Developmental exposure to vitamin D deficiency and subsequent risk of schizophrenia.

Over the last half century, a body of convergent evidence has accumulated linking disruption of early brain development with an increased risk of mental disorders, including schizophrenia. The orderly cascade of brain development may be disrupted by exposure to suboptimal concentrations of a range of biological substrates and micronutrients. We hypothesized that those exposed to vitamin D deficiency during early life, have an increased risk of neurodevelopmental disorders, including schizophrenia. The hypothesis was based on the link between an increased risk of schizophrenia in (a) those born in winter and spring, when vitamin D deficiency is more prevalent, and (b) the offspring of dark-skinned migrants living in cold climates, who have a markedly increased risk of vitamin D deficiency. In this review, we summarize evidence from analytic epidemiology related to this hypothesis. Two case-control studies based on Danish neonatal dried blood spots have found that neonatal vitamin deficiency is associated with an increased risk of schizophrenia. However, recent genetic analyses have also suggested that common variants linked to schizophrenia may lead to lower vitamin D concentrations (possibly mediated via reduced outdoor activity). We summarize limitations of the current evidence and outline suggestions that can guide future research. Based on currently available data, there is insufficient evidence to support public health recommendations related to this topic. However, we cannot reject the hypothesis that the provision of vitamin D supplementation to pregnant women and/or offspring in groups vulnerable to vitamin D deficiency may subsequently reduce the incidence of schizophrenia in the offspring.

Vitamin D and schizophrenia: 20 years on.

Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.

Vitamin D supplementation compared to placebo in people with First Episode psychosis - Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.

The Therapeutic Potential of Mangosteen Pericarp as an Adjunctive Therapy for Bipolar Disorder and Schizophrenia.

New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders.

Prevalence and correlates of suboptimal vitamin D status in people living with psychotic disorders: Data from the Australian Survey of High Impact Psychosis.

OBJECTIVE: Having sufficient sera concentrations of 25-hydroxyvitamin D is important for a range of health outcomes including cardiometabolic diseases. Clinical studies in people with psychotic disorders suggest that a sizable proportion has suboptimal vitamin D status (i.e. vitamin D deficiency or insufficiency). Individuals with psychosis also have many of the risk factors associated with suboptimal vitamin D status such as smoking, obesity, and reduced physical activity. The aim of this study was to examine the prevalence and socio-demographic and clinical correlates of vitamin D status using a large, population-based sample of adults with psychotic disorders. METHODS: Data were collected as part of the Survey of High Impact Psychosis, a population-based survey of Australians aged 18-64 years with a psychotic disorder. 25-Hydroxyvitamin D concentration was measured in 463 participants. 25-Hydroxyvitamin D concentration was dichotomised into optimal (above 50 nmol/L) and suboptimal (below 50 nmol/L). The influence of a range of socio-demographic and clinical variables on vitamin D status was examined using logistic regression. RESULTS: Nearly half (43.6%) of the participants had suboptimal vitamin D status. Those with (a) increased physical activity or (b) positive symptoms had significantly reduced odds of having suboptimal vitamin D status. However, there were no significant associations between suboptimal vitamin D status and other psychiatric symptom measures or cardiometabolic risk factors. CONCLUSION: Many people with psychotic disorders have suboptimal vitamin D status. As part of the routine assessment of physical health status, clinicians should remain mindful of vitamin D status in this vulnerable population and encourage the use of appropriate vitamin D supplements.

Gestational vitamin D deficiency and autism spectrum disorder.

BACKGROUND: There is growing interest in linking vitamin D deficiency with autism spectrum disorders (ASDs). The association between vitamin D deficiency during gestation, a critical period in neurodevelopment, and ASD is not well understood. AIMS: To determine the association between gestational vitamin D status and ASD. METHOD: Based on a birth cohort (n=4334), we examined the association between 25-hydroxyvitamin D (25OHD), assessed from both maternal mid-gestation sera and neonatal sera, and ASD (defined by clinical records; n=68 cases). RESULTS: Individuals in the 25OHD-deficient group at mid-gestation had more than twofold increased risk of ASD (odds ratio (OR)=2.42, 95% confidence interval (CI) 1.09 to 5.07, P=0.03) compared with the sufficient group. The findings persisted in analyses including children of European ethnicity only. CONCLUSIONS: Mid-gestational vitamin D deficiency was associated with an increased risk of ASD. Because gestational vitamin D deficiency is readily preventable with safe, inexpensive and readily available supplementation, this risk factor warrants closer scrutiny. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Vitamin D as a neurosteroid affecting the developing and adult brain.

Vitamin D deficiency is prevalent throughout the world, and growing evidence supports a requirement for optimal vitamin D levels for the healthy developing and adult brain. Vitamin D has important roles in proliferation and differentiation, calcium signaling within the brain, and neurotrophic and neuroprotective actions; it may also alter neurotransmission and synaptic plasticity. Recent experimental studies highlight the impact that vitamin D deficiency has on brain function in health and disease. In addition, results from recent animal studies suggest that vitamin D deficiency during adulthood may exacerbate underlying brain disorders and/or worsen recovery from brain stressors. An increasing number of epidemiological studies indicate that vitamin D deficiency is associated with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Vitamin D supplementation is readily available and affordable, and this review highlights the need for further research.

A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders.

IMPORTANCE: Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE: To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES: Age and sex. MAIN OUTCOMES AND MEASURES: Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS: During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE: This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research.

Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement.

• The recommended level for serum 25-hydroxyvitamin D (25(OH)D) in infants, children, adolescents and during pregnancy and lactation is ≥ 50 nmol/L. This level may need to be 10-20 nmol/L higher at the end of summer to maintain levels ≥ 50 nmol/L over winter and spring. • Sunlight is the most important source of vitamin D. The US recommended dietary allowance for vitamin D is 600 IU daily in children aged over 12 months and during pregnancy and lactation, assuming minimal sun exposure. • Risk factors for low vitamin D are: lack of skin exposure to sunlight, dark skin, southerly latitude, conditions affecting vitamin D metabolism and storage (including obesity) and, for infants, being born to a mother with low vitamin D and exclusive breastfeeding combined with at least one other risk factor. • Targeted measurement of 25(OH)D levels is recommended for infants, children and adolescents with at least one risk factor for low vitamin D and for pregnant women with at least one risk factor for low vitamin D at the first antenatal visit. • Vitamin D deficiency can be treated with daily low-dose vitamin D supplements, although barriers to adherence have been identified. High-dose intermittent vitamin D can be used in children and adolescents. Treatment should be paired with health education and advice about sensible sun exposure. Infants at risk of low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the first year of life. • There is increasing evidence of an association between low vitamin D and a range of non-bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.

Vitamin D and health in adults in Australia and New Zealand: a position statement.

The prevalence of vitamin D deficiency varies, with the groups at greatest risk including housebound, community-dwelling older and/or disabled people, those in residential care, dark-skinned people (particularly those modestly dressed), and other people who regularly avoid sun exposure or work indoors. Most adults are unlikely to obtain more than 5%-10% of their vitamin D requirement from dietary sources. The main source of vitamin D for people residing in Australia and New Zealand is exposure to sunlight. A serum 25-hydroxyvitamin D (25-OHD) level of ≥ 50 nmol/L at the end of winter (10-20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal musculoskeletal health. Although it is likely that higher serum 25-OHD levels play a role in the prevention of some disease states, there is insufficient evidence from randomised controlled trials to recommend higher targets. For moderately fair-skinned people, a walk with arms exposed for 6-7 minutes mid morning or mid afternoon in summer, and with as much bare skin exposed as feasible for 7-40 minutes (depending on latitude) at noon in winter, on most days, is likely to be helpful in maintaining adequate vitamin D levels in the body. When sun exposure is minimal, vitamin D intake from dietary sources and supplementation of at least 600 IU (15 µg) per day for people aged ≤ 70 years and 800 IU (20 µg) per day for those aged > 70 years is recommended. People in high-risk groups may require higher doses. There is good evidence that vitamin D plus calcium supplementation effectively reduces fractures and falls in older men and women.

Effects of vitamin D supplementation on cognitive and emotional functioning in young adults--a randomised controlled trial.

BACKGROUND: Epidemiological research links vitamin D status to various brain-related outcomes. However, few trials examine whether supplementation can improve such outcomes and none have examined effects on cognition. This study examined whether Vitamin D supplementation led to improvements in diverse measures of cognitive and emotional functioning, and hypothesised that supplementation would lead to improvements in these outcomes compared to placebo. METHODS/PRINCIPAL FINDINGS: Healthy young adults were recruited to a parallel-arm, double-blind trial conducted at The University of Queensland. Participants were randomly allocated to receive Vitamin D (one capsule daily, containing 5000 IU cholecalciferol) or identical placebo capsule for six weeks. All participants and outcome assessors were blinded to group assignment. Primary outcome measures assessed at baseline and 6 weeks were working memory, response inhibition and cognitive flexibility. Secondary outcomes were: hallucination-proneness, psychotic-like experiences, and ratings of depression, anxiety and anger. 128 participants were recruited, randomised and included in primary analyses (vitamin D n = 63; placebo n = 65). Despite significant increases in vitamin D status in the active group, no significant changes were observed in working memory (F = 1.09; p = 0.30), response inhibition (F = 0.82; p = 0.37), cognitive flexibility (F = 1.37; p = 0.24) or secondary outcomes. No serious adverse effects were reported. CONCLUSIONS: Our findings indicate that vitamin D supplementation does not influence cognitive or emotional functioning in healthy young adults. Future controlled trials in targeted populations of interest are required to determine whether supplementation can improve functioning in these domains. Australian and New Zealand Clinical Trials Registry; ACTRN12610000318088.

Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

BACKGROUND: Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. METHODS: Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. RESULTS: DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. CONCLUSIONS: These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

Evidence of altered prefrontal-thalamic circuitry in schizophrenia: an optimized diffusion MRI study.

MRI diffusion tensor imaging (DTI), optimized for measuring the trace of the diffusion tensor, was used to investigate microstructural changes in the brains of 12 individuals with schizophrenia compared with 12 matched control subjects. To control for the effects of anatomic variation between subject groups, all participants' diffusion images were nonlinearly registered to standard anatomical space. Significant statistical differences in mean diffusivity (MD) measures between the two groups were determined on a pixel-by-pixel basis, using Gaussian random field theory. We found significantly elevated MD measures within temporal, parietal and prefrontal cortical regions in the schizophrenia group (P > 0.001), especially within the medial frontal gyrus and anterior cingulate. The dorsal medial and anterior nucleus of the thalamus, including the caudate, also exhibited significantly increased MD in the schizophrenia group (P > 0.001). This study has shown for the first time that MD measures offer an alternative strategy for investigating altered prefrontal-thalamic circuitry in schizophrenia.

Thermal damage prediction for collagenous tissues part I: a clinically relevant numerical simulation incorporating heating rate dependent denaturation.

Subablative thermotherapy is frequently used for the treatment of joint instability related diseases. In this therapy, mechanically deformed collagenous tissues are thermally shrunk and the stability of the tissue is re-established. In this research, the thermal damage fields generated by three different clinical heating modalities (monopolar and bipolar radio frequency and Ho:YAG laser) are compared numerically using finite element analysis. The heating rate dependent denaturation characteristics of collagenous tissues are incorporated into the model using experimental data from in vitro experimentation with rabbit patellar tendons. It is shown that there are significant differences among the thermal damage profiles created by these modalities, explaining the main reason for the discrepancies reported in the literature in terms of the efficacy and safety of each modality. In the complementary paper, the accuracy of the model presented here is verified by in vitro experimentation with a model collagenous tissue and by quantifying the denaturation-induced birefringence change using Optical Coherence Tomography and Magnetic Resonance Imaging.

Behavioural characterization of vitamin D receptor knockout mice.

Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addition to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviourally phenotype VDR knockout mice. We characterized the behaviour of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioural screen (using the SHIRPA protocol), rotarod, gait analysis, Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behaviour but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.

Transient prenatal Vitamin D deficiency is associated with hyperlocomotion in adult rats.

Rat experiments have shown that prenatal Vitamin D deficiency leads to altered neonatal brain morphology, cell density and neurotrophin expression. In the current study we examined the hypothesis that Vitamin D deficiency during early development alters adult behaviour even when there is an intervening period in which the animal receives normal Vitamin D in later development. Rats were conceived and born to Vitamin D deficient dams (Birth); conceived, born and weaned from Vitamin D deficient dams (Weaning); or deficient in Vitamin D from conception to 10 weeks of age (Life). Litters were standardized to three males and three females per litter. All rat offspring were rendered normocalcaemic with calcium supplemented water (2 mM) after weaning. Control animals were born to mothers fed a normal diet but subject to similar litter size and calcium supplementation. At 10 weeks all animals were tested on the holeboard test, elevated plus maze test, social interaction observation, acoustic startle response test, prepulse inhibition of the acoustic startle response and a forced swim test. Early Vitamin D deficiency (Birth group) enhanced locomotion in the holeboard test and increased activity in the elevated plus maze. Thus, transient prenatal Vitamin D deficiency induces hyperlocomotion in adulthood, without severe motor abnormalities.

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle.

There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI.

Thermomechanical analysis of soft-tissue thermotherapy.

Soft-tissue thermotherapy based on sub-ablative heating of collagenous tissues finds wide-spread application in medicine such as tissue welding, thermokeratoplasty, skin resurfacing, elimination of discogenic pain in the spine and treatment of joint instability. In this paper, heat-induced thermomechanical response characteristics of collagenous tissues are quantified by means of in vitro experimentation with a representative model tissue (New Zealand white rabbit patellar tendon). Three distinct heat-induced thermomechanical response regimes (defined by the rate of deformation and the variation of material properties) are identified. Arrhenius damage integral representation of collagenous tissue thermal history is shown to be adequate in establishing the master response curves for quantification of thermomechanical response for modeling purposes. The trade-off between the improved kinematical stability and compromised mechanical stability of the heated collagenous tissue is shown to be the major challenge hindering the success of subablative thermotherapies.