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.

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.

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.

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.

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.

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.

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.

Recruitment and retention of participants in longitudinal studies after a natural disaster.

Climate change and population growth will increase vulnerability to natural and human-made disasters or pandemics. Longitudinal research studies may be adversely impacted by a lack of access to study resources, inability to travel around the urban environment, reluctance of sample members to attend appointments, sample members moving residence and potentially also the destruction of research facilities. One of the key advantages of longitudinal research is the ability to assess associations between exposures and outcomes by limiting the influence of sample selection bias. However, ensuring the validity and reliability of findings in longitudinal research requires the recruitment and retention of respondents who are willing and able to be repeatedly assessed over an extended period of time. This study examined recruitment and retention strategies of 11 longitudinal cohort studies operating during the Christchurch, New Zealand earthquake sequence which began in September 2010, including staff perceptions of the major impediments to study operations during/after the earthquakes and respondents' barriers to participation. Successful strategies to assist recruitment and retention after a natural disaster are discussed. With the current COVID-19 pandemic, longitudinal studies are potentially encountering some of the issues highlighted in this paper including: closure of facilities, restricted movement of research staff and sample members, and reluctance of sample members to attend appointments. It is possible that suggestions in this paper may be implemented so that longitudinal studies can protect the operation of their research programmes.

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.

Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis focused on randomized controlled trials (RCT) of multinutrients consisting of at least four vitamins and/or minerals as interventions for participants with psychiatric symptoms. A systematic search identified 16 RCTs that fit the inclusion criteria (n = 1719 participants) in six psychiatric categories: depression, post-disaster stress, antisocial behavior, behavioral deficits in dementia, attention-deficit/hyperactivity disorder, and autism. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to rate the evidence base. Significant clinical benefit was assessed using minimal clinically important differences (MIDs). Due to heterogeneity in participants, multinutrient formulas, outcome measures, and absence of complete data, only the Attention-Deficit/Hyperactivity Disorder (ADHD) category was eligible for meta-analyses. In ADHD populations, statistically and clinically significant improvements were found in global functioning, Mean Difference (MD) -3.3, p = 0.001, MID -3.26; Standardized Mean Difference (SMD) -0.49 p = 0.001 MD -0.5), clinician ratings of global improvement (MD -0.58, p = 0.001, MID -0.5) and ADHD improvement (MD -0.54, p = 0.002, MID -0.5), and clinician (but not observer) measures of ADHD inattentive symptoms (MD -1.53, p = 0.05, MID -0.5). Narrative synthesis also revealed a pattern of benefit for global measures of improvement, for example: in autism, and in participants with behavioral deficits in dementia. Post-natural disaster anxiety and the number of violent incidents in prison populations also improved. Broad-spectrum formulas (vitamins + minerals) demonstrated more robust effects than formulas with fewer ingredients. This review highlights the need for robust methodology-RCTs that report full data, including means and standard deviations for all outcomes-in order to further elucidate the effects of multinutrients for psychiatric symptoms.

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.

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.

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.

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.

Psychotropic Medication Prescription Rates and Trends for New Zealand Children and Adolescents 2008-2016.

Objectives: The prescription of psychotropic medication used to treat psychiatric disorders has increased worldwide over the past two decades and has been discussed widely in the literature; however, limited data have been available for New Zealand. The current article aimed to address this knowledge gap. Methods: Prescription data obtained from The Pharmaceutical Management Agency of New Zealand (PHARMAC) were analyzed to obtain prescription dispensing rates and trends for antidepressants, antipsychotics, anxiolytics, sedatives and hypnotics, and stimulants/attention-deficit/hyperactivity disorder medications for youth aged 0-17 years in New Zealand during 2008-2016, including a gender and ethnicity breakdown for 2016 to provide a "snapshot" of prescription demographics. These data sets contained all individual prescriptions dispensed in New Zealand during this time period, alongside a unique encrypted National Health Index number to distinguish individuals and demographic data. Results: In 2016, 2.36% of New Zealand youth, totaling 26,175 individuals, were prescribed at least one psychotropic medication, an increase of 65.03% from 2008. Rate of prescription for youth in 2016 and percentage increase since 2008 for each medication class were as follows: antidepressants: 1.07%, 78.33% increase; antipsychotics: 0.37%, 105.60% increase; anxiolytics: 0.15%, 50% increase; and sedatives and hypnotics: 0.22%, 37.50% increase. Stimulants were prescribed to 1.06% of the population, a 41.33% increase since 2011. In 2016 the number of prescriptions was split roughly equally between males and females, with more males receiving stimulant prescriptions and more females receiving antidepressant prescriptions. Stimulants were the medication most likely to be prescribed to Maori, Pacific, and Middle Eastern/Latin American/African groups, with antidepressants most likely for European and Asian groups. Maori tended to be prescribed medications at rates lower than the general population. Conclusions: Overall, prescription rates and the increase in prescription of psychotropic medication to children and adolescents in New Zealand fall within the mid range compared to other Western countries worldwide.