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Major depressive disorder (MDD) is a complex and common disorder, with many factors involved in its onset and development. The clinical management of this condition is frequently based on the use of some pharmacological antidepressant agents, together with psychotherapy and other alternatives in most severe cases. However, an important percentage of depressed patients fail to respond to the use of conventional therapies. This has created the urgency of finding novel approaches to help in the clinical management of those individuals. Nutraceuticals are natural compounds contained in food with proven benefits either in health promotion or disease prevention and therapy. A growing interest and economical sources are being placed in the development and understanding of multiple nutraceutical products. Here, we summarize some of the most relevant nutraceutical agents evaluated in preclinical and clinical models of depression. In addition, we will also explore less frequent but interest nutraceutical products which are starting to be tested, also evaluating future roads to cover in order to maximize the benefits of nutraceuticals in MDD.

ABSTRACTBackgroundFolate and vitamin B12 insufficiencies have been associated with increased risk of depression. This systematic review aimed to clarify if, compared with placebo, treatment with folate and/or vitamin B12 reduces depression scale scores, increases remission, and prevents the onset of clinically significant symptoms of depression in people at risk. MethodsThis systematic review searched the PubMed, PsychInfo, Embase, and Cochrane databases from inception to 6 June 2014, using the following terms and strategy: (vitamin B12 or vitamin B9 or folate or folic acid or cobalamin or cyanocobalamin) and (depression or depressive disorder or depressive symptoms) and (randomized controlled trial or RCT). The electronic search was supplemented by manual search. Two independent reviewers assessed all papers retrieved for eligibility and bias, and extracted crude data. Review Manager 5 was used to manage and analyze the data. ResultsTwo hundred and sixty-nine manuscripts were identified, of which 52 were RCTs and 11 fulfilled criteria for review. We found that the short-term use of vitamins (days to a few weeks) does not contribute to improve depressive symptoms in adults with major depression treated with antidepressants (5 studies, standardized mean difference = −0.12, 95% confidence interval – 95% CI = −0.45, 0.22), but more prolonged consumption (several weeks to years) may decrease the risk of relapse (1 study, odds ratio (OR) = 0.33, 95% CI = 0.12, 0.94) and the onset of clinically significant symptoms in people at risk (2 studies, risk ratio = 0.65, 95% CI = 0.43, 0.98). ConclusionsThe number of available trials remains small and heterogeneity between studies high. The results of these meta-analyses suggest that treatment with folate and vitamin B12 does not decrease the severity of depressive symptoms over a short period of time, but may be helpful in the long-term management of special populations.

•Folate has been linked with the synthesis of monoamines which play an essential role in symptoms of depression.•Folate deficiency has been associated with depression.•The study aimed to evaluate the efficacy of folic acid or l-methylfolate as an adjunct therapy for depression treatment.•Folate, as an adjunct to SSRI/SNRIs improves depression scale scores, patient remission, and response rates. Evaluate depression scores, response, and remission rates in patients with major depression receiving adjunct therapy with folate (L-Methylfolate or folic acid) compared to selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI or SNRI) monotherapy. Academic Search Premier, CINAHL Complete, Cochrane Database of Systematic Reviews, Medline with Full Text, PsychInfo, PubMed, ClinicalTrials.org, and Google Scholar were searched utilizing specific key words. Identified studies were independently screened for inclusion by two reviewers, were assessed for risk of bias using the Revised Cochrane risk-of-bias tool (RoB2), then meta-analyzed using a random effects model with Review Manager (5.4) software. The initial search revealed 293 articles with 6 randomized control trials ultimately meeting inclusion criteria. In patients with depression, analysis of 5 studies revealed a significantly lower Hamilton Depression Rating Scale (HAM-D) score in individuals treated with adjunct therapy with l-Methylfolate/folic acid [Mean Difference (MD): -2.16 (95 % CI -3.62 to -0.69), p = 0.004], as well a combined HAM-D and Beck Depression Inventory-II (BDI-II) scores [standardized mean difference (SMD): -0.61 (95 % Confidence Interval {CI} -0.97 to -0.24), p = 0.002]. This adjunct therapy also yielded an improved response rate [Risk Ratio (RR): 1.36 (95 % CI: 1.16–1.59) P = 0.0001], increase in remission rate [RR: 1.39 (95 % CI: 1.00–1.92) P = 0.05], and reduction in depression scores after varying durations of treatment, 4 week: [SMD = -0.38 (95 % CI: –0.55 to -0.22) P ≤ 0.00001]; 6 week: [SMD = –0.94 (95 % CI: –1.85 to -0.03) P = 0.04]; ≥ 8 week: [SMD= -0.57 (95 % CI: -0.91 to -0.23) P = 0.0009]. Adjunct therapy with l-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.

Diabetic retinopathy (DR) is a form of microangiopathy. Reducing oxidative stress in the mitochondria and cell membranes decreases ischemic injury and end-organ damage to the retina. New approaches are needed, which reduce the risk and improve the outcomes of DR while complementing current therapeutic approaches. Homocysteine (Hcy) elevation and oxidative stress are potential therapeutic targets in DR. Common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity. Patients with DR have high incidences of deficiencies of crucial vitamins, minerals, and related compounds, which also lead to elevation of Hcy and oxidative stress. Addressing the effects of the MTHFR polymorphism and addressing comorbid deficiencies and insufficiencies reduce the impact and severity of the disease. This approach provides safe and simple strategies that support conventional care and improve outcomes. Suboptimal vitamin co-factor availability also impairs the release of neurotrophic and neuroprotective growth factors. Collectively, this accounts for variability in presentation and response of DR to conventional therapy. Fortunately, there are straightforward recommendations for addressing these issues and supporting traditional treatment plans. We have reviewed the literature for nutritional interventions that support conventional therapies to reduce disease risk and severity. Optimal combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid, and n-acetylcysteine are identified for protecting the retina and choroid. Certain medical foods have been successfully used as therapy for retinopathy. Recommendations based on this review and our clinical experience are developed for clinicians to use to support conventional therapy for DR. DR from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have similar retinal findings and responses to nutritional therapies.

To evaluate the effects of Ocufolin on retinal microcirculation in patients with mild diabetic retinopathy carrying MTHFR polymorphisms. In a prospective, case-controlled study, eight patients with mild diabetic retinopathy and MTHFR polymorphisms and 15 normal controls (NC) were recruited. MTHFR polymorphisms were subtyped as normal, C677T, or A1298C. Best-corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The eight retinopathy patients received Ocufolin for 6 months, and their imaging was performed at baseline, 4 months, and 6 months. The NC group was imaged once. BCVA and vascular indices of DR + PM patients at baseline were below those of NC and improved after Ocufolin administration. Compared to baseline, DR + PM patients had significantly improved BCVA during the follow-up period (P < 0.05). RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05), approaching NC. Ocufolin may be effective in improving both visual acuity and retinal microcirculation in patients with DR + PM. Further studies with increasing sample size, and longer duration, including cases with severe DR, are needed.

This case series describes the aggregate rate of recovery in five consecutive subjects (six eyes) with retinal vein occlusion (RVO) who received l-methylfolate and other vitamins via Ocufolin®, a medical food. Subjects were followed for 10–33 months by a single ophthalmologist. Ocufolin® was prescribed at the time of diagnosis and subjects remained on the regimen throughout the time of observation. Examinations were performed in an un-masked fashion at 3-month intervals with recording of best corrected visual acuity (BCVA), average retinal nerve fiber layer (ARNFL) and central macular thickness (CMT), and fundus (examination of the retina, macula, optic nerve, and vessels) photography. Testing was done for vitamin deficiencies, vascular and coagulable risk factors, and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Vitamin deficiencies and vascular risk factors were found in all subjects, and all four tested subjects carried at least one MTHFR polymorphism. By the end of the study period BCVA in all subjects was 20/25 or better. Cystoid macular edema was identified and measured by optical coherence tomography (OCT). The percent change was calculated and plotted at 3-month intervals using the percent change in thickness from the time of diagnosis and percent change toward normative values for ARNFL and CMT. The total reduction in thickness of ARNFL and CMT from time of diagnosis was 44.19% and 30.27%, respectively. The comparison to normative data shows a reduction of ARNFL from 164.2% to 94% and CMT from 154.4% to 112.7% of normal thickness (100%). Plots showed the aggregate recovery was most rapid over the first 3 months and slowed over the next 3 months with most of the recovery taking place within 6 months of treatment. The rate of improvement in BCVA and resolution of retinal thickening was found to be better than predicted on historical grounds. No subjects progressed from nonischemic to ischemic RVO. Vitamin deficiencies, vascular risk factors, and genetic predisposition to oxidative stress were common in this RVO series. It appears that addressing these factors with Ocufolin® had a salutary effect on recovery.

We evaluate the effects of methylenetetrahydrofolate reductase ( polymorphisms on retinal tissue perfusion in patients with mild diabetic retinopathy (DR + PM) taking the medical food, Ocufolin , for 6 months. Prospective, case-controlled study. Eight early diabetic retinopathy patients with common reduced function polymorphisms (DR+PM) and 15 normal controls (NC) were recruited. polymorphisms were subtyped as normal, , or . Best corrected visual acuity (BCVA) was evaluated. Retinal blood flow velocity (BFV) was measured using Retinal Function Imager. Retinal tissue perfusion (RTP, blood flow rate per inner retinal volume) was calculated within a 2.5 mm diameter circle centered on the fovea. The medical food is intended to address ocular ischemia with high doses of vitamin B-complexes and antioxidants, including L-methylfolate, methylcobalamin, zinc, copper, lutein, vitamins C, D, E, and n-acetylcysteine. The subjects were provided with a medical food for a period of 6 months. BCVA and vascular indices of DR + PM patients at baseline were initially below those of NC and improved after medical food. Compared to baseline, DR + PM patients after the medical food had significantly improved BCVA during the follow-up period (P < 0.05). In comparison, overall RTP and arteriolar BFV were significantly increased at 6 months (P < 0.05). The changes varied with subtypes. In patients with the and the compound mutations, RTP was increased at 6 months as compared to that at baseline and 4 months (P < 0.05). In patients with only the mutation, all microcirculation metrics were increased from baseline at 4 and 6 months, but with less improvement at 6 months than at 4 months (P < 0.05). Medical food was effective in improving both visual acuity and retinal tissue perfusion in DR + PM patients. The degree of improvement of retinal microcirculation varied among subtypes.

Rationale This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment. Objective We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia. Methods The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model. Results Although we included ten RCTs with 925 patients in total (seven folic acid RCTs ( n  = 789), two methylfolate RCTs ( n  = 96), and one folinic acid RCT ( n  = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total ( N  = 7, n  = 340; standardized mean difference (SMD) = − 0.20, 95% confidence interval (CI) = − 0.41, 0.02, p  = 0.08, I 2  = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms ( N  = 5, n  = 281; SMD = −0.25, 95% CI = −0.49, −0.01, p  = 0.04, I 2  = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments ( N  = 4, n  = 241; risk ratio = 0.32, 95% CI = 0.12–0.82, p  = 0.02, I 2  = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments. Conclusions Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.

The nutritional management of depression has long been discussed, due to the perceived benefit of a nutritional product having less side effects than pharmaceutical agents. Candidate nutrients for managing depression include vitamin D, B vitamins, tryptophan, branch chain amino acids, probiotics, omega-3 fatty acids, folate/methylfolate (also known as vitamin B9), and s-adenosylmethionine. This paper provides a narrative review of three nutrients which have significant scientific support for the management of depression. A deficiency in each nutrient is associated with depression, and interventional studies indicate that the correction of the nutritional deficiency may provide clinical benefit. We present epidemiological evidence, a mechanistic explanation and a review of interventional studies for these nutrients. Finally, relevant nutritional guidelines are presented with their conclusion for the role of each nutrient in the management of depression.