Role of Vitamin D in Patients with Schizophrenia Suffering from COVID-19

*Fatemeh Gholami, Saman Farshid, Parmida Soleimani and Rohollah Valizadeh*

## **Abstract**

People with schizophrenia are at high risk for vitamin D deficiency. There is more likely as association between vitamin D and COVID-19 development and even severe outcomes following SARS-CoV-2 infection. It should be noted that other factors except schizophrenia are also related to the severity of the COVID-19 such as heart conditions, respiratory disorders, overweight, and hypertension in which are prevalent in patients with schizophrenia linked with vitamin D deficiency. This book aimed to determine the relationship between the level of vitamin D and COVID-19 severity in patients with schizophrenia.

**Keywords:** schizophrenia, vitamin D, 25(OH) D, respiratory infection, COVID-19, coronavirus disease

## **1. Introduction**

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei province, China. The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on 11 March 2020. While it is estimated that 80% of those infected with COVID-19 are asymptomatic or have a self-limiting disease, the case fatality rate for those hospitalized with COVID-19 was 2.3%, increasing to 10.5% in those with cardiovascular disease, 7.3% in those with diabetes mellitus, 6% in those with hypertension and 5.6% for cancer [1]. COVID-19 was distributed worldwide and showed various symptoms, including lung involvement, liver and kidney damage, and conjunctivitis. COIVD-19 is considered a disease with multi-organ failure ability [2–7]. After declaring the Pandemic by WHO, researches were done further to find remedy and vaccines [8–10]. Vitamin D is one of the subjects that had controversial effects on the treatment or recovery process of patients with COVID-19. Now we elaborate on the details of vitamin D [11].

Vitamin D, a steroid hormone, plays the main role in the immune system [12, 13]. Vitamin D influences many reactions against the normal immune response to pathogens. Vitamin D can facilitate the recovery of COVID-19 because both cytokine storms and inflammation are related to severe outcomes in patients with COVID-19

who have high prevalence of pneumonia and lung failure, especially in older patients with lots of comorbidities results in high mortality rate. More than 70% of all schizophrenia (SCZ) patients also have one or more clinical conditions, including diabetes type II [14–16], chronic pulmonary disease [17], heart diseases, obesity, and hypertension, so the life span in these people decreases [18–20] and may be vulnerable to infection with SARA-CoV-2 [21].

People who have psychotic disorders are at high risk for vitamin D deficiency [22]. There is a close relationship between COVID-19 and SCZ. The results of a study showed that SCZ is associated with high mortality following COVID-19 development [23].

Low accessibility to suitable medical care aggravates this scenario [24]. Patients with SCZ and their home care providers may have problem seeking health services. Additionally, even if they want to ask for medical assistance, due to the stigma surrounding SCZ, there is more likely to not take proper assessment or treatment [25].

Patients with schizophrenia are prone to be infected with worse outcomes, especially if they are suffering from several comorbidities. They are vulnerable to worsening psychiatric symptoms and relapse due to fear of the disease, stress, and the boredom associated with compulsory isolation. Thus, health and care providers need more attention and support to prevent COVID-19 among in this group and should detect both psychiatric and respiratory problems as soon as possible.

In this chapter, we tried to describe the reason for high COVID-19 morbidity and mortality among individuals with SCZ through a literature review.

## **2. Development of vitamin D deficiency in patients with schizophrenia**

Schizophrenia may be developed by environmental and genetic factors [26]. According to epidemiological research, schizophrenia is seen more in people: 1) born in the winter and spring seasons [27], 2) living in the urban area in childhood [28–31], and 3) living at high latitudes [32]. On the other hand, we know that dark skin needs much sunlight exposure to produce enough vitamin D, so children with dark skin who migrate to cold climates have more chance of developing SCZ due to low levels of vitamin D during gestation [33]. A Danish case–control study indicated that vitamin D deficiency in neonates is associated with an increased risk for SCZ in later life. People with 25OHD less than 20.4 nmol/L [34] had a 44% increased risk of SCZ compared to people over 40.1–53.5 nmol/L [22].

However, randomized clinical trials to investigate the effects of maternal vitamin D supplements on the development of SCZ in their children may never happen due to two reasons. First, there is no strong evidence suggesting high dose of 25OHD for


#### **Table 1.**

*Summary of hypothesis related to vitamin D and SCZ.*

*Role of Vitamin D in Patients with Schizophrenia Suffering from COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.108352*

health targets. Second, it is unethical to screen pregnant women for vitamin D deficiency and allocate this group to take vitamin D supplements or the placebo. Finally, it is hard to follow up on large mother-offspring samples for 2–3 decades to determine the risk of SCZ development [35]. A summary of the hypothesis related to vitamin D and SCZ is presented in **Table 1**.

## **3. Prevalence of vitamin D deficiency in schizophrenia**

Vitamin D deficiency and insufficiency are in different people worldwide, but its burden, such that the prevalence of serum 25OHD < 25/30 nmol/L ranges from 5 to 18%, depends on the Food and Agriculture Organization (FAO) world region, varies from 24 to 49% in the case of serum 25OHD < 50 nmol/L [37]. It is not clear which dose of vitamin D levels are sufficient, insufficient, and deficient, and we showed typical thresholds in **Table 2**. The main circulating form of vitamin D is 25OHD which is usually taken as a proxy of vitamin D status in blood [39, 40]. Two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of SCZ [26, 41]. A meta-analysis study including 31 studies showed that there were statistically significant differences in the mean 25OHD between SCZ and the control group in which; the control group in the case–control and cohort studies consisted of healthy subjects with no history of psychiatric disorders, while in the cross-sectional studies, psychiatric patients but non-schizophrenic were considered to be the control group. Consequently, it can be concluded that, compared with healthy people or other psychiatric patients, peripheral blood mean 25OHD is low in patients with SCZ [26].

Generally, patients suffering from SCZ have poor general health, poor nutrition, low activity, and more comorbidity. So it is important to be cautious in any causal interpretation for patients with SCZ [42]. Some studies have inconsistent results from existing vitamin D supplementation trials in patients with SCZ [43, 44]. We can conclude that vitamin D deficiency can increase the risk of SCZ development, and it is strongly recommended to do ongoing research.

## **4. Vitamin D deficiency and respiratory infection risk with SARS-CoV-2 virus**

There are two critical questions emanating from the title of this part. The first is whether there is an association between susceptibility to develop COVID-19 and vitamin D deficiency or not. The second is whether vitamin D use in deficient people can prevent or improve infection with SARS-CoV-2 or change the course of its disease.


Improvement of the immune system by correct nutrition is a considerable factor. Vitamin D as a nutrient plays a significant role in the immune system. However, there is little evidence about the role of vitamin D in preventing COVID-19 and its consequences [45].

COVID-19 pandemic has raised challenges in terms of the benefits of vitamin D used to prevent and even treat it. Sufficient blood vitamin D can help in a satisfactory cellular response and in protecting against the severity of infections caused by microorganisms such as SARS-CoV-2 [45]. Vitamin D deficiency is related to severe outcomes following COVID-19 [46]. In a systemic review and meta-analysis consisting of 14 studies, the effect of vitamin D supplementation in lowering the risk of non-COVID-19 respiratory tract infections in patients with lower vitamin D levels was found [47]. Moreover, a systematic review consisting of 7 meta-analyses on 30 clinical trials showed the same results [48]. Higher COVID-19 mortality rates in Europe have been identified in patients suffering from vitamin D deficiency [45].

There is still limited evidence in favor of the effect of vitamin D in people with COVID-19 in the treatment process [49]. A meta-analysis consisting of eight observational studies revealed that people with vitamin D < 50 nmol/l (i.e., <20 ng/ml) have 64% more risk of community-acquired pneumonia [50].

The results of the meta-analysis showed that vitamin D deficiency could result in the severe form of COVID-19, especially in the elder people [49], which is explained by both lower exposure to sunlight and lower 7-dehydrocholesterol values in the skin compromising the cutaneous synthesis of 25OHD in the elderly [51]. Moreover, aging is accompanied by lots of chronic diseases [52].

We recommend developing cohort studies, especially clinical trials on different age groups in various climatic conditions, to evaluate the causality between vitamin D and COVID-19.

## **4.1 Mechanism: vitamin D regulating inflammation**

The association of vitamin D and C-reactive protein (CRP) level, an anti-inflammatory factor, is proposed. Vitamin D use is associated with a reduction in CRP level [53], while in patients with SCZ, an inverse relationship was found between CRP levels and vitamin D [54]. Low serum level of vitamin D seems to be associated with the inappropriate function of the immunomodulatory. Also, insufficient vitamin D levels result in less efficient antigen presentation and macrophage function. Low vitamin D may potentially contribute to a delayed response to the body's initial contact with the SARS-CoV-2 virus.

## **5. Schizophrenia and COVID-19**

A large cohort study was carried out on 1092 patients with/without SCZ hospitalized due to COVID-19. Only 15 patients had SCZ. The overall in-hospital mortality rate was 9%. Patients with CSZ had more mortality compared to non-SCZ patients (26.7% vs. 8.7%) (Adjusted odds ratio: 4.36). We know that an adjusted odds ratio of more than one is considered a risk factor, while here, it is 4.36 [23]. Vitamin D deficiency is associated with higher risk of respiratory infection. There are more respiratory infections and deaths in patients with SCZ where vitamin D deficiency is prevalent. This potentially offers a modifiable risk factor to reduce the risk for and the severity of respiratory infection in people with SCZ [21].

## **5.1 Prognostic factors in developing COVID-19**

## *5.1.1 Age and gender*

In spite of the fact that females experience more morbidity (not mortality) than males [54], the relative risk of mortality following COVID-19 was higher for males than females in all regions and almost all age groups. The overall relative risk ranged from 1.11 in Portugal to 1.54 in France, showing the risk factor role of gender in COVID-19 consequences. In most regions, sex differences increase until 60–69 years [55]. Clinicians obviously noted that COVID-19 mortality rises with aging, unlike other respiratory diseases [56]. People ≥65 years have a strikingly higher mortality rate following COVID-19 compared to younger adults, and males have a higher mortality rate following COVID-19 compared to females. Over the 42-day period, there were 178,568 deaths following COVID-19 deaths. Mortality was influenced by age and sex in patients with COVID-19. Compared with individuals≤54 years, the incident rate ratio [57] was 8.1, indicating the high mortality rate following COVID-19, and also IRR was 62.1 for patients≥65 years or older. Totally mortality rate due to COVID-19 was 77% higher in males compared to females (IRR = 1.77) [58].

In addition, age may also have interaction with SCZ in respect of the mortality rate following SARS-CoV-2 infection. A retrospective case–control study showed that patients with SCZ >65 years had higher risk compared to the patients with SCZ aged 18–65 years (Adjusted odds ratio = 1.74) [59].

## *5.1.2 Ethnicity*

In the general population, mortality following infection with SARS-CoV-2 among people from ethnic minorities is four times higher than in the white European population [60]. In an observational study, as compared to white patients, African-American people suffering from SCZ had higher prevalence of SARS-CoV-2 infection (adjusted odds ratio: 2.33) and higher mortality rate (6.2% vs. 3.7%), and men had higher mortality rate than women (6.6% vs. 3.4%) [61].

## *5.1.3 Comorbidities*

The risk factors for severe SARS-CoV-2 infection, such as cardiovascular disease (CVD), chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) [62–64], are frequent in patients with SCZ compared to the general people. More than 70% of all patients with SCZ have one or more comorbidity, including diabetes type II [15, 16], chronic pulmonary disease [17], hypertension, heart diseases, and obesity, so overall survival in these patients decreases [18–20] and is the vulnerable group to COVID-19 with high mortality [21]. Patients with SCZ and/or with other mental problems such as bipolar disorders had high risk of mortality following COVID-19. This can be justified by their immunological profile. Variation in the human leukocyte antigen complex is one of the most consistently replicated findings in genome-wide association studies in patients with SCZ and bipolar disorders [65]. In conclusion, the highest risk of mortality in individuals with SCZ and/or bipolar disorders is not far off [66].

## **5.2 Vitamin D deficiency in schizophrenia implications for COVID-19 infection**

The global age-standardized prevalence of SCZ is 0.28% [67]. Among COVID-19 risk factors identified in patients with SCZ, the presence of comorbidities, stigma experience, poor insight into somatic symptoms, cognitive impairment, and delusions have been identified as factors that can lead to misperception of the risk related to the virus. Moreover, patients with SCZ are often heavy smokers with lower vitamin D levels, and it is unknown how it can affect their chance of COVID-19 survival. A case–control study on patients with COVID-19 in southern France showed that the mortality rate was 9.0%. The patients with SCZ had increased mortality compared to the non-SCZ patients (26.7% vs. 8.7%, respectively). In contrast, the patients with SCZ were admitted to the ICU less than those without SCZ. SCZ is associated with further COVID-19 mortality, confirming the existence of health disparities described in other somatic diseases [23].

Lack of vitamin D causes deterioration in the health of our body and thus increases the risk of mental disorders. Research is ongoing, but studies have shown that sunlight provides a significant protective effect for respiratory problems and inflammation disorders. In the context of the coronavirus pandemic, research has been conducted on the relationship between vitamin D, CZ, and increased rates of acute respiratory infection.

There is more respiratory infection and mortality in patients with SCZ whose vitamin D deficiency is prevalent [68]. A case series study including 14 elderly COVID-19 positive inpatients presenting with dementia or SCZ and other medical conditions was done. All patients received 800 IU daily vitamin D prior to the infection. Most of the patients were asymptomatic or with very few symptoms. There was no need for an intensive care unit, or deaths were not reported. But cognitive functioning of the patients was unchanged. It can be concluded pre-existing vitamin D use may reinforce the immune system and lower the severity of COVID-19 in elderly patients with psychiatric disorders [69].

## **6. Conclusions**

It seems vitamin D deficiency is associated with an increased risk of acute respiratory infection and mortality after the development of COVID-19. There are further respiratory tract infections and mortality in patients with schizophrenia because vitamin D deficiency is prevalent in these patients. Patients with schizophrenia are prone to be infected with worse outcomes, especially if they suffer from several comorbidities. They are vulnerable to worsening psychiatric symptoms and relapse due to fear of the disease, stress, and the boredom associated with compulsory isolation. Thus, health and care providers need more attention and support to prevent COVID-19 in this group and should detect psychiatric and respiratory problems as soon as possible. *Role of Vitamin D in Patients with Schizophrenia Suffering from COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.108352*

## **Author details**

Fatemeh Gholami1,2, Saman Farshid3 , Parmida Soleimani4 and Rohollah Valizadeh5 \*

1 Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran

2 Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

3 Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran

4 Department of Psychology, Roudehen Branch, Islamic Azad University, Tehran, Iran

5 Urmia University of Medical Sciences, Urmia, Iran

\*Address all correspondence to: rohvali4@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 7**

## Vitamin D Deficiency: Implications in COVID-19 and Schizophrenia

*Sepehr Saberian, Fahim Atif, Donald Stein and Seema Yousuf*

## **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 wellstudied 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% [6–8]. 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:


## **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].

#### **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).*

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**.

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].


*Vitamin D Deficiency: Implications in COVID-19 and Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.106801*


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 *PRODH*, gene's transcription was significantly modulated by vitamin D [33]. This enzyme plays an important role in proline catabolism; as a result, proline levels decreased with increasing proline dehydrogenase concentrations and vice versa [34]. Not surprisingly, VDD was found to be associated with higher proline levels. Furthermore, hyperprolinemia was shown to contribute to 33% of the relationship between VDD and schizophrenia [33].

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

### *Vitamin D Deficiency: Implications in COVID-19 and Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.106801*

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 proinflammatory 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

## *Vitamin D Deficiency: Implications in COVID-19 and Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.106801*

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.

## **Conflict of interest**

The authors declare no conflict of interest.

*Vitamin D Deficiency - New Insights*

## **Author details**

Sepehr Saberian1 , Fahim Atif<sup>2</sup> , Donald Stein<sup>2</sup> and Seema Yousuf<sup>2</sup> \*

1 Morehouse School of Medicine, Atlanta, USA

2 Emory University School of Medicine, Atlanta, USA

\*Address all correspondence to: seema.yousuf@emory.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 4
