Örebro University School of Medicine Degree project, 30 ECTS 2016-01-07
Vitamin D levels in patients with psychosis: a marker of
burden of care?
Version 1
Author: Victor Szigeti, Bachelor of Medicine
Supervisor: Mats Humble, Consultant at the psychiatric department Region Örebro County
Co-supervisor: Susanne Bejerot Professor, Department of medical science and Michael Andresen, Consultant at the
1 Table of Contents
2 Abstract ... 2
3 Introduction ... 3
3.1 Vitamin D ... 3
3.2 Vitamin D and its role in CNS and development of the brain ... 3
3.3 Vitamin D and mental health ... 4
3.4 Psychiatric illnesses with psychosis ... 4
3.5 Vitamin D and psychosis ... 4
4 Material and method ... 5
4.1 Statistical analysis ... 7 4.2 Ethics ... 7 5 Results ... 7 5.1 Descriptive data ... 7 5.2 Inference ... 8 6 Discussion ... 11 7 Limitations ... 13 8 Conclusion ... 13 9 Acknowledgement ... 14 10 References ... 15 11 Appendix ... 17 Letter of intent ... 18 Ethical considerations ... 19 Press release ... 20
2 Abstract
Background: The interest in the correlation between vitamin D (25-OHD) and mental illness is a relatively new field in psychiatric research. Earlier studies have shown that the vitamin D status among psychiatric patients frequently meets the levels for insufficiency and deficiency. Patients with psychosis often need a lot of care because of their disease. These observations underlie the hypothesis that low serum levels of vitamin D in patients with psychosis correlates to high burden of care.
Method: Patients with ICD-10 “F2*”-diagnosis (schizophrenia, schizotypal disorder,
delusional, and other non-mood psychotic disorders F20-F29) were extracted from the access database and linked to vitamin D samples collected at Örebro University hospital. 83 patients, (33 females and 50 males) where included in the study. Medical record review was used to calculate length of patient stay measured by days as an in-patient one and two years prior to the sample was taken.
Results: 83 patients (88%) had vitamin D levels below what is considered as normal. No significant correlation between in-patient days and vitamin D levels was found. When analyzing the correlation between age and OHD levels in groups divided by gender, 25-OHD levels were lower among younger females (p=0.039).
Conclusion: The majority of the study population had vitamin D levels below reference level. However, a correlation between levels of vitamin D and in-patient days could not be found and thus are not a useful predictor of burden of care in this population.
3 Introduction
3.1 Vitamin D
Cholecalciferol (Vitamin D3) is produced in the epidermis when 7-dehydrocholesterol comes in contact with ultraviolet B light from the sun. Cholecalciferol is not the active form of vitamin D [1]. To become activated, vitamin D3 is metabolised in the liver, which activates vitamin D3 to 25-Hydroxycholecalciferol (25-hydroxy-vitamin D or calcidiol or 25-OHD). After being converted to 25-hydroxy-vitamin the kidneys processes 25-hydroxy-vitamin to its most active form 1,25-Dihydroxycholecalciferol (calcitriol). Vitamin D is stored in our body as the less active form calcidiol, levels of which indicate whether or not a person is sufficient in vitamin D. In addition to the cholecalciferol derived from the skin, we also get vitamin D3 from our food almost identical to that produced in the skin [1,2]. The traditional view of vitamin D is that its main purpose is to regulate the level of calcium and phosphate ions in our body by altering bone metabolism and absorption from the intestinal tract [2].However, increasing evidence suggests that vitamin D has a role in for example cell cycle regulation, stimulation of the immune system, reducing inflammation and affecting the brain structure [3,4].
Normal calcidiol levels have been defined as being between 69-99 nmol/l based on a healthy Swedish population [1]. Vitamin D insufficiency ranges from 25-50 nmol/l and vitamin D deficiency is defined as <25 nmol/l [5].
There are several studies that have shown a correlation between psychosis and ethnicity, especially when dark skinned people immigrate to countries of higher latitude [6-9].
These populations commonly have vitamin D insufficiency or even vitamin D deficiency [5-7]. Ottesen et al. demonstrated in their cross-sectional study that vitamin D deficiency is more common in immigrants with psychosis compared to non-immigrants [7].
3.2 Vitamin D and its role in CNS and development of the brain
Vitamin D has endocrine, paracrine and autocrine effects and acts by binding to its vitamin D receptor. The most active form of vitamin D (calcitriol) has a role in the metabolism of neurotransmitters such as dopamine, noradrenalin and acetylcholine, substances that are part of pathogenesis in psychiatric illness. Vitamin D also acts by enhancing nerve growth factor (NGF) and by affecting other neurotrophic factors [10-12]. Recent animal studies have shown that transient vitamin D deficiency during prenatal and natal period leads to changes in the
brain both structurally with permanent larger lateral ventricles and functionally by changed dopaminergic function [13,14].
3.3 Vitamin D and mental health
The interest in the relationship between vitamin D and mental illness is a relatively new field in psychiatric research [1,15]. For example, several studies have shown pertinence between affective disorders, schizophrenia, psychosis and vitamin D levels [5,10,16,17]. This interest has led to several questions, one of which being: could the prenatal and the early childhood levels of vitamin D predict the risk for children to develop psychosis later in life? [18-20]. The dopamine and glutamate hypotheses are two pathophysiological models of what may cause schizophrenia. The dopamine hypothesis assumes that dysregulation in dopaminergic (mesolimbic and mesocortical) pathways causes the classical symptoms in a schizophrenic patient [21,22]. There are studies that have found vitamin D3 receptors and 1-alpha
hydroxylase (that activates vitamin D) with highest presence in hypothalamus and in the large neurons (presumably dopaminergic) in the substantia nigra [23]. The glutamate hypothesis is a modification of the dopamine hypothesis and arose out of clinical observations that NMDA receptor antagonists (e.g. ketamine) can cause symptoms of schizophrenia in patients [24]. In my literature research I have not found any studies that connect vitamin D to the glutamate system.
3.4 Psychiatric illnesses with psychosis
Psychosis is characterized by a collection of symptoms such as hallucinations, delusions and incoherent speech. Examples of psychotic syndromes are schizophrenia, schizoaffective syndrome, delusional disorder, schizophreniform syndrome and substance-induced psychosis [25]. There are also disorders that mimic psychosis such as NMDA-receptor encephalitis. In this disorder antibodies are directed against N-methyl-D-aspartate-receptor (NMDA-receptor) [26,27].
3.5 Vitamin D and psychosis
Several studies in recent years have focused on exploring the association between psychosis and vitamin D levels [5,7,16]. Crews et al. implemented a case-control study where they studied vitamin D levels in first-episode psychosis patients. Crews et al. found that the levels of D-vitamin were significantly lower in cases compared to controls as, “vitamin D deficiency was present in 36.2% (n=25) of cases and 15.9% (n= 11) of controls”. Crews et al. did also investigate if vitamin D levels correlated to in-patient days. Vitamin D samples were taken
when the patients were admitted to the hospital with a first episode of psychosis. However, Crews et al. did not find such a correlation [5].
In a study of vitamin D deficiency among immigrants and Norwegians with psychosis compared with the general population, patients with psychosis had vitamin D deficiency in a higher proportion compared to the general population [7].
McGrath et al. implemented a Finnish birth cohort study based on earlier epidemiology and animal experiments. The study examined if vitamin D supplementation during the first year of life reduced the risk for schizophrenia later in life and results showed a reduced risk of
schizophrenia in males after supplementation [19].
These three studies are examples that indicate a correlation between patients with psychosis and low vitamin D levels and is the basis of the hypothesis that a low vitamin D level in patients with psychosis correlates with the burden of psychiatric healthcare. To calculate a patient’s burden of care, days of hospitalization within one year is a good estimation.
The hypothesis in this study is that low serum levels of vitamin D in patients with psychosis correlates to high burden of care.
The aim of this study is to investigate if blood concentrations of vitamin D in patients with psychosis can predict burden of care and in which extent vitamin D is tested among these patients.
4 Material and method
From InfoMedix, the patient administration system in use in Örebro County, we created data to an external Access database with support from Prodstat. The database was established September 9th 2015 and the tables included were diagnosis, the number of visits and
admission to the care facility during the period of January 1st 2008- December 31st 2013 (see attached file in appendix).
From the Access database we extracted all patients that had been diagnosed with an ICD-10 “F2*”-diagnosis (schizophrenia, schizotypal disorder, delusional, and other non-mood
psychotic disorders F20-F29) between January 1st 2008 and December 31st 2013 (see attached file). All the “F2-diagnoses” were linked to each patient´s personal code number.
The results from the database with F2-diagnoses were exported to an excel file where
duplicates were removed. In the next step we added all vitamin D samples (which we ordered from the chemical laboratory at Örebro University hospital) that have been taken in the psychiatric care between January 1st 2008 and December 31st 2013 to the same excel file. All the vitamin D samples were linked to the patient´s personal code numbers, thus both the F2-diagnoses and vitamin D levels had one common key (the personal code number). We used the excel function “COUNTIF” to calculate how many of the F2-diagnoses had a
corresponding vitamin D sample in the excel file instead of making this manually. At first we had about 1,500 patients with F2-diagnoses (which fulfilled the criteria) and 196 samples of vitamin D from all patients with a psychiatric diagnosis under the studied period. After we inserted these two variables in the excel file using the “COUNTIF” function, only 88 patients remained.
A further five patients were excluded from study after reviewing their medical records of which four were lost to follow up because of death and one patient did not fulfill the inclusion criteria of disease >2 years (see Flowchart).
The remaining 83 patients constituted the study group. The inclusion criterion was at least 2 years duration of a F2-diagnosis. Ethnicity of non-western origin was estimated from the patients´ surnames. Age and gender information were derived from the database. When patient records were read, the number of in-patient days of each patient one and two years prior to the vitamin D was noted.
4.1 Statistical analysis
Statistical analyses were made by using, Statistica. Analyses of in-patient days comparing males and females were made with the Mann-Whitney U Test. Correlations between vitamin D levels and in-patient days were made with the Spearman´s rank order correlation. T-tests were used when vitamin D levels in males and females and differences in age between genders were calculated.
4.2 Ethics
Ethical considerations to take into account in this project are that a medical student read the patient's psychiatric records, which might violate patient privacy. This project, however, aims to find relationships that can enhance the quality of mental health of psychotic patients, for example by increasing knowledge that can improve care practices to promote the health of psychiatric patients with psychotic illness in the long term.
This study is a quality assurance project and therefore ethical approval is not mandatory. Approval to carry out this work was obtained from the psychiatric manager at the Örebro University Hospital clinic.
5 Results
The results in this study is based on a group of 83 patients with ICD-10 “F2*”-diagnosis, (50 males and 33 females), aged 20-91 years. 10 patients were estimated to have a non-western ethnicity.
5.1 Descriptive data
Patients were divided into four groups depending on vitamin D serum levels: <25 nmol/L; 25-50 nmol/L; 25-50-75 nmol/L and >75 nmol/L. Thirteen (16%) patients had levels below 25
nmol/L, 38 (46%) patients had levels between 25-50 nmol/L, 22 (26%) had levels between 50-75 nmol/L and 10 (12%) patients had levels above >75 nmol/L. (See Figure 1)
88 (5,9%) of the 1500 patients with ICD-10 “F2*”-diagnosis had a vitamin D sample that was taken between the period January 1st 2008 and December 31st 2013.
Figure 1.
Figure 1 showing the vitamin D levels in the 83 patients. In the four bars the percentage in each group is calculated. <25 nmol/L is defined as deficiency and 25-50 nmol/L as insufficiency 50-75 nmol/L as below normal and >75 nmol/L is defined as a normal value.
5.2 Inference
In the year prior to when vitamin D levels were measured, male patients had a mean in-patient stay of 11.1 days and the females 17.6 days. Looking at the in-patient care 2 years prior to the vitamin D sample collection, males stayed at hospital 29.0 days and females 30.7 days. When comparing the number of in-patient days in males and females one and two years before the vitamin D level were taken, results were statistically insignificant (1 year before p= 0.985 and 2 years before p=0.911 shown in table 1).
0 5 10 15 20 25 30 35 40
<25 nmol/L (16%) 25-50 nmol/L (46%) 50-75 nmol/L (26%) >75 nmol/L (12%)
Number of patients
Table 1. Relationship between gender and 25-OHD levels, age and in-patient days in patients diagnosed with psychosis.
Female (Mean values) Male (Mean values) Associated values p-values Statistical method 25-OHD (nmol/L) 46.79 46.17 t-value= 0.130 0.898 T-test
Age (Years) 52.61 47.12 t-value=
1.637 0.105 T-test In-patient days/ 1 year (days) 17.58 11.14 Z= 0.019 0.985 Mann-Whitney U Test In-patient days/ 2 years (days) 30.73 29.04 Z= 0.112 0.911 Mann-Whitney U Test
The correlations between the 25-hydroxycholecalciferol and in-patient days 1 year and 2 years prior to vitamin D measurements were non-significant (1 year p=0.994 and 2 year p=0.382; Spearman´s rank order correlation) (see Figures 2 and 3).
Figure 2.
Figure 2 showing a scatterplot with the range of vitamin D levels (25-OHD, x-axis) and in-patient days (y-axis) one year prior to when the vitamin D sample was collected among the 83 patients.
Figure 3.
Figure 3 showing a scatterplot with the range of vitamin D levels (25,OHD, x-axis) and in-patient days (y-axis) two years prior to when the vitamin D sample was collected among the 83 patients.
Vitamin D levels were also analysed to detect differences between males and females.
However the mean levels of 25-hydroxy-vitamin D were almost equal between genders (46.79 nmol/L in females and 46.17 nmol/L in males, p=0.898). When comparing age and the levels of vitamin D in subgroups of males and females, vitamin D levels were significant lower among younger females p=0.039 but no age correlation was found in males p=0.679 (Figure 4). Also, there was no difference in age between males and females p=0.105.
Figure 4.
Figure 4 showing a scatterplot with the range of vitamin D levels (25-OHD, y-axis) and the age (x-axis) among the n=83 patients. Both females (blue spots) and males (red spots) are included in figure. The figure also displays p-values comparing age and vitamin D among the groups of males and females separately.
The levels of 25-hydroxycholecalciferol varies during the year with lower values in November, December January, February and Mars, this was visualized for this cohort in figure 5.
Figure 5.
Figure 5 showing the seasonal variation of vitamin D levels (25-OHD) from January-December. Vitamin D (y-axis) and month (x-axis)
6 Discussion
In this study we investigated if low vitamin D levels could indicate if patients with an ICD-10 “F2*”-diagnosis (schizophrenia, schizotypal disorder, delusional, and other non-mood
psychotic disorders F20-F29) have more in-patient days than a patient with normal vitamin D levels. However, this was not the case. We studied the number of in-patient days both one and two years prior to when the vitamin D sample was taken. When counting in-patient days in the medical record only 21 patients (25%) had one or more in-patient days one year prior to when vitamin D was taken and 33 patients (39%) two years prior to when vitamin D was assessed.
In this study we found that 88% of the patients with an ICD-10 “F2*”-diagnosis had vitamin D levels below what is normal, defined as 69-99 nmol/L in a healthy Swedish population [1]. The benchmarks in Swedish healthcare are values > 75 nmol/L. Our findings concur with several previous studies with similar populations [1,5,20,28]. One question that must be discussed is, why patients with diagnoses within the schizophrenia spectrum have lower values of vitamin D compared to the general population. It is unknown whether low levels of vitamin D are an expression of the lifestyle of those with psychosis that differ from the
Crews et al. found that vitamin D levels in patients with a first episode of psychosis were significantly lower compared to matched controls [5]. This observation indicates that
something else apart from just different lifestyle choices affects the 25-hydroxycholecalciferol levels among these patients. Excepting the previously mentioned observations, we must be open-minded in the future for still unknown contributory processes affecting vitamin D levels.
When we started the study consisted of 1,500 patient with ICD-10 “F2*”-diagnosis and 196 samples of vitamin D were the substrates. When we compiled the patients with ICD-10
“F2*”-diagnosis and vitamin D samples it turned out that only 88 patients (5,9%) where tested concerning their vitamin D status. This is an observation that indicates that the psychiatric care should be testing this group more often; several studies have shown that patients with psychosis often are at risk for low vitamin D level [1,5,20,28]. The explanation for the low number of vitamin D samples may be due to lack of knowledge of the connection between vitamin D and psychosis. This suggest that the information regarding the correlation of vitamin D and psychosis must be improved in psychiatric care such that vitamin D
substitution can be offered for this group of patients. Patients with psychosis are a disease stricken group not only because of their psychiatric disease; they are also suffering from somatic disease to a greater extent than the general population. Chang et al. found lower life expectancy among men with schizophrenia (14.6 years) and in females with schizoaffective disorders (17.5 years). Some of the contributory causes of lowering life expectancy were attributed to cardiovascular disease, diabetes and cancer [31]. Interestingly, Grandi et al. found an inverse association between low vitamin D and cardiovascular disease in their study [32]. Vitamin D has an important part in bone metabolism and patients with psychosis have increased risk for osteoporosis, low vitamin D among these patients is a related cause [5]. These findings suggest that low vitamin D should be observed and take a stand on in these patients.
Another observation in this study is that psychiatric patients with a foreign ethnicity seem to be tested less often than patients with a Swedish origin. Why there is a difference how
frequently vitamin D levels are tested in psychotic patients if they are of Swedish origin or of foreign ethnicity, is not clear. But this difference is problematic considering that there is a higher risk for psychosis when people of non-western descent move to Nordic climates [6,8].
very ill patients are out-patients in Sweden. Perhaps a better way to estimate burden of care would be the total number of contacts with psychiatric care during one year or the number of psychiatric medications the patient is prescribed. The identification of valid markers for burden of care is needed for future studies in this field.
7 Limitations
A limitation in this study is that this is a medical record review and the patients have not been questioned about if they have taken any vitamin D substitution. It is possible that the vitamin D values could be externally affected. On the other hand, it is possible that patients with psychosis may not realize that there might be a connection between vitamin D and their disease since it is a quite new field in psychiatry. Another limitation is that the vitamin D levels have not been adjusted for seasonal variation. Variation in levels of vitamin D depends on the season because the metabolism of cholesterol to vitamin D is dependent on sunlight and the sunlight is less prominent during the months associated with autumn and winter in Scandinavia [2]. Seasonal variation could be adjusted for by “multiplying individual values with the quotient between the mean of the year and the mean of the season” as Humble et al. did in their study [1]. In this study 25-OHD was not adjusted for season. The adjustment was not done because the p-values were far away from significant and it would only minutely affect the p-value.
8 Conclusion
People with an ICD-10 “F2*”-diagnosis have been found to have low vitamin D levels. Patients with psychosis need substantial resources from psychiatric care both structurally with help from a lot of different professions and economically [6,9]. This need can be
demonstrated by the fact that one of the observed patients in this study had 297 in-patient days in one year and another patient had 372 in-patient days in two years. Observations of low vitamin D levels in patients with psychosis and the high needs of care among the same
patients underlies the question of a correlation between vitamin D and burden of care, which was the basis for this study. When reviewing the medical records, it was obvious that the vitamin D levels and in-patient days were not correlated in this study, possibly because the vast majority of the patients were not treated as in-patients at all. This suggests that a better
way to define burden of care is warranted for future studies. The hypothesis that “low serum levels of vitamin D in patients with psychosis correlates to high burden of care” was not confirmed by this study.
9 Acknowledgement
I want to thank Sean Hoath a last year medical student at Glasgow University, and
neuroscience student Jonatan Nordmark at University College London for their help editing my paper concerning the English language. I also want to thank my supervisors for the support during the process of writing this paper.
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Letter of intent
Dec 12, 2015
Corresponding author: Victor Szigeti
Dept. of Psychiatry
Örebro University Hospital, Örebro, Sweden Email-address: vicszv111@studentmail.oru.se Dear Editor,
Attached is our paper titled Vitamin D levels in patients with psychosis: a marker of burden of care, we would be grateful if you would consider publishing our manuscript in BMC psychiatry.
This paper is generated from a retrospective cohort study of n=83 patients with ICD-10 “F2*”-diagnosis part of psychiatric care in Örebro region county. In the participants we observed levels of vitamin D and calculated in-patient days, both one and two years prior to vitamin D was measured. Our hypothesis was to see if low vitamin D correlated to higher number of in-patient days.
We found that 88% of the patients had vitamin D levels below what is normal. Vitamin D was only measured in 5,9 % of the patients. This study like similar studies- show high proportion of low vitamin D levels among the patients and that the total number of tested patients was low. This study could contribute to greater knowledge of the importance to test patients with psychosis concerning their vitamin D levels. No significant correlation between in-patient days and vitamin D levels was found.
The paper is original and none of it´s content has been published elsewhere. We hope to here from you as soon as possible.
Yours sincerely Victor Szigeti, Bachelor of Medicine
Ethical considerations
This study is a retrospective cohort study where an ethical consideration to take into account is that I need to read the patient's psychiatric records, which might violate the patient privacy. Before making a medical record review you often have to get access to confidential data that make it possible to identify a person. In my case I needed the patients personal code number belonging to patients with ICD-10 “F2*”-diagnosis (schizophrenia, schizotypal disorder, delusional, and other non-mood psychotic disorders F20-F29). When making a quality assurance project you have to handle the confidential data really careful because the study population has maybe not been informed of that they participate in a study.
After extracting the patients with “F2*”-diagnosis in our study 1500 patients where included. When having a large number of data it is important to be safety with the logistics and delete all the unnecessary data. Because of the large number of patients with “F2*”-diagnosis in our study, I only extracted the patients with “F2*”-diagnosis and a vitamin D sample from this file, then only 89 patients remained. I implemented this procedure at office of the psychiatric care and did save the information of the 89 patients on an USB memory. It is important to keep materials as the USB memory locked away when not using it.
Studies often involve help from several people which needed to take part of the process, it is important that people who comes in contact with confidential data have professional secrecy. Data including things like personal code number etc. should under no circumstances be emailed because of the risk to pass on data. When making a study it is important with an adequate aim so that money for research are used in the best way for the patients. This project aims to find relationships that can enhance the quality of mental health of psychotic patients, for example by increasing knowledge that can improve e.g. care practices to promote the health of psychiatric patients with psychotic illness in the long term.
Since this study is a quality assurance project ethical approval is not mandatory. I signed an agreement with the psychiatric manager at Örebro University Hospital clinic to hand in a handwritten report of the results after finishing the study.
Press release
Psykisk sjukdom är något som en stor del av individer i samhället idag kan relatera till på något sätt. Psykossjukdom är en sjukdom som hör till den psykiatriska vården och
karakteriseras av symtom som hallucinationer, vanföreställningar och osammanhängande tal. Ett exempel på syndrom som inkluderar psykos är schizofreni. Inom psykiatrisk forskning har man gjort observationer på patienter med psykossjukdom t.ex. att D-vitamin ofta ligger lågt. Detta har gjort att forskare velat titta närmare på D-vitaminets betydelse hos psykospatienter. I denna studie ville vi undersöka D-vitamin nivåerna i blodet hos patienter med
psykossjukdom. Efter att tagit ett blodprov där man ser D-vitamin nivån i blodet ville vi se om det fanns något samband mellan hur mycket en patient vårdas inneliggande (d.v.s. antalet vårddygn) på sjukhus pga. sin psykossjukdom och hur värdet av D-vitamin ligger. I denna studie var hypotesen att låga D-vitamin nivåer kommer korrelera med större behov av inneliggande vård. I studien undersöktes 83 patienter med psykossjukdom och som hade genomgått provtagning gällande D-vitamin nivåer i blodet. Efter att vi genomfört denna studie kom vi fram till att 88 % av patienterna hade D-vitaminvärden under vad som anses som normalt. Vi kunde däremot inte påvisa ett samband där ett lågt D-vitaminvärde korrelerade med mer inneliggande vårddygn på sjukhus.
