Inflammation and Vitamin C in Women with Prenatal Depression and Anxiety: Effect of Multinutrient Supplementation.

Elevated inflammation has been associated with adverse mood states, such as depression and anxiety, and antioxidant nutrients, such as vitamin C, have been associated with decreased inflammation and improved mood. In the current study comprising a cohort of pregnant women with depression and anxiety, we hypothesised that elevated inflammation would be associated with adverse mood states and inversely associated with vitamin C status and that multinutrient supplementation would optimise vitamin concentrations and attenuate inflammation. Sixty-one participants from the NUTRIMUM trial had blood samples collected between 12 and 24 weeks gestation (baseline) and following 12 weeks of daily supplementation with a multinutrient formula containing 600 mg of vitamin C or active placebo. The samples were analysed for inflammatory biomarkers (C-reactive protein (CRP) and cytokines) and vitamin C content and were related to scales of depression and anxiety. Positive correlations were observed between interleukin-6 (IL-6) and all of the mood scales administered (p < 0.05), including the Edinburgh Postnatal Depression Scale, the Clinical Global Impressions-Severity Scale, the Montgomery and Åsberg Depression Rating Scale, the Depression Anxiety Stress Scale 21, and the Generalized Anxiety Disorder-7 (GAD-7). CRP correlated weakly with GAD-7 (p = 0.05). There was an inverse correlation between CRP and the vitamin C status of the cohort (p = 0.045), although there was no association of the latter with the mood scales (p > 0.05). Supplementation with the multinutrient formula resulted in a significant increase in the vitamin C status of the cohort (p = 0.007) but did not affect the inflammatory biomarker concentrations (p > 0.05). In conclusion, greater systemic inflammation was associated with worse mood states; however, 12-week multinutrient supplementation did not alter inflammatory biomarker concentrations. Nevertheless, the vitamin C status of the cohort was improved with supplementation, which may aid pregnancy and infant outcomes.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Pyroluria: Fact or Fiction?

Objective: The term "Mauve factor" (pyrroluria) dates back to 1958 when Dr. Abram Hoffer defined the condition as elevated levels of pyrroles in the urine, currently called hydroxyhemepyrrolin-2-one (HPL). It was suggested that the raised pyrrole levels lead to depletions in zinc and vitamin B6, which, in turn, were hypothesized to result in a range of psychiatric disorders, such as schizophrenia, anxiety, and depression. Treatment implications are supplementation with zinc and B6. This article aimed to review the scientific literature associating pyrroluria with psychiatric symptoms, explore the validity of HPL testing, explore the role of nutrients as treatment options for pyrroluria, and discuss future research directions. Methods: A PRISMA review was conducted using search results from electronic databases PubMed, MEDLINE, PsycINFO, EMBASE from inception to February 2020 using the following keywords: hydroxyhemepyryrrolin (HPL), kryptopyrrole (KP), mauve factor, pyroluria, pyrroluria, monopyrroles. Article reference lists were also scanned and included where relevant. Results: Seventy-three articles were identified of which only three studies identified significantly higher HPL levels in a psychiatric population compared with controls, and there were no placebo-controlled treatment trials directed at pyrroluria. The other 13 clinical studies either showed no association or did not provide adequate data to show group differences in HPL levels. Despite an extensive history of practitioners diagnosing and treating a wide variety of mental health conditions associated with pyrroluria as well as clinical observations of elevated HPL being associated with psychiatric disorders, there was no clear research that showed the following: (1) elevated HPL is robustly associated with increased mental health symptoms, (2) elevated HPL in urine is associated with increased urine excretion of zinc and B6, and (3) high-dose zinc and B6 are an efficacious treatment for mental health problems associated with elevated HPL. Conclusions: Elevated HPL is a clinically observed, but poorly researched biomarker with unclear associations with mental disorders. Based on current evidence, HPL testing is not recommended as a screening or treatment tool. Further research is required in the following areas: establishment of which specific clinical populations exhibit elevated HPL, validation of the chemistry and validity of testing, and controlled trials to establish efficacy of high-dose zinc and B6 as treatment of elevated pyrroles.

Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin-Mineral Supplement?

Objective: We investigated whether changes in serum nutrient levels mediate clinical response to a micronutrient intervention for ADHD. Method: Data were compiled from two ADHD trials (8-10 weeks), one in adults (n = 53) and one in children (n = 38). Seven outcomes included change in ADHD symptoms, mood, overall functioning (all clinician-rated) as well as response status. Change in serum/plasma nutrient levels (vitamins B12 and D, folate, ferritin, iron, zinc, and copper) were considered putative mediators. Results: A decrease in ferritin and an increase in copper were weakly associated with greater likelihood of being identified as an ADHD responder; none of the other nutrient biomarkers served as mediators. Conclusion: Further research looking at nutrients more broadly from other tissues are required to confirm these initial observations of the limited value of nutrient levels in deciphering mechanism of action. Monitoring these biomarkers on their own is unlikely helpful in understanding clinical response to a broad-spectrum micronutrient approach.

Are over-the-counter fish oil supplements safe, effective and accurate with labelling? Analysis of 10 New Zealand fish oil supplements.

AIM: Fish oil supplements are regulated in New Zealand under the Dietary Supplement Regulations (Section 42, Food Act 1981) and therefore are not subject to the same level of scrutiny and regulations as medicines. We investigated accuracy of labelling, stated health benefits of fish oil supplements sold in New Zealand, and risks relating to possible mercury content. METHOD: The amounts of omega-3 fatty acids contained per capsule were determined by an independent laboratory using gas chromatography on 10 of the most popular over-the-counter fish oil supplements sold in New Zealand and were compared with amounts stated on product labels. Information on doses recommended to achieve a specific health benefit were taken from the 10 labels as well as the company websites. These recommended doses were compared with published recommended doses identified as being effective in those health areas stipulated on the labels, based on either systematic reviews, meta-analyses and/or consensus statements. Mercury was analysed by an independent laboratory using inductively coupled plasma mass spectrometry. RESULTS: The actual amounts of EPA and DHA per capsule in 90% of the over-the-counter fish oil supplements analysed were within 10% of the amount stated on the product labels. Only one product was greater than 10% below the stated dose on the label. All products suggested benefit across heart, brain and joint health and all but two products stated a range of capsules required to achieve that health benefit (eg, 2-6 capsules). Based on the maximum number of capsules recommended (which ranged from 3-6 capsules), only three products would likely confer the dose identified as optimal for achieving a health benefit across all three health areas. Only two products recommended doses that would likely confer a health benefit both at the minimum and maximum number of capsules. More products would likely benefit brain and heart health than joint health. Mercury was not detected in any sample. CONCLUSIONS: It is reassuring that the doses of 90% of the products were accurate and that mercury was not detected in any sample; however, less than a third of the supplements would likely confer all the health benefits stated, even at the highest recommended daily doses. This paper has highlighted the ongoing challenges associated with the regulation of "health claims" associated with dietary supplements in New Zealand. Indeed, the literature on health effects is contradictory at best. Clearer definitions of the types of health statements that can be made and the research necessary to support them requires regulatory clarification.

Can broad-spectrum multinutrients treat symptoms of antenatal depression and anxiety and improve infant development? Study protocol of a double blind, randomized, controlled trial (the 'NUTRIMUM' trial).

BACKGROUND: Untreated antenatal depression and anxiety can be associated with short and long term health impacts on the pregnant woman, her infant and the rest of the family. Alternative interventions to those currently available are needed. This clinical trial aims to investigate the efficacy and safety of a broad-spectrum multinutrient formula as a treatment for symptoms of depression and anxiety in pregnant women and to determine the impact supplementation has on the general health and development of the infant. METHODS: This randomised, controlled trial will be conducted in Canterbury, New Zealand between April 2017 and June 2022. One hundred and twenty women aged over 16 years, between 12 and 24 weeks gestation and who score ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) will be randomly assigned to take the intervention (n = 60) or an active control formula containing iodine and riboflavin (n = 60) for 12 weeks. After 12 weeks, participants can enter an open-label phase until the birth of their infant and naturalistically followed for the first 12 months postpartum. Infants will be followed until 12 months of age. Randomisation will be computer-generated, with allocation concealment by opaque sequentially numbered envelopes. Participants and the research team including data analysts will be blinded to group assignment. The EPDS and the Clinical Global Impressions Scale of Improvement (CGI-I) will be the maternal primary outcome measures of this study and will assess the incidence of depression and anxiety and the improvement of symptomatology respectively. Generalized linear mixed effects regression models will analyse statistical differences between the multinutrient and active control group on an intent-to-treat basis. A minimum of a three-point difference in EPDS scores between the groups will identify clinical significance. Pregnancy outcomes, adverse events and side effects will also be monitored and reported. DISCUSSION: Should the multinutrient formula be shown to be beneficial for both the mother and the infant, then an alternative treatment option that may also improve the biopsychosocial development of their infants can be provided for pregnant women experiencing symptoms of depression and anxiety. TRIAL REGISTRATION: Trial ID: ACTRN12617000354381 ; prospectively registered at Australian New Zealand Clinical Trials Registry on 08/03/2017.

Broad spectrum micronutrient formulas for the treatment of symptoms of depression, stress, and/or anxiety: a systematic review.

Introduction: Vitamin and mineral nutritional supplements are becoming increasingly popular as alternative treatments for anxiety and depression, as issues such as side effects from medication, failure to respond to psychotherapy and workforce limitations pose barriers for successful treatment.Areas covered: This review covered double-blind, randomized controlled trials (DBRCTs) testing formulas including at least four vitamins and/or minerals used for the treatment of symptoms of anxiety, stress, or depression in adults not currently taking medication for psychiatric difficulties.Expert opinion: The majority of the 23 trials reviewed were conducted on people without psychological difficulties, limiting the generalizability of the results in people with diagnosed mood and anxiety difficulties. Sixteen studies demonstrated positive effects for symptoms of anxiety, depression, or stress. Micronutrient supplementation in healthy nonclinical adults has limited benefits for mood and anxiety symptoms, although may convey some subtle general improvements. The evidence for adults with physical or mental ill health is more positive although limited by small samples and variability in nutrients studied. Broad-spectrum nutrient products may be more effective than a selected few. While an effect of micronutrients cannot be dismissed, the variability of the studies makes it extremely challenging to identify specific treatment benefits.

A Pilot Randomized Treatment-Controlled Trial Comparing Vitamin B6 with Broad-Spectrum Micronutrients for Premenstrual Syndrome.

Objective: Premenstrual syndrome (PMS) affects 20%-30% of women but current medical treatments are limited in their efficacy. The objective of this study was to compare efficacy of a broad-spectrum micronutrient formula (consisting mainly of minerals and vitamins) to a single vitamin (B6) for treatment of PMS, for which B6 has already been shown to be efficacious. Methods: This double-blind, randomized, treatment-controlled trial allocated 78 (72 completed) regularly menstruating women with PMS to consume micronutrients or vitamin B6 (80 mg/day) daily following a two-cycle baseline period, for three menstrual cycles. The primary outcome measure, Daily Record of Severity of Problems (DRSP), established PMS as well as tracked change in five PMS symptoms: psychological, somatic, total symptoms, impact ratings, and worst day ratings. Results: Linear-mixed model analyses indicated both treatments produced comparable reduction in PMS symptoms with medium effect sizes (ES) across all PMS variables as measured by the DRSP (micronutrient ES = 0.50-0.56; B6 ES = 0.43-0.56), with 72% of the micronutrient and 60% of the vitamin B6 group identified as in full remission in PMS symptoms after three cycles. The micronutrient-treated participants showed greater improvement than the B6 group (between group d = 0.51, p < 0.05) in health-related quality of life. For those women (n = 28) who met criteria for premenstrual dysphoric disorder (PMDD), the DRSP ES were larger for those who had been in the micronutrient condition (ES = 1.28-1.67) as compared with those on B6 (ES = 0.50-0.75), although the group differences were not statistically reliable. There were no group differences in side effects, nor any serious adverse effects reported. Conclusions: Both treatments provided similar benefit for reducing PMS symptoms, with greater effect of micronutrients on quality of life as well as potential clinical benefit of micronutrients for PMDD. This study provides further efficacy data on B6 and also identifies the nutritionally broader spectrum intervention as possibly having specific advantages for those whose symptoms are more severe. As this is the first study to investigate these treatments for PMDD, systematic replication is required.

Author Correction: Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel Mineral-Vitamin Treatment for Reduction in Cigarette Smoking: A Fully Blinded Randomized Placebo-Controlled Trial.

INTRODUCTION: Many smokers do not achieve abstinence using current smoking cessation options. This randomized controlled trial (RCT) investigated a novel nutritional supplement to assist with quitting smoking. METHODS: Following a baseline phase where cigarettes per day and nicotine dependence were measured, participants (n = 107) were randomized to placebo (n = 50) or micronutrient conditions (n = 57). A 4-week pre-quit phase permitted titration up to 12 capsules/day. During the quit phase (12 weeks), participants were registered with a public Quitline while consuming micronutrients or placebo. Carbon monoxide levels were measured to confirm smoking cessation. RESULTS: Forty-five (42%) participants completed the trial. Treatment and placebo groups did not differ on the primary outcome of continuous abstinence at 12 weeks using intention-to-treat analysis; however, 28% of the micronutrient-treated group had quit versus 18% for placebo (odds ratio [OR] = 1.78, 95% confidence interval [CI] = 0.71 to 4.48), with number needed to treat = 10. Comparison of cigarette consumption (cigarettes per day) between micronutrient and placebo groups showed that those taking micronutrients reported reduced consumption throughout the trial, notably at pre-quit weeks 1 and 4, and at quit phase week 4. There were no serious adverse events, blinding was successful, and there were no substantive group differences in side effects or dropout rate. CONCLUSION: This is the first RCT investigating the impact of micronutrients on smoking reduction, finding that micronutrients reduced harm through reduction in number of cigarettes smoked relative to placebo. The small sample and high dropout rate limit confidence in the conclusions and generalizability of the study; however, assessed by number needed to treat, micronutrients are comparable to other smoking cessation treatments but with fewer side effects. Future research using larger and longer trials including cost-effectiveness and biomarker measures is encouraged. IMPLICATIONS: Micronutrients are being increasingly studied for the treatment of psychiatric conditions, but direct application of micronutrients as a treatment for addictions is novel. There is extensive evidence that micronutrients alleviate stress. Given that tobacco smoking is often used to cope with stress, taking micronutrients may moderate the stress of withdrawal and increase the chance of a successful quit attempt. This study is the first known RCT to investigate the use of micronutrients to support smoking cessation. Treatments that are safe, effective, relatively inexpensive, and readily available are needed and micronutrient supplements offer one such possible alternative.

Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder.

It has been widely hypothesized that both diet and the microbiome play a role in the regulation of attention-deficit/hyperactivity disorder (ADHD) behaviour. However, there has been very limited scientific investigation into the potential biological connection. We performed a 10-week pilot study investigating the effects of a broad spectrum micronutrient administration on faecal microbiome content, using 16S rRNA gene sequencing. The study consisted of 17 children (seven in the placebo and ten in the treatment group) between the ages of seven and 12 years, who were diagnosed with ADHD. We found that micronutrient treatment did not drive large-scale changes in composition or structure of the microbiome. However, observed OTUs significantly increased in the treatment group, and showed no mean change in the placebo group. The differential abundance and relative frequency of Actinobacteria significantly decreased post- micronutrient treatment, and this was largely attributed to species from the genus Bifidobacterium. This was compensated by an increase in the relative frequency of species from the genus Collinsella. Further research is required to establish the role that Bifidobacterium contribute towards neuropsychiatric disorders; however, these findings suggest that micronutrient administration could be used as a safe, therapeutic method to modulate Bifidobacterium abundance, which could have potential implications for modulating and regulating ADHD behaviour. Our pilot study provides an initial observation into this area of research, and highlights an interesting avenue for further investigation in a larger cohort. Furthermore, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome.

An Observational Preliminary Study on the Safety of Long-Term Consumption of Micronutrients for the Treatment of Psychiatric Symptoms.

Objectives: There is an increasing body of literature documenting the efficacy of micronutrients (vitamins and minerals) interventions for the treatment of psychiatric problems in the short term; however, long-term safety is largely unexplored. The goal of this observational study was to investigate the safety of two commercially available broad-spectrum micronutrient formulas (EMPowerplus and Daily Essential Nutrients) given at doses above the Recommended Dietary Allowances for the long-term treatment of individuals with psychiatric symptoms. Design: Participants on long-term treatment with micronutrients (medication-free) for psychiatric problems (attention-deficit hyperactivity disorder [ADHD, n = 21], anxiety/depression [n = 13]) were identified from ongoing research studies and the community through purchasing records. Seventeen children and 17 adults had blood tests to assess their full blood count, coagulation profile, liver and kidney function, fasting glucose, iron studies, key nutrients, and prolactin. Questionnaires assessed psychological/psychiatric functioning. Seventeen of the participants had completed the same measures pretreatment. Results: The average length of consuming micronutrients was 2.66 years (standard deviation = 2.86). Excluding B12 (which was elevated for almost all participants), 94.6% of all blood test results were within the test reference ranges. One participant was diagnosed with hemochromatosis based on iron studies. No other clinically relevant adverse changes in blood results were identified pre- and post-treatment. No clinically significant adverse effects were reported. Post-treatment psychometrics identified that 85% of the participants were in nonclinical ranges for measures of ADHD, depression, anxiety, and stress. Conclusions: We report preliminary evidence for the safety of long-term commercially available micronutrients, although questions remain. Overall, the substantial psychiatric benefits observed appear to outweigh the minimal observed risks in these participants. Screening for potential medical problems is recommended before initiating treatment. Long-term pharmacovigilance monitoring is required to ascertain any rare but significant adverse events.

Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables.

BACKGROUND: Intent-to-treat analyses from a randomized controlled trial showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement, but no group differences on clinician, parent and teacher ratings of overall ADHD symptoms. There was an advantage of micronutrients over placebo in improving overall function, emotional regulation, aggression, and reducing impairment as well as improving inattention based on clinician but not parent observation. No group differences were observed on hyperactive-impulsive symptoms. We investigated predictors of response defined by pre-treatment variables. METHOD: We conducted analyses of data from a clinical trial of children (7-12 years) with ADHD, whereby participants were randomized to receive micronutrients or placebo for 10 weeks followed by a 10 week open-label (OL) phase. We included only children who had been exposed to micronutrients for a full 10 week period and demonstrated satisfactory adherence, either in RCT phase (n = 40) or OL phase (those who received placebo during RCT phase; n = 31). Seven outcomes were examined: change in ADHD symptoms (clinician/parent), ADHD responder, overall responder, change in mood, change in functioning, and change in aggression. Demographic, developmental variables, current clinical and physical characteristics, MTHFR genotype at two common variants, and pre-treatment serum/plasma levels (vitamin D, B12, folate, zinc, copper, iron, ferritin, potassium, calcium, magnesium, and homocysteine) were all considered as putative predictors. RESULTS: Substantial nutrient deficiencies pre-treatment were observed only for vitamin D (13%) and copper (15%), otherwise most children entered the trial with nutrient levels falling within expected ranges. Regression analyses showed varying predictors across outcomes with no one predictor being consistently identified across different variables. Lower pre-treatment folate and B12 levels, being female, greater severity of symptoms and co-occurring disorders pre-treatment, more pregnancy complications and fewer birth problems were identified as possible predictors of greater improvement for some but not all outcome measures although predictive values were weak. Lower IQ and higher BMI predicted greater improvement in aggression. CONCLUSIONS: This study replicates Rucklidge et al. (2014b) showing the limited value of using serum nutrient levels to predict treatment response although we cannot rule out that other non-assayed nutrient levels may be more valuable. Additionally, no specific demographic or clinical characteristics, including MTHFR genetic status, were identified that would preclude children with ADHD from trying this treatment approach.

Methylomic changes in response to micronutrient supplementation and MTHFR genotype.

Exposure times and dosage required for dietary components to modify DNA methylation patterns are largely unknown. AIM: This exploratory research represents the first genome-wide analysis of DNA methylation changes during a randomized-controlled-trial (RCT) for dietary supplementation with broad spectrum vitamins, minerals and amino acids in humans. METHODS: Genome-wide changes in methylation from paired, peripheral blood samples were assessed using the Infinium Methylation EPIC 850 K array. RESULTS: Methylation increased at 84% of the most significant differentially methylated CpGs; however, none showed significance after adjustment for genome-wide testing. CONCLUSION: Micronutrient supplementation is unlikely to have a substantial biological effect on DNA methylation over 10 weeks; however, the trend toward hypermethylation that we observed is likely to become more marked with longer exposure periods.

Database Analysis of Depression and Anxiety in a Community Sample-Response to a Micronutrient Intervention.

BACKGROUND: Depression and anxiety are common mental health concerns worldwide. Broad-spectrum multi-vitamin/mineral approaches have been found to alleviate a number of psychiatric symptoms. We investigated the effects of a nutrient intervention program, which includes optimizing vitamin D levels, on depression and anxiety outcomes from community-based program. METHODS: We evaluated self-reported health measures of depression and anxiety collected as part of a community-based program focused on optimizing overall health through nutritional supplementation, education and lifestyle advice. RESULTS: Data were collected from 16,020 participants, with measures including European Quality of Life Five Dimensions (EQ-5D) and Targeted Symptoms List (TSL) providing self-reported depression and anxiety. More than 56% of participants were identified as having elevated levels of depression and anxiety at baseline as reported on the EQ-5D. After one year in the program, 49.2% (n = 7878) of participants who reported any level of depression or anxiety at baseline reported improvement at follow-up. Of those who reported severe/extreme depression at baseline (n = 829), 97.2% reported improvement after one year. Regression analyses revealed a significant association of improvement in depression and anxiety with higher vitamin D status (>100 nmol/L) and more strenuous physical activity. CONCLUSION: Overall, people from the general population who suffer from mood and anxiety problems may benefit from improved nutritional status achieved with nutritional supplements.

Epigenetics, nutrition and mental health. Is there a relationship?

Many aspects of human development and disease are influenced by the interaction between genetic and environmental factors. Understanding how our genes respond to the environment is central to managing health and disease, and is one of the major contemporary challenges in human genetics. Various epigenetic processes affect chromosome structure and accessibility of deoxyribonucleic acid (DNA) to the enzymatic machinery that leads to expression of genes. One important epigenetic mechanism that appears to underlie the interaction between environmental factors, including diet, and our genome, is chemical modification of the DNA. The best understood of these modifications is methylation of cytosine residues in DNA. It is now recognized that the pattern of methylated cytosines throughout our genomes (the 'methylome') can change during development and in response to environmental cues, often with profound effects on gene expression. Many dietary constituents may indirectly influence genomic pathways that methylate DNA, and there is evidence for biochemical links between nutritional quality and mental health. Deficiency of both macro- and micronutrients has been associated with increased behavioural problems, and nutritional supplementation has proven efficacious in treatment of certain neuropsychiatric disorders. In this review we examine evidence from the fields of nutrition, developmental biology, and mental health that supports dietary impacts on epigenetic processes, particularly DNA methylation. We then consider whether such processes could underlie the demonstrated efficacy of dietary supplementation in treatment of mental disorders, and whether targeted manipulation of DNA methylation patterns using controlled dietary supplementation may be of wider clinical value.

A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression.

OBJECTIVES: This trial investigated whether probiotics improved mood, stress and anxiety in a sample selected for low mood. We also tested whether the presence or severity of irritable bowel syndrome symptoms, and levels of proinflammatory cytokines, brain-derived neurotrophic factor and other blood markers, would predict or impact treatment response. METHOD: Seventy-nine participants (10 dropouts) not currently taking psychotropic medications with at least moderate scores on self-report mood measures were randomly allocated to receive either a probiotic preparation (containing Lactobacillus helveticus and Bifidobacterium longum) or a matched placebo, in a double-blind trial for 8 weeks. Data were analysed as intent-to-treat. RESULTS: No significant difference was found between the probiotic and placebo groups on any psychological outcome measure (Cohen's d range = 0.07-0.16) or any blood-based biomarker. At end-point, 9 (23%) of those in the probiotic group showed a ⩾60% change on the Montgomery-Åsberg Depression Rating Scale (responders), compared to 10 (26%) of those in the placebo group ([Formula: see text], p = ns). Baseline vitamin D level was found to moderate treatment effect on several outcome measures. Dry mouth and sleep disruption were reported more frequently in the placebo group. CONCLUSIONS: This study found no evidence that the probiotic formulation is effective in treating low mood, or in moderating the levels of inflammatory and other biomarkers. The lack of observed effect on mood symptoms may be due to the severity, chronicity or treatment resistance of the sample; recruiting an antidepressant-naive sample experiencing mild, acute symptoms of low mood, may well yield a different result. Future studies taking a preventative approach or using probiotics as an adjuvant treatment may also be more effective. Vitamin D levels should be monitored in future studies in the area. The results of this trial are preliminary; future studies in the area should not be discouraged.

Study Protocol for a Randomized Double Blind, Treatment Control Trial Comparing the Efficacy of a Micronutrient Formula to a Single Vitamin Supplement in the Treatment of Premenstrual Syndrome.

Background: The recent addition of Premenstrual Dysphoric Disorder (PMDD) to the Diagnostic and Statistical Manual (5th ed.) has highlighted the seriousness of this disorder. Many alternatives to psychoactive medication in the form of vitamins, minerals, and plant extracts have been trialled by women seeking a natural treatment approach. We plan to explore whether a well validated micronutrient formula, EMPowerplus Advanced, can outperform a recognized single nutrient treatment, vitamin B6, for the treatment of Premenstrual Syndrome (PMS). Methods: This will be a randomized treatment control study. Eighty women will be recruited and assigned to one of two treatment groups; EMPowerplus Advanced or vitamin B6. Baseline daily data will be collected for an initial two cycles, followed by three months of active treatment. A natural follow up will take place three cycles post treatment. Results: The primary outcome measure will be PMS change scores as based on results from the Daily Record of Severity of Problems (DRSP). The number of treatment responders for each of the two groups will yield a comparison score between the two treatments, with participants deemed as a responder if they show a total PMS score improvement of 50% from their baseline scores on the DRSP. Conclusion: If a micronutrient formula proves more effective for treating PMS, not only does it give women suffering from the condition a viable treatment option, but it may also suggest one cause of PMS; that is insufficient minerals and vitamins.