Objective: To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive l-methylfolate calcium 15 mg.Method: 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. Results: 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 openlabel 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. Conclusions: 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. Trial Registration: ClinicalTrials.gov identifier: NCT00321152 Clin Psychiatry 2016;77(5):654-660 dx.doi.org/10.4088/JCP.15m10181 J

In a real-world clinical setting, patients with diabetic peripheral neuropathy treated with LMF-MC-PP achieved significant improvements in total symptom score (NTSS-6) and in quality of life and functioning, together with greater medication satisfaction. A limitation of this study was the use of a survey instrument to collect data on patient outcomes.

After covariate adjustment, HYH+CFLN significantly slowed cognitive decline compared to No-HYH+No-CFLN. Longer CFLN treatment duration, milder baseline severity, and magnitude of homocysteine reduction from baseline were all significant predictors. There are a number of factors that could account for disagreement with other clinical trials of B vitamin treatment of HYH. Moreover, CFLN is chemically distinct from commonly used B vitamins as both LMF and MeCbl are the fully reduced and bioactive functional forms; CLFN also contains the glutathione precursor, N-acetyl-cysteine. The findings of other B vitamin trials of HYH can, therefore, only partly account for treatment effects of CFLN. These findings warrant further evaluation with a randomized, placebo-controlled trial.

ClinicalTrials.gov identifier: NCT00955955.

Abstract. We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin ® /CerefolinNAC ® (CFLN: Lmethylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [ ± σ] = 18.6 ± 16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [ ± σ] = 12.6 ± 5.6 months). Thirtyseven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [ ± σ] = 13.3 ± 17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

Objective: l-Methylfolate has been shown in retrospective and prospective studies to enhance antidepressant response. The aim of this study was to prospectively assess change in depression severity and medication satisfaction in patients prescribed l-methylfolate within a naturalistic setting.Method: Between November 2010 and April 2012, patients who reported being treated for major depressive disorder rated their experiences before and after 3 months on the prescription medical food l-methylfolate (Deplin) 7.5 mg or 15 mg, through an automated telephone system. Survey questions included the 9-item Patient Health Questionnaire (PHQ-9), as well as quality of life and medication satisfaction questions. The primary outcome was change in depression severity from baseline to endpoint.Results: Of 554 patients, 502 reported that l-methylfolate was added to their existing antidepressant and 52 were treated with l-methylfolate alone, without an antidepressant. Enrolled participants reported a mean reduction of 8.5 points (58.2% decrease) in their PHQ-9 score (mean baseline PHQ-9 score = 14.6, mean follow-up PHQ-9 score = 6.1; P = .000); 376 (67.9%) responded to treatment (50% reduction in baseline PHQ-9 score) and 253 (45.7%) achieved remission (follow-up PHQ-9 score < 5) after an average of 95 days of therapy. In addition, patients achieved significant reductions in self-reported impairment in their work/home/social life (P = .000). Medication satisfaction with l-methylfolate (mean satisfaction score = 7.0) was significantly higher than with prior medication (mean satisfaction score = 5.2; P = .000).Conclusions: Results show that in a naturalistic setting, patients managed with l-methylfolate achieved statistically significant improvements in self-reported depression symptoms and functioning and greater satisfaction with their medication treatment.

Purpose: Diabetic peripheral neuropathy (DPN) is prevalent among the population with type 2 diabetes, and treatment approaches are limited. The combination of L-methylfolate-methylcobalamin-pyridoxal-5-phospate (LMF-MC-PP, Metanx ®) is a prescription medical food that has demonstrated significant improvements in sensory perception and quality of life as well as reduced neuropathic pain in patients with DPN. The present study examined the effects of LMF-MC-PP on sensory perception and epidermal nerve fiber density (ENFD) among patients with confirmed DPN. Methods: Patients with type 2 diabetes and diagnosed with diabetic peripheral polyneuropathy, based on loss of vibratory perception, warm-cold discrimination or monofilament sensation, underwent bilateral lower extremity ENFD assessments via skin punch biopsy and were started on LMF-MC-PP. ENFD and monofilament testing were repeated at 6 months. Findings: Of 123 patients evaluated, all had monofilament testing at baseline and 6 months and 122 had assessments at both time points. A significant (p < 0.05) improvement in ENFD from baseline to 6 months was observed. A significant (p = 0.0001) improvement in monofilament testing also was observed. Overall, more patients had intact sensation after 6 months, with 60 (48.8%) of 123 patients having positive monofilament test at baseline as compared to 95 (77.2%) positive after 6 months. An analysis of the association between improvements in ENFD and monofilament testing found that the two tended to occur together, and this was significant (p < 0.05) for the right limb. Implications: Clinically important and statistically significant improvements in ENFD and monofilament sensation were associated with LMF-MC-PP in patients with DPN. When compared to the decrease in ENFD expected among DPN patients, the improvements are even more clinically sig-V. F. McNamara et al. 167 nificant. These findings should be validated in a larger, placebo-controlled study.

No abstract