of patients (7 to 20 y of age, mean age 16 y) prescribed l-methylfolate calcium at a psychiatry clinic in Amherst, NY, between January 1, 2010 and November 10, 2015 was conducted. Patients to whom l-methylfolate calcium 15 mg/d (n=139) or 7.5 mg/d (n=7) was administered were identified; 44 patients who were prescribed but to whom l-methylfolate calcium was not administered were included as a comparator population. Common neuropsychiatric diagnoses included anxiety disorders (68% in the treatment population vs. 50% in the comparator population) and mood disorders (57% in the treatment population vs. 52% in the comparator population). Antidepressants (69% vs. 55%) and mood stabilizers or antiepileptic drugs (63% vs. 57%) were frequently prescribed in combination with l-methylfolate calcium. Adverse events occurred less frequently in the treated population, possibly due to the addition of l-methylfolate calcium (10% vs. 25%, P=0.02). The most common adverse events in the treated population were impaired sleep (5 patients) and increased anxiety (3 patients). Rates of laboratory abnormalities did not differ significantly between the treated and comparator populations (P=0.13). Positive subjective treatment experiences were reported by 22.5% of treated patients and negative subjective treatment experiences were reported by 5.4% of treated patients. L-methylfolate calcium was well-tolerated in a pediatric/adolescent population and may provide benefits for patients with a range of neuropsychiatric conditions.

Does L-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?: Evidence of Lack of Benefit From a Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

PURPOSE/BACKGROUND: Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with L-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. METHODS: Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of L-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. RESULTS: L-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on L-methylfolate over time (χ = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). CONCLUSIONS: L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.

Novel dietary supplement association reduces symptoms in endometriosis patients.

Endometriosis is characterized by disabling symptoms that afflict young women with severe physical discomfort, difficulty in relationship life, and infertility; however, the currently available therapeutic strategies are unsatisfactory. Goal of this research was to identify a new combination of natural active ingredients that, administered as dietary supplements, could have the effect of reducing inflammatory response in endometriosis patients, decreasing the symptoms the disease produces and its harmful effects on affected organs. A cohort of endometriosis patient was treated for 3 months with a composition including quercitin, curcumin, parthenium, nicotinamide, 5-methyltetrahydrofolate, and omega 3/6. Using a VAS scale, we demonstrated a significant reduction of the symptoms in endometriosis patients treated with the dietary composition respect to the controls. Moreover, we demonstrated also a significant reduction in the serum levels of PGE2 and CA-125. Further study are required to compare the effect of this combination of molecules with standard therapies and to evaluate if the use of these dietary supplements in combination with standard therapies may lead to the improvement of the regular medical treatment for endometriosis.

Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

Enhancement of recovery from mental illness with l-methylfolate supplementation.

People suffering from depression, schizophrenia, and dementia often have measurably lower levels of serum folate compared to people not experiencing psychiatric disorders. Augmentation of SSRI and SNRI antidepressant medications with l-methylfolate has been demonstrated to increase their effectiveness and onset of action. Even the use of l-methylfolate as a stand-alone monotherapy has been observed to exert antidepressant properties. The role of folate in mental illness has been known for many decades, but the strategic use of l-methylfolate supplementation has not yet been accepted as a standard regimen. It is the proposal of this paper that advanced nurse practitioners should consider the use of l-methylfolate as an adjunct to antidepressant medications at the initiation of therapy as part of a standard regimen in their clinical practice.

5-Methyl-tetrahydrofolate in prevention of recurrent preeclampsia.

OBJECTIVE: To evaluate the efficacy of 5-methyl-tetrahydrofolate (5-MTHF) supplementation in prevention of recurrent preeclampsia. METHODS: Retrospective cohort of women who received daily oral 5-MTHF 15 mg supplementation as prophylactic treatment since first trimester for recurrent preeclampsia were compared with women who did not. All asymptomatic singleton gestations with prior preeclampsia (in the previous pregnancy) were included. Women with chronic hypertension were excluded. The primary outcome was the incidence of preeclampsia. RESULTS: Three hundred and three singleton gestation met the inclusion criteria: 157 received 5-MTHF, while 146 did not (control group). Women who received 5-MTHF had a significantly lower incidence of recurrent overall preeclampsia (21.7% versus 39.7%; odds ratio (OR) 0.57, 95% confidence interval (CI) 0.25, 0.69), severe preeclampsia (3.2% versus 8.9%; OR 0.44, 95% CI 0.12-0.97) and early-onset preeclampsia (1.9% versus 7.5%; OR 0.34, 95% CI 0.07-0.87) compared to control. The intervention group delivered about 10 d after the control and had higher birth weight. CONCLUSION: This retrospective study showed that women with prior preeclampsia who received daily oral 5-MTHF 15 mg supplementation had a significantly lower incidence of overall preeclampsia, severe preeclampsia and early-onset preeclampsia. Randomized controlled trials are needed to confirm our findings.

Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia.

Folic acid supplementation is the mainstay treatment of hyperhomocysteinemia (HHcy). However, no recommendations are currently available in regard to the optimal replacement therapy. Therefore, this prospective study hypothesized that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-methyltetrahydrofolate (5-MTHF) would reduce plasma levels of fasting total homocysteine (tHcy) in patients with mild/moderate HHcy. Patients with a new diagnosis of mild/moderate HHcy were evaluated for the methylenetetrahydrofolate reductase genotype and the presence of major features of metabolic syndrome. All enrolled subjects received a cyclic 5-MTHF oral supplementation and were reevaluated after each treatment cycle for a total of 2 years. In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 µmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 ± 13.6 to 12.18 ± 3.03 µmol/L, P < .001). The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up. The risk of failure in tHcy level normalization was increased in patients with metabolic syndrome (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.46-8.36), higher baseline tHcy levels (HR, 1.045; 95% CI, 1.018-1.073), or methylenetetrahydrofolate reductase homozygous mutation (HR, 6.59; 95% CI, 2.64-16.4). This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy.

A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study.

PURPOSE: Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin). METHODS: Thirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m². The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS. RESULTS: MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m²) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin® C(max) ratio for methyleneTHF was 113 at 200 mg/m² and 52 at 60 mg/m²; the AUC(last) ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (C(max) ratio 23, AUC(last) ratio 13 at 200 mg/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²). CONCLUSION: Modufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.

Natural folates from biofortified tomato and synthetic 5-methyl-tetrahydrofolate display equivalent bioavailability in a murine model.

Folate deficiency is a global health problem related to neural tube defects, cardiovascular disease, dementia, and cancer. Considering that folic acid (FA) supply through industrialized foods is the most successful intervention, limitations exist for its complete implementation worldwide. Biofortification of plant foods, on the other hand, could be implemented in poor areas as a complementary alternative. A biofortified tomato fruit that accumulates high levels of folates was previously developed. In this study, we evaluated short-term folate bioavailability in rats infused with this folate-biofortified fruit. Fruit from tomato segregants hyperaccumulated folates during an extended ripening period, ultimately containing 3.7-fold the recommended dietary allowance in a 100-g portion. Folate-depleted Wistar rats separated in three groups received a single dose of 1 nmol of folate/g body weight in the form of lyophilized biofortified tomato fruit, FA, or synthetic 5-CH3-THF. Folate bioavailability from the biofortified tomato was comparable to that of synthetic 5-CH3-THF, with areas under the curve (AUC(0-∞)) of 2,080 ± 420 and 2,700 ± 220 pmol · h/mL, respectively (P = 0.12). Whereas, FA was less bioavailable with an AUC(0-∞) of 750 ± 10 pmol · h/mL. Fruit-supplemented animals reached maximum levels of circulating folate in plasma at 2 h after administration with a subsequent steady decline, while animals treated with FA and synthetic 5-CH3-THF reached maximum levels at 1 h. Pharmacokinetic parameters revealed that biofortified tomato had slower intestinal absorption than synthetic folate forms. This is the first study that demonstrates the bioavailability of folates from a biofortified plant food, showing its potential to improve folate deficiency.

Homocysteine lowering interventions for peripheral arterial disease and bypass grafts.

BACKGROUND: Elevated plasma levels of the amino acid homocysteine (hyperhomocysteinaemia) are associated with narrowing or blocking of the arteries (atherosclerosis). Treatment to lower homocysteine levels has been shown to be both effective and cheap in healthy volunteers. However, the impact of reducing homocysteine levels on the progression of atherosclerosis and patency of the vessels after treatment for atherosclerosis is still unknown and forms the basis for this review. This is the second update of a review first published in 2002. OBJECTIVES: To assess the effects of plasma homocysteine lowering therapy on the clinical progression of disease in people with peripheral arterial disease (PAD) and hyperhomocysteinaemia including, as a subset, those who have undergone surgical or radiological intervention. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Disease Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Trial databases were searched by the TSC (January 2013) for details of ongoing and unpublished studies. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised trials in which participants with PAD and hyperhomocysteinaemia were allocated to either homocysteine lowering therapy or no treatment, including participants before and after surgical or radiological interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. Information on adverse events was collected from the trials. MAIN RESULTS: Two randomised trials with a total of 161 participants were included in this review. The studies did not report on mortality and rate of limb loss. One randomised trial with a total of 133 participants showed that there was a significant improvement in ankle brachial index (ABI) in participants who received folic acid compared with placebo (mean difference (MD) 0.07, 95% confidence interval (CI) 0.04 to 0.11, P < 0.001) and in participants who received 5-methyltetrahydrofolate (5-MTHF) versus placebo (MD 0.05, 95% CI 0.01 to 0.10, P = 0.009). A second trial with a total of 18 participants showed that there was no difference (P non-significant) in ABI in participants who received a multivitamin B supplement (mean ± SEM: 0.7 ± 01) compared with placebo (mean ± SEM: 0.8 ± 0.1). No major events were reported. AUTHORS' CONCLUSIONS: Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease. Further, well constructed trials are urgently required.

Homocysteine lowering by folate-rich diet or pharmacological supplementations in subjects with moderate hyperhomocysteinemia.

BACKGROUND/OBJECTIVES: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with "moderate" hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. SUBJECTS/METHODS: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 µg from a natural folate-rich diet, 200 µg [6S]5-methyltetrahydrofolate (5-MTHF), 200 µg folic acid or placebo. Participants were stratified according to their MTHFR genotype. RESULTS: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. CONCLUSIONS: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations.

Folates and S-adenosylmethionine for major depressive disorder.

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.

Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial.

BACKGROUND: Dietary factors might affect depressive symptoms. OBJECTIVE: In secondary data analyses, we examined effects of supplementation with B vitamins or n-3 (omega-3) fatty acids on depressive symptoms in cardiovascular disease survivors. DESIGN: The SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) trial was a secondary prevention trial (2003-2009; n = 2501) in which individuals aged 45-80 y were randomly assigned, by using a 2 × 2 factorial design, to receive 0.56 mg 5-methyl-tetrahydrofolate and vitamins B-6 (3 mg) and B-12 (0.02 mg); EPA and DHA (600 mg) in a 2:1 ratio; B vitamins and n-3 fatty acids; or a placebo. Depressive symptoms were evaluated at years 3 and 5 with the 30-item Geriatric Depression Scale (GDS). Overall and sex-specific ORs and 95% CIs were estimated in 2000 participants by using factorial logistic regression. RESULTS: After a median of 4.7 y of supplementation, there was no association between allocation to receive B vitamins and depressive symptoms. However, the allocation to receive n-3 fatty acids was positively associated with depressive symptoms (GDS >10) in men (adjusted OR: 1.28; 95% CI: 1.03, 1.61) but not in women. CONCLUSIONS: We showed no beneficial effects of a long-term, low-dose supplementation with B vitamins or n-3 fatty acids on depressive symptoms in cardiovascular disease survivors. The adverse effects of n-3 fatty acids in men merit confirmation.

Dietary supplement drug therapies for depression.

Many dietary supplements are readily accessible and commonly used for the treatment of depression. A dietary supplement is a product intended to supplement the diet but is not intended to treat, diagnose, prevent, or cure disease. The U.S. Food and Drug Administration can take action against dietary supplement manufacturers for products only after they are marketed, mainly if the product is found to be unsafe or if false or misleading claims are made about the product. Few dietary supplement products have been adequately studied for their safety and efficacy. Of the five products reviewed in this article (L-methylfolate, S-adenosyl-L-methionine [SAM-e], omega-3 fatty acids, L-tryptophan, and inositol), only omega-3 fatty acids and SAM-e have sufficient supporting evidence for their efficacy to warrant safe use.

[Does 5-methyltetrahydrofolate offer any advantage over folic acid?]. / Le 5-méthyltétrahydrofolate a-t-il des avantages par rapport a l'acide folique?

Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high-risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement "pteroylmonoglutamic acid (PMG)" was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention.

Prevention of neural-tube defects with periconceptional folic acid, methylfolate, or multivitamins?

BACKGROUND/AIMS: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). METHODS AND RESULTS: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in an 83-91% reduction in NTD recurrence, while the results of the Hungarian (ii) randomized controlled trial and (iii) cohort-controlled trial using a multivitamin containing 0.8 mg folic acid showed 93 and 89% reductions in the first occurrence of NTD, respectively. On the other hand, (iv) another multicenter randomized controlled trial proved a 71% efficacy of 4 mg folic acid in the reduction of recurrent NTD, while (v) a public health-oriented Chinese-US trial showed a 41-79% reduction in the first occurrence of NTD depending on the incidence of NTD. CONCLUSIONS: Translational application of these findings could result in a breakthrough in the primary prevention of NTD, but so far this is not widely applied in practice. The benefits and drawbacks of 4 main possible uses of periconceptional folic acid/multivitamin supplementation, i.e. (i) dietary intake, (ii) periconceptional supplementation, (iii) flour fortification, and (iv) the recent attempt for the use of combination of oral contraceptives with 6S-5-methytetrahydrofolate (methylfolate), are discussed. Obviously, prevention of NTD is much better than the frequent elective termination of pregnancies after prenatal diagnosis of NTD fetuses.

L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline.

Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.

Folate in depression: efficacy, safety, differences in formulations, and clinical issues.

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.