Toward 'element balance' in ADHD: an exploratory case control study employing hair analysis.

Background: Head hair analysis has been used for decades to clarify mineral relationships to symptoms of ADHD, but there is little consensus among findings. We sought to explore 33 hair element concentrations and their 528 calculated ratios among two groups of boys, one with ADHD and one without.Method: 107 boys aged 7-12 years were recruited; 55 with ADHD and 52 non-ADHD Controls. Hair minerals were compared using Mann-Whitney U tests, p<0.01 was used for significance. Dietary data were obtained using a 138 item food frequency questionnaire (FFQ).Results: There were three group differences on individual elements: bismuth/Bi: 8 fold higher in ADHD, chromium/Cr: 15% lower in ADHD and germanium/Ge: 11% lower in ADHD, Cr level being the strongest predictor of ADHD symptoms. We found thirty significant group differences in element ratios, two thirds involving Bi and eight of these showing that as ADHD severity increased, the ratios with Bi as the denominator decreased (r ranging from -0.263 to -0.433, p<0.01). From the FFQ, tinned fruit was consumed more often in the ADHD group. Hair arsenic levels were somewhat elevated across both ADHD and Control groups.Discussion: While element 'imbalance' appears to be associated with ADHD, we did not replicate any previous study results of group differences on individual elements. We have raised the possibility that the ratios may be far more important than any one individual element in better elucidating the effects that minerals may have on the pathogenesis of ADHD. These are cautionary findings requiring replication.

Is mandatory prospective trial registration working? An update on the adherence to the International Committee of Medical Journal Editors guidelines across five psychiatry journals: 2015-2020.

OBJECTIVE: Previous research indicated that the International Committee of Medical Journal Editors guidelines of prospective trial registration with clearly identified primary and secondary outcome measures are only adhered to in 14.4% of studies published in the top five psychiatry journals between 1 January 2009 and 31 July 2013. This study examined if adherence has improved. METHODS: The registration information, article information, primary outcome measures (POMs), participant numbers and funding source were extracted from studies published in the same five psychiatry journals between 1 January 2015 and 31 December 2019. Discrepancies between POMs in the articles and registry were tracked. RESULTS: Of the 7268 publications, 268 studies required registration. Three (1.1%) were unregistered, 107 (39.9%) were retrospectively registered, and 158 (58.9%) were prospectively registered. Of the 158 prospectively registered studies, 16 (10.1%) had unclear POMs in the article or registration, 22 (13.9%) had discrepancies between registered and published POMs, and 33 (20.9%) had no POM discrepancies but had retrospectively updated POMs in the registry. Of the 22 studies with discrepancies, nine (40.9%) were determined to favour statistically significant results. Overall, 87 (32.5%) of the 268 studies were prospectively registered with no discrepancies between registered and published POMs and no changes to registered POMs or timeframes. CONCLUSION: Although this rate of one third of published articles fully adhering to the guidelines is an improvement compared to previous research, further efforts still need to be made by both authors and journals to ensure full transparency in the reporting of studies in psychiatry.

Resting-state networks and neurometabolites in children with ADHD after 10 weeks of treatment with micronutrients: results of a randomised placebo-controlled trial.

Children with attention-deficit/hyperactivity disorder (ADHD) show significant abnormalities on MR imaging in network communication and connectivity. The prefrontal-striatal-cerebella circuitry, involved in attention is particularly disrupted. Neurometabolites, the biochemical structures that support neurological structural integrity, particularly in the prefrontal cortex and striatum are associated with symptoms. This study aimed to explore changes in neurometabolite levels through treatment with vitamins and minerals (micronutrients), hypothesising that treatment would impact neural circuitry and correspond to a reduction in symptoms. Twenty-seven non-medicated children (M = 10.75 years) with DSM5 diagnosed ADHD were randomised to receive daily micronutrients or placebo for 10 weeks. Main outcome measures included the Clinical Global Impression-Improvement Scale and ADHD-RS-IV Clinician Ratings of ADHD symptoms. Magnetic resonance spectroscopy of the bilateral pre-frontal cortex and bilateral striatum, resting state fMRI and structural images were acquired 1 week pre-treatment, and in the last week of intervention. Results did not show any significant differences in the measured brain metrics and the levels of neurometabolites between treatment and placebo groups after ten weeks of treatment with micronutrients. In the treatment group there was a trend for: decreased choline in the striatum; decreased glutamate in the prefrontal cortex; increased grey matter in the anterior thalamus; increased white matter in the fornix and improved network integrity of the default mode network, dorsal attention network and frontal executive network. The small sample size of the current study limits results, future studies with higher power are warranted to explore any association between micronutrient treatment and neurological changes.

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.

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.

Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial.

BACKGROUND: Evaluation of broad-spectrum micronutrient (vitamins and minerals) treatment for childhood ADHD has been limited to open-label studies that highlight beneficial effects across many aspects of psychological functioning. METHOD: This is the first fully blinded randomized controlled trial of medication-free children (n = 93) with ADHD (7-12 years) assigned to either micronutrients (n = 47) or placebo (n = 46) in a 1:1 ratio, for 10 weeks. All children received standardized ADHD assessments. Data were collected from clinicians, parents, participants and teachers across a range of measures assessing ADHD symptoms, general functioning and impairment, mood, aggression and emotional regulation. RESULTS: Intent-to-treat analyses showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement (ES = 0.46), with 47% of those on micronutrients identified as 'much' to 'very much' improved versus 28% on placebo. No group differences were identified on clinician, parent and teacher ratings of overall ADHD symptoms (ES ranged 0.03-0.17). However, according to clinicians, 32% of those on micronutrients versus 9% of those on placebo showed a clinically meaningful improvement on inattentive (OR = 4.9; 95% CI: 1.5-16.3), but no group differences on improvement in hyperactive-impulsive symptoms (OR = 1.0; 95% CI: 0.4-2.5). Based on clinician, parent and teacher report, those on micronutrients showed greater improvements in emotional regulation, aggression and general functioning compared to placebo (ES ranged 0.35-0.66). There were two dropouts per group, no group differences in adverse events and no serious adverse events identified. Blinding was successful with guessing no better than chance. CONCLUSIONS: Micronutrients improved overall function, reduced impairment and improved inattention, emotional regulation and aggression, but not hyperactive/impulsive symptoms, in this sample of children with ADHD. Although direct benefit for core ADHD symptoms was modest, with mixed findings across raters, the low rate of adverse effects and the benefits reported across multiple areas of functioning indicate micronutrients may be a favourable option for some children, particularly those with both ADHD and emotional dysregulation. Trial registered with the Australian New Zealand Clinical Trials Registry ACTRN12613000896774.

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.

Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial.

BACKGROUND: The role of nutrition in the treatment of attention-deficit hyperactivity disorder (ADHD) is gaining international attention; however, treatments have generally focused only on diet restriction or supplementing with one nutrient at a time. AIMS: To investigate the efficacy and safety of a broad-based micronutrient formula consisting mainly of vitamins and minerals, without omega fatty acids, in the treatment of ADHD in adults. METHOD: This double-blind randomised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients (n = 42) or placebo (n = 38) for 8 weeks (trial registered with the Australian New Zealand Clinical Trials Registry: ACTRN12609000308291). RESULTS: Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales. However, clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms. Post hoc analyses showed that for those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo. There were no group differences in adverse events. CONCLUSIONS: This study provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile.

Psychological functioning 1 year after a brief intervention using micronutrients to treat stress and anxiety related to the 2011 Christchurch earthquakes: a naturalistic follow-up.

OBJECTIVE: We investigated whether micronutrients given acutely following the Christchurch earthquakes continued to confer benefit 1 year following the treatment. METHODS: Sixty-four adults from the original 91 participants experiencing heightened anxiety or stress 2-3 months following the 22nd February 2011 earthquake and who had been randomized to receive three different doses of micronutrients completed on-line questionnaires assessing mood, anxiety, stress, and symptoms associated with post-traumatic stress disorder 1 year after completing the initial study. Twenty-one out of 29 nonrandomized controls who did not receive the treatment also completed the questionnaires. RESULTS: Both the treated and control groups experienced significant improvement in psychological functioning compared with end-of-trial. However, treated participants had better long-term outcomes on most measures compared with controls (ES=0.69-1.31). Those who stayed on micronutrients through to follow-up or stopped all treatment reported better psychological functioning than those who switched to other treatments including medications. About 10% of the sample continued to have post-traumatic stress disorder symptoms. CONCLUSIONS: Disaster survivors improve psychologically over time regardless of receiving intervention; however, those taking micronutrients during the acute phase following a disaster show better outcomes, identifying micronutrients as a viable treatment for acute stress following a natural disaster with maintenance of benefits 1 year later. ACTRN 12611000460909

Efficacy and safety of a mineral and vitamin treatment on symptoms of antenatal depression: 12-week fully blinded randomised placebo-controlled trial (NUTRIMUM).

BACKGROUND: Broad-spectrum micronutrients (minerals and vitamins) have shown benefit for treatment of depressive symptoms. AIMS: To determine whether additional micronutrients reduce symptoms of antenatal depression. METHOD: Eighty-eight medication-free pregnant women at 12-24 weeks gestation, who scored ≥13 on the Edinburgh Postnatal Depression Scale (EPDS), were randomised 1:1 to micronutrients or active placebo (containing iodine and riboflavin), for 12 weeks. Micronutrient doses were generally between recommended dietary allowance and tolerable upper level. Primary outcomes (EPDS and Clinical Global Impression - Improvement Scale (CGI-I)) were analysed with constrained longitudinal data analysis. RESULTS: Seventeen (19%) women dropped out, with no group differences, and four (4.5%) gave birth before trial completion. Both groups improved on the EPDS, with no group differences (P = 0.1018); 77.3% taking micronutrients and 72.7% taking placebos were considered recovered. However, the micronutrient group demonstrated significantly greater improvement, based on CGI-I clinician ratings, over time (P = 0.0196). The micronutrient group had significantly greater improvement on sleep and global assessment of functioning, and were more likely to identify themselves as 'much' to 'very much' improved (68.8%) compared with placebo (38.5%) (odds ratio 3.52, P = 0.011; number needed to treat: 3). There were no significant group differences on treatment-emergent adverse events, including suicidal ideation. Homocysteine decreased significantly more in the micronutrient group. Presence of personality difficulties, history of psychiatric medication use and higher social support tended to increase micronutrient response compared with placebo. CONCLUSIONS: This study highlights the benefits of active monitoring on antenatal depression, with added efficacy for overall functioning when taking micronutrients, with no evidence of harm. Trial replication with larger samples and clinically diagnosed depression are needed.

Use of micronutrients attenuates cannabis and nicotine abuse as evidenced from a reversal design: a case study.

Prior research shows that micronutrients, particularly amino acids, can assist individuals with substance dependence to quit various drugs of abuse, including cannabis, alcohol, and cocaine. As part of a wider investigation of the impact of micronutrients (mostly vitamins and minerals) on psychiatric symptoms, such as Attention-Deficit/Hyperactivity Disorder (ADHD), depression, and anxiety, we observed that many participants reduced or eliminated use of alcohol, cigarettes, and cannabis. One case using a single-case reversal (off-on-off-on-off) design is presented and shows not only on-off control of psychiatric symptoms as micronutrients are consumed or withdrawn, but also simultaneous on-off use of cannabis and cigarettes, despite not directly targeting this substance use as part of the treatment protocol. This case adds to a growing body of research supporting the use of micronutrients in the treatment of psychiatric symptoms and suggests it may extend to substance dependence. Micronutrients, by assisting with mood regulation and reductions in anxiety, may assist with successful cessation of drug use. Alternatively, they may directly impact on the brain reward circuitry believed to be involved in the expression of addictions, thereby providing the appropriate precursors and cofactors necessary for adequate neurotransmitter synthesis. This case should continue to stimulate researchers to consider the role of nutrients, in particular vitamins and minerals, in drug treatment programs and encourage more rigorous trials.

Efficacy and safety of a vitamin-mineral intervention for symptoms of anxiety and depression in adults: A randomised placebo-controlled trial "NoMAD".

BACKGROUND: Anxiety and depression are increasingly burdening society. We investigated whether micronutrients (vitamins and minerals), improve anxiety and depression symptoms in an adult community setting. METHODS: Participants (n = 150) describing functionally-impairing symptoms of anxiety/depression randomly received micronutrients or placebo for 10 weeks. Primary outcome measures were Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder Scale-7 (GAD-7), and Clinical Global Impression-Improvement scale (CGII). They were monitored online with regular phone contact with a clinical psychologist. RESULTS: Linear mixed-effects modelling showed significant improvements in both groups, with the micronutrient group improving significantly more quickly on both the PHQ-9 (t = -2.17, p = 0.03) and the GAD-7 (t = -2.23, p = 0.03). Subsequent models with covariates showed that participant characteristics moderated time-by-group interactions; micronutrients provided fastest improvement relative to placebo for younger participants, those from lower socioeconomic groups and those who had previously tried psychiatric medication. On the CGII, there were no group differences at end-point ((F1,148) = 1.36, p = 0.25, d = 0.19, 95 % CI [-0.13 to 0.51]), with 49 % of the micronutrient and 44 % of the placebo groups being identified responders. Participants on micronutrients had significantly increased bowel motions compared with placebo. There was no increased suicidal ideation, no serious adverse events and the blind was adequately maintained. Drop out was low at 8.7 %. LIMITATIONS: The improvement under placebo and lack of formal diagnoses limit generalizability. CONCLUSIONS: Despite limited clinician contact, all participants improved significantly, though improvements were faster with micronutrients. Participants in some subgroups demonstrated a lower response to placebo, identifying where micronutrients may offer greatest potential as an intervention.

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.

Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses.

OBJECTIVE: To compare two micronutrient (vitamins and minerals) formulas (Berocca™ and CNE™) and assess their impact on emotions and stress related to the 6.3 earthquake on February 22(nd) 2011 in Christchurch, New Zealand. METHODS: 91 adults experiencing heightened anxiety or stress 2-3 months following the earthquake were randomized to Berocca™, CNE™ low dose (CNE4), or CNE™ high dose (CNE8), for 28 days and monitored weekly via on-line questionnaires and followed 1 month post-trial. A nonrandomized control group (n = 25) completed questionnaires at baseline and 4 weeks. RESULTS: All treatment groups experienced significant declines in psychological symptoms (p < .001). CNE™ groups experienced greater reduction in intrusive thoughts as compared with Berocca™ (p = .05), with no group differences on other measures of psychological symptoms. However, CNE8 group reported greater improvement in mood, anxiety, and energy (p < .05) with twice as many reporting being "much" to "very much" improved and five times more likely to continue taking CNE™ post-trial than Berocca™ group. Treated participants had better outcomes on most measures over 4 weeks as compared to controls. CONCLUSIONS: This study supports micronutrients as an inexpensive and practical treatment for acute stress following a natural disaster with a slight advantage to higher doses ACTRN 12611000460909.

Protocol for a randomised placebo-controlled trial investigating the efficacy and safety of a vitamin-mineral formula targeting dysregulated emotions in teenagers: The balancing emotions of adolescents with micronutrients (BEAM) study.

Background: Emotional dysregulation (ED) is a significant contributing factor to psychological distress in young people. ED is a transdiagnostic dimension characterized by an excessive reactivity to negative emotional stimuli with affective (anger) and behavioral (aggression) components, and is present across anxiety, mood and behavioral disorders. Due to early onset, high prevalence and persistence, ED in childhood is one of the most psychosocially impairing and cost-intensive mental health conditions, with not enough children improving with conventional treatments. Clinical trials have established preliminary efficacy of micronutrients (vitamins and minerals) in the treatment of ED. This project expands the research to examine micronutrient efficacy for teenagers with ED. Methods: This study is the first double-blind (participant and investigators) 8 week randomized controlled trial (with 8 week open-label extension and one year follow-up) designed to explore the efficacy and safety of micronutrients compared with placebo in 150 medication-free emotionally dysregulated youth (12-17 years), referred via self-referral, delivered remotely throughout New Zealand, using a website for monitoring symptoms, with a psychologist available online via text, email and video for assessment and monitoring. The primary outcome measures will be the Clinical Global Impression (CGI-I), the reactivity subscale of the Emotion Dysregulation Inventory (EDI) and the Clinician Rated Temper and Irritability Scale (CL-ARI). Discussion: Micronutrient intervention delivered alongside online assessment and monitoring has the potential to transform delivery of mental health care to young people who may not be willing or able to access traditional therapies. We also hope that this intervention shows acceptability across different ethnicities.

Effects of a high-prebiotic diet versus probiotic supplements versus synbiotics on adult mental health: The "Gut Feelings" randomised controlled trial.

Background: Preliminary evidence supports the use of dietary interventions and gut microbiota-targeted interventions such as probiotic or prebiotic supplementation for improving mental health. We report on the first randomised controlled trial (RCT) to examine the effects of a high-prebiotic dietary intervention and probiotic supplements on mental health. Methods: "Gut Feelings" was an 8-week, 2 × 2 factorial RCT of 119 adults with moderate psychological distress and low prebiotic food intake. Treatment arms: (1) probiotic supplement and diet-as-usual (probiotic group); (2) high-prebiotic diet and placebo supplement (prebiotic diet group); (3) probiotic supplement and high-prebiotic diet (synbiotic group); and (4) placebo supplement and diet-as-usual (placebo group). The primary outcome was assessment of total mood disturbance (TMD; Profile of Mood States Short Form) from baseline to 8 weeks. Secondary outcomes included anxiety, depression, stress, sleep, and wellbeing measures. Results: A modified intention-to-treat analysis using linear mixed effects models revealed that the prebiotic diet reduced TMD relative to placebo at 8 weeks [Cohen's d = -0.60, 95% confidence interval (CI) = -1.18, -0.03; p = 0.039]. There was no evidence of symptom improvement from the probiotic (d = -0.19, 95% CI = -0.75, 0.38; p = 0.51) or synbiotic treatments (d = -0.03, 95% CI = -0.59, 0.53; p = 0.92). Improved anxiety, stress, and sleep were noted in response to the prebiotic diet while the probiotic tentatively improved wellbeing, relative to placebo. No benefit was found in response to the synbiotic intervention. All treatments were well tolerated with few adverse events. Conclusion: A high-prebiotic dietary intervention may improve mood, anxiety, stress, and sleep in adults with moderate psychological distress and low prebiotic intake. A synbiotic combination of high-prebiotic diet and probiotic supplement does not appear to have a beneficial effect on mental health outcomes, though further evidence is required. Results are limited by the relatively small sample size. Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372753, identifier ACTRN12617000795392.

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.