Vitamin D Deficiency And Risk Of Mental Conditions Essay

Vitamin D is a versatile neurosteroid molecule that is intricately involved in brain function of the developing, adult and senescent brain (Groves et al. 2014). The presence of Vitamin D’s (VD) active form has been implicated in neurotransmission modulation, the production and regulation of neurotrophic factors and neuroprotection (Groves et al. 2016). VD involvement in these processes is via both genomic and non-genomic pathways. Given the diverse array of VD functions, it is unsurprising that VD deficiency has been implicated as a risk factor in numerous mental conditions (MC) including Schizophrenia Disorder (SD), Alzheimer’s Disease (AD) and Autism Spectrum Disorder (ASD), (Groves et al. 2014). Mechanisms by which VD deficiency increases risk of developing MC is an active area of research, the existing knowledge of which will be explored below. Vitamin D within the Central Nervous System (CNS)Vitamin D has multiple receptors distributed throughout the human brain.

One such nuclear receptor (VDR) is densely expressed in regions of cell proliferation and differentiation in the developing brain, suggesting VD has an important role in the regulation of neurotrophic factors (Landel et al 2017). Neurotrophic factors involve the production of growth factors, axonal growth, cell differentiation, solidification of dopaminergic and glutamatergic pathways, and apoptosis (Groves et al. 2014). Thereby, a lack of VD may result in non-conventional neurotrophic growth factor expression which would implicate the above components of CNS development. Vitamin D also regulates calcium homeostasis, the maintenance of which is crucial in preserving calcium’s role in neurotransmitter release and uptake (Eyles et al. 2013). Excess calcium leads to over-amplification of signalling, often resulting in neural damage. Vitamin D Deficiency And Risk Of Mental Conditions Essay. Conversely, calcium deficits lead to diminished signal transmission and thus loss of cell signalling.

One way VD regulates this is by acting on long lasting voltage dependent calcium channels to globally amplify or dampen neuronal signals, thus protecting against neurotoxicity and premature signal depletion (Harms et al. 2011).

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Symptoms of Neurological Disorders Associated with VD Deficiency

Schizophrenia Disorder is an enigmatical group of psychotic illnesses, of which no diagnostic biomarkers have been identified. Although not a diagnostic biomarker, anatomical studies have identified SD patients on average have enlarged lateral ventricles and a reduction in volume of the temporal lobe in comparison to non-SD controls (McCarley et al. 1999). Research points to the unlikelihood of a single cause for SD, but a complex set of risk factors that alter one’s susceptibility. One such factor is developmental vitamin D deficiency, or DVD (Kellett et al. 1978). Autism Spectrum Disorder is a broad term encompassing a large spectrum of neurodevelopmental disorders and symptoms. Both genetic and environmental risk factors are implicated in ASD prevalence (Abrahams and Geschwind 2008).

An inverse association between childhood ASD expression and circulating levels of 25(OH)D3 (VD) has been identified (Mazahery et al. 2016). Alzheimer’s Disease is a neurodegenerative condition with both genetic and sporadic forms. It is characterised anatomically by the build-up of beta amyloid plaques, tau tangles and cortical degradation (Serrano-Pozo et al. 2011). It has been demonstrated that the regulation of calcium homeostasis by VD is inhibited by beta amyloid, exposing neurons to neurotoxic calcium levels (Gezen-Ak et al. 2014). Vitamin D Deficiency And Risk Of Mental Conditions Essay.It is important to note that VD deficiency does not have causal links with MC, nor is it the sole risk factor. It is more accurate to think of VD deficiency as one of many risk factors at play which acts and interacts with a collection of other risk factors, all of which increase or decrease the polygenic risk of neurological disorders ensuing.

QBI’s Burne Laboratory

Queensland Brain Institute’s Developmental Neurobiology research group focuses largely on VD deficiency during development (DVD) and the implications deficiency has on the progression of mental conditions (MC). It is led by behavioural neuroscientist, Associate Professor Thomas Burne. Animal models are used extensively so as to limit confounding variables that would be innate in many other experimental frameworks (such as with neurological illness in-patients). With collaborators, this group is at the forefront of research surrounding DVD deficiency as a risk factor for MC. One such study identified a correlation between neonatal vitamin D deficiency and heightened risk of Schizophrenia within a population based sample (McGrath et al. 2010). This furthers the original 1978 observance that Schizophrenic patients have a disproportionate number of winter month birthdays (Kellett et al. 1978).

The group further hypothesised that optimal neonatal vitamin D levels may reduce the prevalence of SD within the sampled population by 43. 6% (McGrath et al. 2010). This is a powerful finding as it strengthens the likelihood of DVD deficiencies involvement as a contributing risk factor throughout development. SD has an estimated cost of US$60 billion per capita in the USA alone (Chong et al. 2016).Vitamin D Deficiency And Risk Of Mental Conditions Essay.  From the results of this study, implementation of simple strategies that raise awareness of VD deficiency have the potential to significantly reduce the contribution of DVD deficiency as a risk factor for SD. Multiple experiments have explored connections between DVD deficiency and MC by holding mouse models at a deficient VD levels prior to mating until the birth of offspring. Analysis of the ensuing DVD deficient progeny have found that mice from deficient origin typically had reduced apoptosis, enlarged lateral ventricles, altered neurogenesis and increased cellular proliferation (Cui et al. 2007; Eyles et al. 2003; Ko et al. 2004). Alterations in neurotransmitter pathways, synaptic plasticity, calcium binding proteins, attentional processing and learning was also highlighted (which is consistent with previous studies). This is significant as it links vitamin D to symptoms of multiple neurological disorders.

For example, enlarged lateral ventricles has found to be an anatomical feature of SD (McCarley et al. 1999). That this effect was observed in a DVD deficient animal model, while controlling for external factors (such as stabilising and monitoring calcium levels), points to VD as a significant risk factor for SD. Furthermore, differential brain structuring is linked to varied dopaminergic and glutaminergic signalling cascades, which in turn affects GABA (inhibitory) and glutamate (excitatory) neurotransmitter signalling (Kesby et al. 2017). This is yet another association where VD interacts with calcium (among other things), acting as a transcription factor for the synthesis and activation of neurotransmitters (Groves et al. 2016). A 2017 paper addressed DVD deficiency as a risk factor in ASD. Results from this population study supported mid-gestational DVD deficiency as a risk factor in ASD (Vinkhuyzen et al. 2017).

An opposing conclusion was drawn during an experiment with mouse models, which concluded that DVD deficiency is not enough in itself to generate ASD in offspring (Langguth et al. 2018). This highlights the role of DVD deficiency as one risk factor which acts in concert with many other factors to alter the overall polygenic risk of an individual expressing a multitude of MC. Vitamin D Deficiency And Risk Of Mental Conditions Essay. It may also support a critical windows hypothesis that will be discussed below. It is also plausible that DVD or VD deficiency doesn’t directly implicate phenotypic expression of MC, but instead VD deficiency is itself a downstream effect from another mechanism which alters the polygenic risk of developing conditions. The wide stretching implications of DVD deficiency is perplexing. Where SD typically has subtle anatomical markers but no neuronal death, AD has distinct tau tangles and amyloid plaques (McCarley et al. 1999; Serrano-Pozo et al. 2011). While AD onset is typically in later life, ASD is usually first diagnosed in early childhood (Serrano-Pozo et al. 2011; Abrahams and Geschwind 2008).

How could all of these widely variant conditions have a common risk factor? The answer may lie in critical windows during gestation. Critical windows are periods of brain development, during which signals are expected to be released and received in order for the brain to wire up ‘typically’ (Selevan et al. 2000). Wiring in a DVD deficient mouse may occur at a later stage in the critical window than a non-deficient mouse. This time lapse may result in a synapse-to dendrite connection occurring at an atypical location. This would have implications for subsequent downstream signals (see Figure 1). Such an effect would help to rationalise VD associations in such a large multitude of MC that each have varied phenotypic expressions. Burne’s lab also explores the implications of adult VD (AVD) deficiency as it pertains to the expression of MC. The group experimentation with mice models which found an association between AVD deficiency and altered neurotransmission, among other neurochemical changes. It was the first study to show this association (Groves et al. 2013). Vitamin D Deficiency And Risk Of Mental Conditions Essay.

Future Work

Experiments testing critical windows hypotheses are imprecise due to the time taken for depletion and repletion of VD. Adding to this difficulty is the intricate association VD has with calcium. However, the effects of VD deficiency during late gestational windows may be measurable at various degrees of deficiency. Despite these challenges, the Burne laboratory as undertaken multiple successful experiments illustrating the effect of DVD and AVD on MC expression. Going forward, analysis of whether VD favours its genomic or non-genomic pathways in deficient states (and if VD operates preferentially at all) may be beneficial in achieving the overarching goal which is to determine the mechanism by which DVD deficiency acts as a risk factor for MC. It may also enable reduction of the prevalence of multiple mental illnesses.

Furthermore, exploration of the developmental mechanisms in which VD deficiency is associated with MC would facilitate in understanding AVD deficiency’s effect on the adult brain. Whether optimal AVD intake is effective in stopping the progression or even reversing the effects of mental illnesses has the potential to be translated into a treatment for listed MC. These are goals the Burne laboratory is constantly working towards.

Fat-soluble Vitamin D is produced when exposed to sunshine or from diet and pregnant women with darker skins have lower plasma vitamin D level when compared with lighter skins¹.

Vitamin D might play a role in genetic transcription, and inflammatory system in the brain. Recently the association of vitamin D intake and mental health has been focused. It is associated with numerous psychiatric disorders, such as schizophrenia, depression and etc. Vitamin D Deficiency And Risk Of Mental Conditions Essay. The reason might be that vitamin D could stimulate genes that produce neurotransmitters such as dopamine and serotonin, affecting brain function. 1,25-dihydroxyvitamin D (1,25(OH)₂D) might have an impact on brain serotonin by regulating the expression of tryptophan hydroxylase 2² and on plasma calcium level³. High level of calcium level in the brain is actually regulated indirectly by low serum 25-Hydroxyvitamin D (25(OH)D) level. Furthermore, 1 alpha-hydroxylase and vitamin D receptors (VDR), involved with the production of 1,25(OH)₂D, could be generated in neurons of the brain. Besides, the regions of the brain, such as dopaminergic–rich regions, governing depression have their own VDR^4,5.

Besides, Vitamin D deficiency has been defined as serum 25(OH)D level lower than 12 ng/mL or 30nmol/L⁶, measured by the Institute of Medicine, while vitamin D insufficiency is defined as 12-20 ng/mL or 30-50 nmol/L. It still remains discrepancy of various subjects as for Recommended Dietary Allowance (RDA) on their vitamin D intake, including infants (400 international units (IU) /d), pregnant women (600 IU/d) and elderly (>50 years, 600-800IU/d)^6,7. This paper will mainly focus on the relationship between vitamin D level and three main mental disorders, autism, schizophrenia and depression. The author will reveal the association between low vitamin D intake and the risk of these diseases, then discuss if vitamin D supplementation will be efficient in the treatment of these three diseases, and further provide implications of the importance of maintaining adequate vitamin D level among pregnant women.

Autism Spectrum Disorder (ASD)

Adequate Vitamin D could be beneficial to bone mineral density and neuronal differentiation, or it will cause an increased risk of autism behavior. ASD is a common mental disorder, manifested in impaired communication abilities and social behaviors and specific behaviors.Vitamin D Deficiency And Risk Of Mental Conditions Essay.  A cross-sectional study has revealed a high affinity of low vitamin D with a high prevalence of ASD among children (n=122)⁸. It has also been proved in a recent cohort study⁹ among large population-4229 mothers and their children with the symptoms of autism-related traits at 6 years old. The level of 25(OH)D was assessed both in maternal mid-gestation serum and infant sera (core blood at birth) first. Samples who have vitamin D insufficiency take (serum level of 25(OH)D < 25 nmol/L) hold a higher social responsiveness scale(SRS)-scored in children at 6 years old, suggesting that vitamin D deficiency might be related to high risk of autism-related traits. However, poor communications might also be associated with ASD.

For the rescue therapy, it might be improved under high doses of vitamin D intake among children, which has been reported in a cross-sectional study⁸.A Randomized Controlled Trial (RCT) study¹⁰ also revealed that supplemented with vitamin D3 300 IU/kg/d for four months in children (3-10 years old, n=120) might improve their ASD symptoms, measured by CARS and Aberrant Behavior Checklist (ABC), SRS. In the future, a larger scale study should be conducted to prove the efficacy of vitamin D supplementation among Children with ASD. Another study further strengthened the importance of taking vitamin D3 supplementation in the treatment of ASD among 500 children (215- ASD). Results have shown a decrease in scores of the autism behavior checklist(ABC) and the Childhood Autism Rating Scale (CARS) after receiving VD3 supplementation for 3 months, indicating the improved symptoms of ASD¹¹.

Besides, pregnant women might also have a large effect on the risk of ASD. Lower risk of ASD or autism-related traits might occur when intake adequate vitamin D during the midterm gestation^9,12. Topics like the early stage or the full term of vitamin D deficiency and brain development could be focused on in the future.

Therefore, it might be an effective therapy for children to improve the symptoms of ASD by receiving vitamin D supplementation for at most three months (< 30IU/kg/d), or an optimal preventing the high risk of ASD by maintaining adequate vitamin D level among pregnant moms. Vitamin D Deficiency And Risk Of Mental Conditions Essay.

Vitamin D and schizophrenia or schizoaffective disorder

Schizophrenia is a chronic but severe mental disorder manifested in impaired cognition ability, social behaviors and loss of interaction with reality. schizoaffective disorder, a similar mental problem as schizophrenia, is characterized by psychotic symptoms such as delusions and mood disorders. The incidence of schizophrenia might be affected by a low level of vitamin D interacted with genetic factor and other environmental factors, such as areas of higher latitude with limited sun exposure.

Neonatal vitamin D deficiency (serum 25(OH)D level < 20.4 nmol/L), especially born in winter and spring has been associated with increased risk of schizophrenia¹³. This case-control study has strengthened the significance for pregnant women to maintain an adequate level of vitamin D level in decreasing the risk of schizophrenia. Nevertheless, it is still highly needed to illuminate the relationship between low level of vitamin D intake and the risk of schizophrenia from four aspects, a larger sample scale of research or RCTs, 25OHD level form different pregnancy stage, unmeasured vulnerable factors to the risk of schizophrenia.

Similar results have been also found in elderly that, low plasma level of vitamin D might be highly related to patients with schizophrenia or schizoaffective disorder, which has been proved in a cross-sectional study (25(OH)D₃ + 25(OH)D₂ <19.9 ng/mL) ¹⁴ and an RCT (< 75 nmol/L)¹⁵. In the former cross-sectional study, 149 Patients (around 47 years old) with schizophrenia or schizoaffective disorder, receiving flexible assertive community treatment (FACT), were tested by Diagnostic and Statistical Manual of Mental Disorder (DSM-IV). Vitamin D Deficiency And Risk Of Mental Conditions Essay. Results might indicate that vitamin D could possibly act as a cause of schizophrenia or schizoaffective disorder. However, some bias has not been eliminated to obtain the accurate association between vitamin D level and schizophrenia such as daily sun exposure and BMI, therefore, a strict assessment system is suggested to be applied in a larger scale of research in future.

As for the efficacy of vitamin D supplementation used for the treatment of schizophrenia, none improvement of schizophrenia has been found in two recent RCTs. A recent RCT has shown that vitamin D supplementation (14,000 IU/week) might not improve schizophrenia symptoms of patients (39-49 years old) treated with Clozapine, however, with a mild improved cognitive function among a small portion of samples (n=17). Here, eight weeks intervention among 23 patients^15, have beenmeasured by Montreal Cognitive Assessment (MoCA). Another RCT¹⁶ has also proved it amongpatients with vitamin D deficiency (< 30 ng/mL) injected with 2 x 300,000IU/mL (n=120) within a four-month intervention. It might be hard to rescue schizophrenia of a later stage-among elderly, instead, one of the hypothesis might be that vitamin D supplementation might be efficient in infants or pregnant moms, an early stage of this type of disease. Furthermore, it still remains unknown about the efficacy of vitamin D supplementation for schizophrenia, including its optimal doses, vitamin D supplementation time for this disease and if it would be more efficient when combined with other therapy. Vitamin D Deficiency And Risk Of Mental Conditions Essay.

Vitamin D and depression

Depression, a common but serious mood disorder and has an impact on your thinking

and perception and reality. A cross-sectional study among 770 Malay and Indian female teachers (41 years old) has shown that, lower vitamin D intake (25(OH)D serum level <20 ng/ml or <50 nmol/l) might have high affinity to the incidence of depression¹⁷. They used the Anxiety and Stress Scale (DASS-21) to measure the level of depression.

A random controlled trial (RCT) among 230 participants (30-75 years old) and a large cohort study among 902 participants (18-65 years old) has proved that low level of 25(OH)D could be used as a biomarker of the presence and severity of depression^18,19.

Different types of depressions (postpartum depression, common depression and etc.) might have varied susceptible to vitamin D supplementation. As for the treatment of depression by vitamin D supplementation, it still remains controversial about the effect of vitamin D supplementation on depression from the perspective of short-term and long-term or intervention with other anti-drugs. It might be beneficial to take vitamin D (1500 IU/d) and fluoxetine when compared with fluoxetine for 2 months in the treatment of depression. In this study, 40 patients (18-65 years old) were found to have a significant decrease in their depression symptoms at their second week of intervention, which was tested with Hamilton Depression Rating Scale and Beck Depression Inventory²⁰.

It seems like vitamin D supplementation could be effective in the treatment of ASD only combined with other therapy or within a short-term intervention. Some other researches have proved this theory in their studies that, it is hard to get improvement in ASD within a long period interval or vitamin D supplementation. An RCT has proved it among 230 participants with low 25(OH)D serum level (<55 nmol/L) who were treated with six months intervention of 40,000 IU vitamin D3/ week¹⁹. It also suggested that a low serum level of 25(OH)D might be a result or co-factor rather than a cause of the incidence of depression. Vitamin D Deficiency And Risk Of Mental Conditions Essay. Another recent randomized double-blind study ²¹also proved it among a small portion of patients with depression. Here, 23 patients (18-65 years old) with depression and low plasma 25(OH)D level (< 50 nmol/L) were assigned to take D supplementation 7 mg/d for three months, meanwhile, they were tested by the Hamilton Rating Scale for Depression (HAM-D17) and Major Depression Inventory (MDI) at their 3 and 6 months. As a result, none reduction in Depression scores have been assessed. For this study, a larger scale of the sample in the future is still highly suggested for a supportive conclusion.

However, this theory cannot be applied among pregnant women because vitamin D supplementation might ameliorate the severity of their depression, which has been reported in a recent single-blind RCT²². Here, pregnant women with low plasma 25(OH)D level (< 30nmol/L), receiving vitamin D supplementation of 2000 IU/d during their third trimester of pregnancy, might decrease the level of maternal depression, including their pregnant late stage and postpartum stage. Since exclusion standard of depression level > 13 has been applied in this study, so it could only show a mild depression score of parental depression. In order to obtain an optimal therapy of vitamin D (doses, duration) on varied levels of depression among pregnant women, a larger scale with an accurate depression measurement tools should be used in a further study. Overall, vitamin D supplementation might improve depression symptoms, especially among pregnant moms (eg. postpartum depression) or a short-term interval combined with other therapy.

Conclusion

This paper mainly focuses on the relationship between vitamin D level and three main mental disorders, autism, schizophrenia and depression. The author has clarified the association between low vitamin D intake and the risk of these diseases, then discuss the efficacy of vitamin D supplementation in the treatment of these three diseases, and further provide suggestions of maintaining adequate vitamin D level among the specific population, especially among pregnant women. Vitamin D Deficiency And Risk Of Mental Conditions Essay.

For ASD, gestational or children vitamin D deficiency has high affinity with a high incidence of autism-related traits or ASD^8,9. ASD might be prevented from pregnant women by taking adequate vitamin D3 and might be rescued among children by receiving at most three months for less than 30 IU/kg/d, however, none studies have shown the preventing therapy of vitamin D in a later stage- children.Besides, the threshold of vitamin D deficiency remains to be established in children and varied efficient vitamin D supplementation doses and duration of intervention need to be further studied.

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As for schizophrenia, neonatal vitamin D deficiency seems to be highly related to a high risk of schizophrenia, meanwhile, elderly vitamin D deficiency might act as a cause of schizophrenia among patients with schizophrenia. It might be hard to rescue schizophrenia of a later stage-among elderly. However, it is possible for pregnant women to maintain an adequate level of vitamin D level in decreasing the risk of schizophrenia¹³. In all, it still remains unclear about the efficacy of vitamin D supplementation for schizophrenia, including its optimal doses and duration time for this disease among pregnant women and if it would be more efficient when combined with other therapy in elderly.

Lastly for depression, lower 25(OH)D serum level (<20 ng/ml or <50 nmol/l) might have a high affinity to the incidence of depression. Although it might not be a consensus on the efficacy of vitamin D supplementation applied in preventing depression, vitamin D supplementation could be effective in a certain population such as pregnant moms (eg. postpartum depression) or a certain situation, a short-term interval combined with other therapy.

Overall, Low vitamin D level has been associated with high risk or incidence of ASD, schizophrenia, and depression. In order to lower the risk of these diseases, it’s better to maintain adequate serum 25(OH)D level (> 20 ng/mL) from pregnancy by taking vitamin D rich-food, such as olive oil, almond and etc., or increased sun exposure. As for the treatment of these diseases, ASD symptoms might be improved among children, while schizophrenia and depression not. Therefore, more RCTs are suggested to be performed for obtaining strong conclusions. Vitamin D Deficiency And Risk Of Mental Conditions Essay.