Vitamin D Deficiency is Associated with the Development of Psychosis and Schizophrenia

HUN 3231

April 6, 2018
 1

Introduction

Approximately one billion people worldwide are classified with a Vitamin D deficiency. The

criteria for a deficiency and insufficiency are levels between 25 and 50 nmol/L. Common at risk groups

include: older people. Children, non-Caucasian individuals, those with darker skin, those with low sun

exposure, those living far away from the equator, and malnourished individuals. 1,2 Vitamin D is most

readily obtained through the diet and endogenous synthesis of Vitamin D due to UV-B light exposure.1

The levels of 25 (OH) vitamin D are greatly dependent on Vitamin D conversion in the skin by the

enzyme 25-hydroxylase and dietary intakes.3 The active form of vitamin D is 1, 25-hydroxyvitamin D and

is considered a neurosteroid hormone with a role in the central nervous system development and

function.4,5 Furthermore, Vitamin D is involved in neurotransmitter creation, neurological protection from

harm and inflammation and important roles in neurological development.2 Vitamin D promotes the

differentiation of nerve cells through the nerve growth factor (NGF).4 The vitamin D receptor is found in

many tissues but it has a particularly high expression in the human brain.3 There are great concentrations

of Vitamin D receptors in the hippocampus and dorsal striatum which are regions associated with

memory, motor behavior, and cognition.5 Due to vitamin D’s role in the central nervous system it is

important to research the effects of deficiencies and the key roles of the vitamin.

Schizophrenia is a neurodevelopmental disorder in which premature changes in cognitive

development result in delayed onset of symptoms such as hallucinations, delusions, disorganized

communication, poor planning, poor motivation, and blunted affect. Approximately 1% of the worldwide

population is affected by schizophrenia.6 Cognitive impairment is associated with the disorder and

expresses itself as reduced processing speed, deficits in memory, impaired executive functioning and

reduced social cognition.3,5 Possible explanations for the emergence of the disorder are associations with

autoimmune diseases, infections, and elevated inflammatory markers in the plasma.7 The connection

between Vitamin D and schizophrenia has been associated with winter or early spring offspring,

deficiencies in rats which resulted in smaller brains and enlargements of the ventricle, and inflammatory
 2

pathways.2,4 Thus low vitamin D levels could be a possible explanation for the emergence of the

symptoms of the disorder.6 Some studies have found that schizophrenia patients tend to have lower levels

of serum vitamin D than healthy individuals with a prevalence of 65.3% in the evaluated population. 1

Overall, schizophrenia is a complex condition with severe symptomatology and since some patients do

not respond well to standard treatments, alternatives must be explored. The purpose of this paper is to

evaluate the current literature to demonstrate whether schizophrenic patients indeed do have lower

Vitamin D levels than controls and whether these levels lead to the condition. Additionally, some studies

conducted on supplementation of vitamin D orally and via sunlight will be explored in order to find

whether raising Vitamin D levels leads to improvements in schizophrenia.

Methods

In order to search for relevant articles, the University of North Florida “UNF OneSearch”

database was used. The research articles were limited to “Full Text”; “Peer Reviewed”; “Academic

Journals” and dated between January 1st, 2005 and April 3, 2018. The words “vitamin D and

schizophrenia” were typed in the search box in order to generate articles that include these words in the

title. The search resulted in 14,951 articles. Exact matches were given preference and the most relevant

articles that included schizophrenic subjects tested for vitamin D deficiency were selected. The final

review includes seven of the most appropriate articles. Furthermore, only cohort, cross sectional, and

randomized controlled studies were included in the analysis. Several studies were excluded due to the

lack of schizophrenic subjects or comorbid conditions that may interfere with vitamin D metabolism.

Main Findings

In order to understand the association between Vitamin D levels and the risk of development,

severity of the illness, and treatment of schizophrenia, it is imperative to first determine whether patients

in fact do have differing levels of Vitamin D compared to healthy controls. Several studies have evaluated

the serum levels of 25 (OH) vitamin D levels in schizophrenic individuals as well as the normal
 3

population. Jamilian et al. measured and compared serum levels of Vitamin D, Calcium, Phosphorus, and

Parathyroid Hormone in schizophrenics, depressed individuals, and in a group of healthy individuals from

the Iranian population. In the study, 100 schizophrenic, 100 depressive and 100 healthy individuals were

recruited. The subjects were given a questionnaire that asked anthropometric and psychological questions

in order to determine classification for each individual. Additionally, serum 25-hydroxyvitamin D levels

were measured and all patients in the schizophrenic group, were determined to be in the acute phase of

the illness. The scientists found that in the 3 groups, the serum Vitamin D levels different only in the

depressive and schizophrenic groups. These groups had significantly (P<0.001) lower vitamin D levels

than the normal population and the levels were not statistically different between the depressive and

schizophrenic patients. Thus, differences between Vitamin D levels may be state or trait dependent since

those afflicted by a psychological illness tended to have higher rates of osteoporosis, and higher

unemployment.4 These components may be confounding and explain the lower levels of vitamin D. This

cross sectional study did find an association with psychological abnormalities and lower levels of vitamin

D. In another cross sectional study, Nehrus et al. investigated the association between vitamin D

deficiency and cognition in a large clinical sample of patients with psychotic abnormalities and healthy

controls using tests for cognition parameters such as verbal learning and level of psychosis. The study

design included 225 patients, 91 of which exhibited schizophrenic traits and 159 healthy controls. The

symptom states of the subjects were evaluated using the PANS scale and IQ tests. Serum levels of

Vitamin D were also determined. According to the results of the study, Vitamin D levels were not

associated with improved memory but were significantly (P<0.001) related to impaired processing speed

and decreased fluency. Furthermore, 33 of the patients exhibited deficiencies and only 5 of the healthy

control were in the deficient category.5 Therefore, the study did find an association between low vitamin

D levels and cognitive impairments, but did not establish a strong link between Vitamin D and

schizophrenia. The aforementioned studies have demonstrated that schizophrenic patients tend to have

lower vitamin D levels than healthy controls.

 4

Since lower vitamin D levels are found in schizophrenic patients, it is logical to explore the

potential relationships between the vitamin and the schizophrenic condition. Cieslak et al., theorized that

low Vitamin D levels play a role in the development of schizophrenia due to telomere length. In the

cohort study 22 schizophrenic patients were tested. Each individual underwent a serum Vitamin D level

test, a PANSS assessment, and the Schedule for the Deficit Syndrome. Schizophrenic patients were found

to have deficiencies of Vitamin D with mean levels of 17.3 +/- 8.87 nmol/L. When related to PANSS

scores, the vitamin D levels were significantly inversely associated with excitement, grandiosity, poverty

of speech, and worse premorbid adjustment. Furthermore, increased levels of Vitamin D were associated

with increased telomere length. In men, Vitamin D levels were associated with greater negative symptoms

and in women with increased aggression. This study demonstrated that low Vitamin D levels may be

correlated with more severe symptoms in schizophrenic patients due to changes in telomere length.2

Another theory of Vitamin D’s relationship with schizophrenia is the increased level of inflammation in

the body due to schizophrenia. Presumably, if high levels of vitamin D could reduce the risks of psychosis

with high levels of CRP (a marker of inflammation), then Vitamin D may be used as a supplemental

treatment. In the cross sectional study, 186 participants gave blood samples, anthropometric

measurements, answers to questionnaires, and season during which vitamin D levels were measured.

Groups were subdivided into high and low Vitamin D, CRP levels, and presence or absence of the

schizophrenic condition. Schizophrenics were found to have 39.6% lower Vitamin D levels and 38.5%

higher CRP than healthy controls. Vitamin D levels were inversely associated (p<0.001) with CRP levels

in schizophrenics but not controls.7 The findings indicate that schizophrenia is associated with lower

vitamin D levels and higher CRP. Yet, the exact connection is unclear. Using an animal model, Kesby et

al. aimed to examine the locomotor responses due to different doses of amphetamine (administration

induces schizophrenic symptoms) in Vitamin D deficient and control rats. In the study, vitamin D

deficient rats were administered with 1ml/kg of D-amphetamine every 7 days for 4 weeks. At the end of

the treatment period, the rats were tested and a significant effect was found on the distance travelled,

indicating an increase in locomotion which is an aspect of schizophrenia.6 Therefore, a deficiency in

 5

Vitamin D was associated with increased locomotion in rats affected by amphetamine. These studies

indicate that low vitamin D levels are generally correlated with more negative symptoms of

schizophrenia, changes in telomere length, and increased locomotion. Although results from Kesby et al.,

were from an animal model and may not apply to humans.

Finally, since some studies have shown associations between Vitamin D levels and schizophrenic

traits, it is valuable to review the literature on Vitamin D’s use as a treatment for schizophrenia. Bogers et

al., attempted to use sunlight in order to increase vitamin D levels through endogenous synthesis. Prior to

the inception of the study, the serum levels of vitamin D were measured in April in 21 patients and 29

healthy controls. The same was performed in June, at the conclusion of the study. In June, the controls

had significantly higher vitamin D than patients 73 nmol/L vs. 35 nmol/L, respectively. Furthermore, due

to springtime sunlight exposure, the patients experienced a significantly increase in vitamin D levels from

29 nmol/L to 37 nmol/L. This is significant but their levels still remain below adequate. This may be due

to the lower starting point or resistance to vitamin D conversion. More research must be conducted to

determine the exact reasons for the discrepancy.1 Besides sunlight, supplements may be used to establish a

connection between vitamin D and severity of schizophrenia. Krivoy et al., conducted a randomized

controlled trial with 45 severely affected patients taking Clozapine. All the patients had Vitamin D levels

below 75 nmol/L and a total score above 70 on the PANSS. Each patient was supplemented with 14,000

IU of Vitamin D weekly for 8 weeks. At baseline, 33 patients were insufficient and the mean serum level

of vitamin D was 39.8 +/- 16.2 nmol/L. At the end, the serum levels increased from 37.2 to 68.6 nmol/L

with a significance of p<0.0001. No association was found between PANSS scores and vitamin D.

Although delayed recall scores significantly improved with association with Vitamin D level increases.3

Thus, Vitamin D levels do not appear to be associated with improvements in schizophrenic symptoms

although the study was short and does not account for a potential delayed effect due to supplementation.

Lastly, it is apparent that increased exposure to sunlight and vitamin D supplementation is associated with

increases in serum vitamin D levels in the studies mentioned, but does not appear to have direct and
 6

significant effects on psychosis.

Discussion

Although several studies have evaluated the effects of Vitamin D on the development, severity,

and treatment of schizophrenia, the effects are minimal and difficult to directly link to the nutrient in

focus. Furthermore, the trials are generally limited by the availability of compliant patients and the short

duration of the studies. The animal studies are also less relevant because they do not test human subjects

and therefore the effects may not translate to human subjects. Possible theories for the minimal

correlations between vitamin D and schizophrenia, are the anti-inflammatory effects of Vitamin D and

lack of it may lead to higher inflammation due to CRP.7 Furthermore, Vitamin D had many receptors in

the brain and a deficiency may lead to lack of signaling important for normal brain function. Another

connection may be the inability to sufficiently convert Vitamin D in the skin due to an unknown factor.

The inconclusive associations must be explored more deeply in order to reach a more definite conclusion.

Conclusion

In summation, the results from the studies explored in this paper are generally minimal and

associations are not strong enough to establish causation. Therefore, Vitamin D may be a safe and

beneficial supplement for those who are deficient but does not seem to directly correlate with major

improvements in PANSS scores or work as adjunct therapy for patients unresponsive to traditional

treatment. As far as application to practice, healthcare professionals should work with patients to help

them maintain normal Vitamin D levels regardless of the presence or absence of schizophrenia. But, since

the literature is limited and further studies are needed, professionals should not indicate that Vitamin D

deficiency is responsible for schizophrenia.

 7

References

1. Bogers, J P A M, Bostoen T, Broekman TG. Low levels of vitamin D poorly responsive to daylight

exposure in patients with therapy-resistant schizophrenia. Nord J Psychiatry. 2016;70(4):262-266.

2. Cieslak K, Feingold J, Antonius D, et al. Low vitamin D levels predict clinical features of

schizophrenia. Schizophr Res. 2014;159(2-3):543-545.

3. Krivoy A, Onn R, Vilner Y, 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.

4. Jamilian H, Bagherzadeh K, Nazeri Z, Hassanijirdehi M. Vitamin D, parathyroid hormone, serum

calcium and phosphorus in patients with schizophrenia and major depression. Int J Psychiatry Clin

Pract. 2013;17(1):30-34.

5. Nerhus M, Berg AO, Simonsen C, et al. Vitamin D deficiency associated with cognitive functioning

in psychotic disorders. J Clin Psychiatry. 2017;78(7):e757.

6. Kesby JP, Cui X, O'Loan J, McGrath JJ, Burne TH, Eyles DW. Developmental vitamin D deficiency

alters dopamine-mediated behaviors and dopamine transporter function in adult female rats.

Psychopharmacology (Berl). 2010;208(1):159-168.

7. Zhu DM, Liu Y, Zhang AG, et al. High levels of vitamin D in relation to reduced risk of schizophrenia

with elevated C-reactive protein. Psychiatry Res. 2015;228(3):565-570.

8