Open access peer-reviewed chapter
Abstract
Deficiencies in vitamin D can have several etiologies, broadly classified as the following: suboptimal exposure to ultraviolet-B (UV-B) light from sunlight, low dietary intake of vitamin-D or reduced absorption due to gastrointestinal pathologies, reduced production due to liver or kidney disease, pseudo-deficiencies caused by end organ resistance despite normal or elevated vitamin D levels, and medication-induced stimulation of hepatic cytochrome P450 enzymes for which vitamin D is a substrate. Deficiencies in this important vitamin can have several adverse clinical implications such as osteomalacia, osteoporosis, muscle pain, and depression to name a few. More recently, vitamin D has been shown to be involved in modulating various aspects of the immune system. Vitamin D receptors have also been found to be present in certain regions of the brain, especially those involved in schizophrenia. We will discuss the implications of vitamin D deficiency and its immunomodulatory role in the setting of the COVID-19 virus, the proposed cellular and molecular mechanisms of action for vitamin D in the context of schizophrenia, and the clinical outcomes associated with these two pathologies as a function of low vitamin D levels.
Keywords
- vitamin D deficiency
- schizophrenia
- COVID-19
- immunomodulation
1. Introduction
Vitamin D plays a crucial role in several biologic processes. As such, maintaining physiologic levels of this vitamin is essential for the proper functioning of various organ systems. Unfortunately, vitamin D deficiency (VDD) is a global health concern with potentially severe clinical outcomes [1]. This is true for both adults as well as the pediatric population. Although a wide range of risk factors exists, the most well-studied and accepted risk factor remains lack of sun exposure. Certain studies have also looked at race and skin color as potential risk factors (more on this later) [2]. Risk factor associated with VDD is an area of continuing research.
Although bone disease is the most well-established consequence of VDD, it is important to appreciate the complex and nuanced ways in which the endocrine system, intestines, and kidneys interact with and depend on vitamin D [3]. Furthermore, previously unknown functionalities of this vitamin have been elucidated in recent years. Perhaps the most fascinating findings have been vitamin D’s ability to modulate the immune system. Various experiments have shown the surprising ability of vitamin D to stimulate the immune system to mount a more potent and effective response against foreign pathogens. Interestingly, these observations have been made in both the innate and adaptive immune systems [4]. Another area of research in the setting of vitamin D has been the brain [5]. Detection of vitamin D receptors in the central nervous system has provided an avenue for researchers to examine how the vitamin may be implicated in various diseases as well as the developmental stages of the brain.
The significant amount of information on these new areas, as well as the excitement surrounding it, is evident in the literature. We have analyzed several studies and experiments to provide an informative and structured review of the most recent progress and discoveries in this area. In this chapter, we first approach VDD broadly by discussing its epidemiology, pathogenesis, and pathophysiology. We then narrow the scope of our discussion to focus on the most recent and exciting findings in the context of vitamin D. Finally, we conclude our review of VDD by exploring how these recent findings are implicated in schizophrenia as well as the novel COVID-19 virus at much more granular level.
2. Epidemiology
The diagnosis of VDD is made when levels of 25-hyroxy vitamin D, or 25(OH)D, levels are found to be below the threshold value of 12ng/mL [3]. The global prevalence of VDD is estimated to be 14-59% in the adult population. Although there is a paucity of data on infants and children in several countries, the global prevalence of VDD in this group is estimated to be higher than the adult population, with some studies reporting rates as high as 80% [6, 7, 8]. Furthermore, prevalence of the disease varies significantly by region, age group, season in which measurements were taken, and gender. Of note is the markedly higher rates seen in the Middle East, especially in Iran(infants, 86%; adults, 51%) [7, 9]. VDD is also seen in some South Asian countries such as India, Pakistan, and Bangladesh, where ~80% of adults are known to be affected; the same statistic in US adults has been reported as ~35% [1]. Conversely, the European population has a relatively lower prevalence compared to other regions, with an estimated 8.3% - 17.7% of the population affected [10].
A significant risk factor for VDD is race. For instance, in the US, 82.1% of African American adults and 62.9% of Hispanic adults are deficient in vitamin D; this is in comparison to the overall VDD rate of 41.6%. This is attributable to the relatively higher melanin levels observed in the skin of these individuals [11]. Melanin is a polymer that not only provides skin pigmentation, but also absorbs ultraviolet (UV) radiation [2, 12]. By doing so, melanin decreases the amount of UV light available to keratinocytes (which are a crucial component of vitamin D synthesis) located within the skin epidermis [13].
In recent decades, younger individuals have been at much higher risk of VDD. This is largely thought to be a result of the accelerating use of technology. Electronic devices such as video game consoles, portable tablets, computers, and cell phones have provided children with entertainment that can be enjoyed indoors. As a result, they are less likely to engage in outdoor activities, which has significantly decreased exposure to sunlight in this age group [11, 14]. Although obesity has also been reported as a risk factor for VDD with various proposed mechanisms of action, a portion of the VDD observed in obese individuals may be a result of confounding effects [15]. In other words, it is possible that obese children also tend to spend more time indoors and do not get sufficient sun exposure. Further studies investigating the true effect of obesity on VDD would require comparing data on obese children who engage in outdoors activities to obese children who do not engage in such activities.
3. Pathogenesis
There are several reasons why VDD may develop. It can be helpful to broadly categorize these etiologies. Although these are varied in their mechanisms of action, they all lead to absolute or functional deficiencies in vitamin D:
Suboptimal exposure to ultraviolet-B (UV-B) light from sunlight: The precursor molecules to initiating vitamin D synthesis, located in the skin, require exposure to UV-B light. As a result, low levels of sun exposure cause decreased vitamin D synthesis [1].
Low dietary intake of vitamin D: The vitamin can also be absorbed through the intestinal tract. Consuming foods that do not contain adequate vitamin D can result in VDD.
Reduced absorption due to gastrointestinal pathologies: Certain diseases of the gastrointestinal tract can result in decreased ability of the intestinal lining to absorb various nutrients, including vitamin D [16].
Reduced production due to liver or kidney disease: As we will discuss later, the liver and kidneys contain important enzymes that are required to produce functional vitamin D. Chronic liver or kidney disease can result in sub-physiologic levels of these enzymes, leading to decreased vitamin D production [17, 18].
Pseudo-deficiencies caused by end organ resistance despite normal or elevated vitamin D levels: Because vitamin D exerts its effects by binding to the vitamin D receptor, signs and symptoms of vitamin D deficiency can manifest if the receptor does not function properly. As a result, vitamin D levels can be normal or even elevated [19].
Medication-induced stimulation of hepatic cytochrome P450 enzymes: The cytochrome P450 enzymes are a family of proteins found in the liver that are responsible for metabolizing a wide range of substrates. Specific cytochrome P450 enzymes, for which vitamin D is a substrate, can be stimulated as a side effect of certain medications. This in turn leads to hypermetabolism of vitamin D and with chronic use, can lead to VDD [20].
4. Pathophysiology
Examination of the pathophysiology of VDD and how it interacts with various organs can clarify the various roles this vitamin plays. Vitamin D3 and vitamin D2, precursors to mature vitamin D, must first enter the liver where they are converted to 25(OH)D [21]. Following another enzymatic conversion by the kidneys, 25(OH)D becomes 1,25(OH)D; this is the mature and functional form of vitamin D [22]. Classically, there are three pathways in which vitamin D has been implicated: the endocrine system by way of the parathyroid glands, the gastrointestinal tract, and the skeletal system. Vitamin D inhibits the secretion of parathyroid hormone (PTH) by the parathyroid glands (PTH increases serum calcium levels, decreases phosphorous levels, and stimulates bone resorption), stimulated intestinal absorption of calcium and phosphate, and increased mineralization in the bones [23]. These pathways are outlined in Figure 1.
Figure 1.
Vitamin D Physiology: Classical Pathway. The Vitamin D precursor enters the liver, where it is enzymatically modified to yield 25(OH)D. It then enters the kidneys, where it is once again enzymatically modified to yield 1,25(OH)D, the functional form of vitamin D. In the intestines, calcium and phosphorous absorption is stimulated (green arrow); in the bones, mineralization is stimulated (green arrow); in the parathyroid glands, PTH (parathyroid hormone) secretion is inhibited (red arrow).
Having discussed the normal functions of vitamin D, we will now examine the sequalae of VDD. Low levels of vitamin D stimulate PTH release from the parathyroid glands, leading to increased serum calcium levels and decreased phosphorous levels. Elevated PTH also induces bone resorption (or breakdown). There is also decreased stimulation of the intestine for absorption of calcium and phosphorous as well as decreased bone mineralization in the setting of VDD. The overall result of VDD, therefore, is decreased bone density, decreased serum phosphorous and calcium levels, and elevated PTH [1]. Depending on the severity of the deficiency, symptomatology can be nuanced and may include any combination of the list included below [24].
Bone fractures from mild trauma
Bone pain
Joint pain
Muscle pain
Fatiguability
Psychological symptoms
This section has focused solely on the classical roles of vitamin D and the clinical outcomes observed as a result of VDD. In addition to these classical roles, there are other roles of vitamin D that have been elucidated more recently. These will be discussed in detail in the following section.
5. Recent developments: schizophrenia and COVID-19
This section will examine new insights on the roles of vitamin D. The main topics of discussion will center around the implications of vitamin D in the immune system as well as the central nervous system. Furthermore, we will present a more focused discussion of these topics in the context of schizophrenia and COVID-19.
5.1 Schizophrenia
Schizophrenia is an often debilitating, chronic mental disorder, where patients present with symptoms such as hallucinations, delusions, altered perception, as well as disorganized speech and behavior [25]. It has been well established that an imbalance of various neurotransmitters in the brain is responsible for these symptoms. The most widely studies neurotransmitters in the context of schizophrenia include dopamine, serotonin, and glutamate [26]. Of these, dopamine activity appears to have the strongest correlation to symptomatology by modulating dopamine-1 (D1) and dopamine-2 (D2) receptors [27, 28]. Specifically, dopamine’s effects on four main pathways within the brain have been implicated in schizophrenia and medication side effects: the mesocortical pathway, mesolimbic pathway, nigrostriatal pathway, and tuberoinfundibular pathway. In terms of disease symptoms, the combination of decreased activity of the mesocortical pathway and increased activity of the mesolimbic pathways are the culprit.
On the other hand, the nigrostriatal and tuberoinfundibular pathways are only affected when anti-psychotic medications are administered [29]. This is due to the presence of D2 receptors in all four regions. Because schizophrenia is a disease of localized dopamine dysregulation in the brain, pharmacologic intervention requires blockage of D2 receptors to restore homeostatic dopamine activity. However, these medications do not specifically target the mesocortical and mesolimbic pathways, but instead act on all brain regions that contain D2 receptors. As mentioned, the D2 receptor is also present in the nigrostriatal and tuberoinfundibular pathways, with unintended blockage causing undesirable side effects including movement disorders (extrapyramidal effects), milk discharge (galactorrhea), enlarged breasts, sexual dysfunction, among others [30].
Most recently, vitamin D’s role in schizophrenia has become major a topic of interest for many researchers. Not only has VDD been shown to be associated with schizophrenia, but it has also been implicated in individuals experiencing single episodes of psychosis [31]. In one report, vitamin D levels of three study groups consisting of schizophrenic patients in remission, schizophrenic patients having an acute episode, and patients without psychiatric illness were analyzed and compared. Interestingly, patients who were in the midst of an acute episode were found to have significantly lower vitamin D levels, with a median of 7.18 ng/mL, as compared to both patients in remission (15.03 ng/mL) and non-schizophrenic patients (15.02 ng/mL) [32]. The authors concluded that there exists a clear association between low vitamin D levels and schizophrenic episodes. This does not imply a causative effect, however, as interactions with other pathways must be considered. In fact, a 2015 study searching for potential interactions of vitamin D with other pathways reported proline as one candidate. It was found that the proline dehydrogenase, or
Recently, the presence of vitamin D receptors (VDR) in the brain has been confirmed. More specifically, high concentrations of this receptor have been demonstrated in the hippocampus, supraoptic and paraventricular nuclei, and substantia nigra [35]. Interestingly, organs classically associated with the site of vitamin D activity (such the kidneys, bone, and gut) contain multiple VDR isoforms, however, the brain contains only one isoform [36]. Once the vitamin D-VDR complex forms, it induces various downstream pathways by binding DNA response elements [5]. These VDR can be found in both the adult and the developing brain. As such, VDD in the developing brain can have serious implications. Studies utilizing rodent models have shown that subphysiologic levels of vitamin D in offspring led to abnormalities in neuronal differentiation, altered anatomy, neurotransmitter imbalance, and abnormal gene expression [37]. These findings are also accompanied by abnormal behavioral and cognitive observations, further confirming the vital role of vitamin D in the proper development of the brain [37, 38]. Two retrospective human studies have also been conducted, both of which demonstrated a significant association between neonatal VDD and increased risk of later developing schizophrenia in adulthood [36].
Although it can be useful to understand the mechanisms by which VDD affects the brain and potentially causes schizophrenia, it is even more important to examine whether vitamin D repletion can restore normal brain function. In one study, administration of vitamin D for an eight-week period in schizophrenic patients treated with the medication Clozapine has been shown to improve cognition, without significant effects on psychotic episodes [39]. Interestingly, a similar study demonstrated that in addition to improving cognition, vitamin D supplementation led to improved symptoms in patients suffering from schizophrenia. Of note is that in this study, vitamin D supplementation was not constrained by the wight-week period, but instead vitamin D levels of > 30ng/mL was used as the threshold [40]. This is an important consideration, because it provides an explanation as to why one study reported isolated improvement in cognition while the other reported improved cognition as well as psychotic symptoms. These results imply that there exists a concentration-dependent relationship between vitamin D levels and symptom improvement.
Considering this body of evidence that has recently become available, it is clear that vitamin D is a vital component for not only proper functioning of the adult brain, but also appropriate growth and maturing of the developing brain. We have also discussed insights gathered from recent studies on the link between VDD and schizophrenia. Lastly, it is important to consider the various levels at which we have examined this topic. From a basic science standpoint, we discussed microscopic and macroscopic changes resulting from VDD seen in the neonatal brain and potential cellular and extracellular mediators of disease. From a clinical standpoint, we’ve reviewed several studies that explored the relationship between VDD and the risk of developing schizophrenia and lastly, we discussed studies in which vitamin D supplementation was shown to improve schizophrenia symptoms. Next, we will explore associations between VDD and the COVID-19 virus, how it might affect various aspects of the disease, and whether supplementation with vitamin D has been shown to be beneficial in mitigating the severity of the disease.
5.2 COVID-19
The coronavirus disease 2019 (COVID-19), which first began as an endemic, but rapidly spread to become a global pandemic, has affected millions of people. With death tolls rising at an unprecedented rate, medical research set out to identify potential therapeutic and prophylactic agents to battle the COVID-19 virus and accompanying fatal symptoms [41]. The main syndrome associated with the COVID-19 is acute respiratory distress syndrome (ARDS). ARDS results from overactivation of the immune system, causing extravasation of large volume of fluids into the lungs [42]. This syndrome is extremely dangerous and can lead to death even with maximal medical intervention. In the search for answers to a therapeutic solution, one viable candidate has been vitamin D.
As previously discussed, recent interest in the role of vitamin D in various physiologic processes has provided a plethora of new insights. One such finding has been vitamin D’s role in modulating the body’s immune system. The mechanism by which this is accomplished involves the same VDR mentioned in the previous section. The receptor has been found in a vast number of immune cells and is thought to modulate the immune system in this way. High concentrations have been found particularly in antigen-presenting cells (APC) such as dendritic cells, CD4+ and CD8+ lymphocytes, as well as macrophages [43]. As an intracellular receptor, VDR binds with vitamin D and upon activation, can regulate the transcription of a number of genes [44]. Transcriptional regulation is not however the only way that vitamin D exerts its effects. It has also been shown to interact directly with protein other than VDR, modify histone and chromatin structure, among others [45]. To understand how vitamin D relates to the COVID-19 virus, we will first examine the immune system’s role, then we will explore how these findings related to COVID-19 specifically.
The immune system has one basic, yet functionally complex goal: to destroy foreign particles that pose a threat to the body. The intricate network of immune cells works to neutralize such threats. In order to do so, they communicate with one and another by way of cytokines and other hormones, which are chemicals that act as messengers by binding to their intended receptors located on cell surfaces. Within the innate immune system, signaling via IFN-γ, STAT-1α, lipopolysaccharide (LPS) and toll-like receptors (TLRs) has been shown to increase the activity of 1α- hydroxylase levels in monocytes; this enzyme is responsible for the last step of vitamin D synthesis [4]. Activation of the enzyme, and the ensuing surge of vitamin D levels in monocytes, leads to differentiation of these cells into mature macrophages. Interestingly, in both macrophages and dendritic cells, vitamin D induces an anti-inflammatory state by simultaneously decreasing pro-inflammatory and increasing anti-inflammatory cytokines [46]. Additionally, lymphocytes also express fewer inflammatory receptors in response to vitamin D.
Within the adaptive immune system, the effects of vitamin D can be more nuanced. For instance, vitamin D induces apoptosis of activated B cells and decreases production of plasma cells. Importantly, there is no effect on B cell differentiation. T cells may respond differentially to vitamin D as a function of cellular state and phenotype [43]. The vitamin D-T cell interaction can result in the downregulating the levels of several cytokines including IL-2, IFN-γ, IL-17, and IL-21; the end result is an overall anti-inflammatory state [46]. One important observation that is common to both B and T cells is the markedly decreased proliferation of autoreactive cells [47]. These cells are responsible for various autoimmune disorders, and as multiple studies have shown, vitamin D can be therapeutic in this setting. Given vitamin D’s extensive immunomodulatory role, it has become increasingly evident that it may have major implications in infectious diseases. In the context of COVID-19, the viral pathogen’s main entry point into the body is the respiratory system. Not only is there a high concentration of VDR in the macrophages located in the lung epithelium, but there are also high levels within the epithelial cells themselves. Activation of VDR in the epithelium stimulates production of several anti-microbial proteins that hinder the entrance of such pathogens. Concurrently, VDR activation in lung macrophages is thought to prevent immune system hyperactivity by way of decreasing inflammatory signals [48].
Vitamin D does not only modulate the effects of COVID-19 by way of immunomodulation. Another very important physiologic pathway involved in COVID-19 infection is the renin-angiotensin-aldosterone system (RAAS). RAAS is involved in regulating blood volume and pressure. It’s imperative to understand how this system works physiologically in order to understand how COVID-19 causes its pathological sequalae. Renin is a hormone produced and secreted by the kidneys in response to changes in blood volume or blood pressure. If either of these parameters are decreased, renin is secreted and induces the conversion of angiotensinogen (produced by the liver) to angiotensin I (AT1). Subsequently, angiotensin I travels to the lungs through the systemic circulation. The lungs contain the enzyme angiotensin converting enzyme (ACE), which is responsible for converting AT1 to angiotensin II (AT2). AT2 then acts on several end organs, resulting in increased blood pressure and volume. The enzyme responsible for breaking down AT2 is angiotensin converting enzyme 2(ACE2). In the setting of COVID-19 infection, the virus causes abnormal downregulation of ACE2. This results in the inability to degrade AT2, yielding exceptionally high concentrations of the hormone. Increased AT2 levels then activate the RAAS, which cause hypertension and above physiologic blood volume. With this dramatic increase in blood volume and pressure, substantially more fluid leaks into the lung parenchyma causing ARDS. Vitamin D has been shown to act at several levels to mitigate these pathologic processes. At the level of RAAS biosynthesis, vitamin D acts as a negative regulator by inhibiting renin synthesis [49]. It also has been shown to increase ACE2 levels, allowing more AT-2 breakdown [50]. Lastly, vitamin D has downstream vasodilatory effects which provide a counterforce against the vasoconstriction caused by AT-2 [51, 52].
Taking together the immunomodulatory functions of vitamin D as well as its role in regulating the RAAS system, we can understand its significant therapeutic potential in the setting of COVID-19. In the immune system, vitamin D stimulates a more robust immune response against pathogens, such as the COVID-19 virus; by modulating RAAS, it decreases volume overload in the circulatory system and potentially decreases the likelihood of developing ARDS.
6. Conclusions
In this chapter, we have discussed several key topics related to VDD. These included the epidemiology, recent basic science and clinical developments, and the role that vitamin D plays in schizophrenia and COVID-19. Epidemiologically, there is a staggering portion of the population who suffers from VDD; this is especially true of certain countries in the Middle East. Aside from geographic location, darker skin colors are also significantly associated with higher rates of VDD. There are also several additional modifiable and non-modifiable risk factors associated with suboptimal vitamin D levels, as discussed previously.
From a basic science standpoint, there have been a number of new discoveries and developments in identifying the role of vitamin D in organ systems besides those involved in the classical pathways. These include the vitamin’s role in modulating the immune system, regulating the circulatory system by way of RAAS, the proper functioning of the central nervous system, as well as appropriate development of the growing brain. Implications of these new findings can then be analyzed in the clinical setting. In the context of schizophrenia, vitamin D supplementation, in a dose and concentration-dependent manner, has been shown to improve symptoms. This has been attributed to the detection of vitamin D receptors in the brain.
Furthermore, the immunologic and circulatory regulation capabilities of vitamin D have made it a topic of interest in searching for a treatment for COVID-19 infection. By stimulating various immune cells involved in both the innate and adaptive immune system, vitamin D plays a role in neutralizing and clearing the COVID-19 virus. Additionally, a feared consequence of the infection is ARDS. By counteracting the pathological disruptions in the RAAS system, vitamin D may help decrease the severity of or even prevent ARDS.
In conclusion, we have seen that vitamin D’s functions in the body are far more nuanced than previously thought. The new insights discussed in this chapter provide a broader range of both physiologic and pathophysiologic effects that this crucial vitamin has throughout the body. Although the roles of vitamin D in the endocrine, gastrointestinal, and skeletal systems are extremely important, it is imperative to also consider its immune system, circulatory system, and nervous system implications moving forward.
References
- 1.
Sizar O, Khare S, Goyal A, Givler A. Vitamin D Deficiency. Treasure Island (FL): StatPearls Publishing; 2022 - 2.
Webb AR, Kazantzidis A, Kift RC, Farrar MD, Wilkinson J, Rhodes LE. Colour counts: Sunlight and skin type as drivers of Vitamin D deficiency at UK latitudes. Nutrients. 2018; 10 (4):457 - 3.
Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, et al. Vitamin D deficiency 2.0: An update on the current status worldwide. European Journal of Clinical Nutrition. 2020; 74 (11):1498-1513 - 4.
Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annual Review of Nutrition. 2003; 23 :117-145 - 5.
Langub MC, Herman JP, Malluche HH, Koszewski NJ. Evidence of functional vitamin D receptors in rat hippocampus. Neuroscience. 2001; 104 (1):49-56 - 6.
Hovsepian S, Amini M, Aminorroaya A, Amini P, Iraj B. Prevalence of Vitamin D deficiency among adult population of Isfahan City. Iranian Journal of Health Population Nutrition. Apr 2011; 29 (2):149-155 - 7.
Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? Journal of Steroid Biochemical and Molecular Biology. 2014; 144PA :138-145 - 8.
Andıran N, Çelik N, Akça H, Doğan G. Vitamin D deficiency in children and adolescents. Journal of Clinical Research in Pediatric Endocrinology. 2012; 4 (1):25-29 - 9.
Tabrizi R, Moosazadeh M, Akbari M, Dabbaghmanesh MH, Mohamadkhani M, Asemi Z, et al. High prevalence of Vitamin D deficiency among Iranian ppulation: A systematic review and meta-analysis. Iranian Journal of Medical Science. 2018; 43 (2):125-139 - 10.
Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, et al. Vitamin D deficiency in Europe: Pandemic?12. The American Journal of Clinical Nutrition. Apr 2016; 103 (4):1033-1044 - 11.
Parva NR, Tadepalli S, Singh P, Qian A, Joshi R, Kandala H, et al. Prevalence of Vitamin D Deficiency and Associated Risk Factors in the US Population (2011-2012). Cureus. 2016; 10 (6):e2741 - 12.
Riley PA. Melanin. The International Journal of Biochemistry & Cell Biology. Nov 1997; 29 (11):1235-1239 - 13.
Bikle DD, Vitamin D. Metabolism and function in the skin. Molecular and Cellular Endocrinology. 2011; 347 (1-2):80-89 - 14.
Glatt DU, McSorley E, Pourshahidi LK, Revuelta Iniesta R, McCluskey J, Beggan L, et al. Vitamin D status and health outcomes in school children in Northern Ireland: Year One Results from the D-VinCHI Study. Nutrients. 2022; 14 (4):804 - 15.
Peterson CA, Belenchia AM. Vitamin D deficiency & childhood obesity: A tale of two epidemics. Missouri Medicine. 2014; 111 (1):49-53 - 16.
Margulies SL, Kurian D, Elliott MS, Han Z. Vitamin D deficiency in patients with intestinal malabsorption syndromes – think in and outside the gut: Malabsorption and vitamin D deficiency. Journal of Digestive Diseases. 2015; 16 (11):617-633 - 17.
Parizadeh SM, Rezayi M, Jafarzadeh-Esfehani R, Avan A, Ghazizadeh H, Emadzadeh M, et al. Association of vitamin D status with liver and kidney disease: A systematic review of clinical trials, and cross-sectional and cohort studies. International Journal for Vitamin and Nutrition Research. 2021; 91 (1-2):175-187 - 18.
Gröber U, Kisters K. Influence of drugs on vitamin D and calcium metabolism. Dermato-Endocrinology. 2012; 4 (2):158-166 - 19.
Choudhury S, Kf J, Ranabir S, Singh TP. Familial vitamin D resistant rickets: End-organ resistance to 1,25-dihydroxyvitamin D. Indian Journal of Endocrine Metabolism. 2013; 17 (7):224 - 20.
Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. Journal of Lipid Research. 2014; 55 (1):13-31 - 21.
Zmijewski MA. Vitamin D and human health. International Journal of Molecular Sciences. 2019; 20 (1):145 - 22.
Bikle DD. Vitamin D: Production, metabolism and mechanisms of action. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000 - 23.
Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. Journal of Pharmacology and Pharmacotherapeutics. 2012; 3 (2):118-126 - 24.
Pilz S, Zittermann A, Trummer C, Theiler-Schwetz V, Lerchbaum E, Keppel MH, et al. Vitamin D testing and treatment: A narrative review of current evidence. Endocrine Connections. 2019; 8 (2):R27-R43 - 25.
Hany M, Rehman B, Azhar Y, Chapman J. Schizophrenia. Treasure Island (FL): StatPearls Publishing; 2022 - 26.
Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: Overview and treatment options. P T. Sep 2014; 39 (9):638-645 - 27.
Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, et al. The role of dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue. Frontiers in Psychiatry. 2014; 5 :47 - 28.
Mouse Models of Schizophrenia: Risk Genes – ScienceDirect. [cited June 15, 2022]. Available from: https://www.sciencedirect.com/science/article/pii/B978012800981900016X - 29.
Olijslagers J, Werkman T, McCreary A, Kruse C, Wadman W. Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significance for antipsychotic drug action. Current Neuropharmacology. 2006; 4 (1):59-68 - 30.
Chokhawala K, Stevens L. Antipsychotic Medications. Treasure Island (FL): StatPearls Publishing; 2022 - 31.
Viani-Walsh D, Kennedy-Williams S, Taylor D, Gaughran F, Lally J. Vitamin D deficiency in schizophrenia implications for COVID-19 infection. Iranian Journal of Psychological Medicine:1-10 - 32.
Yüksel RN, Altunsoy N, Tikir B, Cingi Külük M, Unal K, Goka S, et al. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: Therapeutic implications for add-on vitamin D augmentation. Therapeutic Advances in Psychopharmacology. 2014; 4 (6):268-275 - 33.
Clelland JD, Read LL, Drouet V, Kaon A, Kelly A, Duff KE, et al. Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association. Schizophrenia Research. 2014; 156 (1):15-22 - 34.
Cecchini NM, Monteoliva MI, Alvarez ME. Proline dehydrogenase is a positive regulator of cell death in different kingdoms. Plant Signaling & Behavior. 2011; 6 (8):1195-1197 - 35.
Eyles DW. Vitamin D: Brain and behavior. JBMR Plus. 2020; 5 (1):e10419 - 36.
Cui X, McGrath JJ, Burne THJ, Eyles DW. Vitamin D and schizophrenia: 20 years on. Molecular Psychiatry. 2021; 26 (7):2708-2720 - 37.
Hawes JE, Tesic D, Whitehouse AJ, Zosky GR, Smith JT, Wyrwoll CS. Maternal vitamin D deficiency alters fetal brain development in the BALB/c mouse. Behavioural Brain Research. 2015; 286 :192-200 - 38.
O’Loan J, Eyles DW, Kesby J, Ko P, McGrath JJ, Burne THJ. Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring. Psychoneuroendocrinology. 2007; 32 (3):227-234 - 39.
Krivoy A, Onn R, Vilner Y, Hochman E, Weizman S, Paz A, et al. Vitamin D supplementation in chronic Schizophrenia patients treated with clozapine: A Randomized, Double-Blind. Placebo-controlled Clinical Trial. EBioMedicine. 2017; 26 :138-145 - 40.
Neriman A, Hakan Y, Ozge U. The psychotropic effect of vitamin D supplementation on schizophrenia symptoms. BMC Psychiatry. 2021; 21 (1):309 - 41.
Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Medical Journal of Australia. 2020; 213 (2):54-56 - 42.
Li X, Ma X. Acute respiratory failure in COVID-19: is it “typical” ARDS? Critical Care. 6 May 2020; 24 :198 - 43.
Ghelani D, Alesi S, Mousa A. Vitamin D and COVID-19: An overview of recent evidence. International Journal of Molecular Sciences. 2021; 22 (19):10559 - 44.
Pike JW, Meyer MB. The Vitamin D receptor: New paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D3. Endocrinology and Metabolism Clinics of North America. 2010; 39 (2):255-269 - 45.
Shirvani A, Kalajian TA, Song A, Holick MF. Disassociation of Vitamin D’s calcemic activity and non-calcemic genomic activity and individual responsiveness: A Randomized Controlled Double-Blind Clinical Trial. Scientific Reports. 2019; 9 :17685 - 46.
Aranow C. Vitamin D and the immune system. Journal of Investigative Medicine. 2011; 59 (6):881-886 - 47.
Yisak H, Ewunetei A, Kefale B, Mamuye M, Teshome F, Ambaw B, et al. Effects of Vitamin D on COVID-19 infection and prognosis: A systematic review. Risk Management and Healthcare Policy. 2021; 14 :31-38 - 48.
Gerke AK, Pezzulo AA, Tang F, Cavanaugh JE, Bair TB, Phillips E, et al. Effects of vitamin D supplementation on alveolar macrophage gene expression: preliminary results of a randomized, controlled trial. Multidisciplinary Respiratory Medicine. 2014; 9 (1):18 - 49.
Kota SK, Kota SK, Jammula S, Meher LK, Panda S, Tripathy PR, et al. Renin–angiotensin system activity in vitamin D deficient, obese individuals with hypertension: An urban Indian study. Indian Journal of Endocrinology Metabolism. 2011; 15 (Suppl. 4):S395-S401 - 50.
Ajabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. Journal of Nephropathology. 2014; 3 (2):41-43 - 51.
McMullan CJ, Borgi L, Curhan GC, Fisher N, Forman JP. The effect of Vitamin D on renin-angiotensin-system activation and blood pressure – A Randomized Control Trial. Journal of Hypertension. 2017; 35 (4):822-829 - 52.
Li YC. Vitamin D regulation of the renin-angiotensin system. Journal of Cellular Biochemistry. 2003; 88 (2):327-331