Hindawi

Psychiatry Journal
Volume 2019, Article ID 7839287, 7 pages
https://doi.org/10.1155/2019/7839287

Research Article
Symptomatic Correlates of Vitamin D Deficiency in
First-Episode Psychosis

1
Ricardo Coentre and Inês Canelas da Silva2
1
Department of Psychiatry, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE/Faculdade de Medicina,
Universidade de Lisboa, Lisboa, Portugal
2
Department of Psychiatry, Hospital Vila Franca de Xira, Vila Franca de Xira, Portugal

Correspondence should be addressed to Ricardo Coentre; [email protected]

Received 21 November 2018; Revised 14 March 2019; Accepted 7 April 2019; Published 2 May 2019

Academic Editor: Luca Ferraro

Copyright © 2019 Ricardo Coentre and Inês Canelas da Silva. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Previous studies indicate that low levels of vitamin D are associated with increased severity of psychiatric symptoms in chronic
multiepisode psychosis (MEP). We aimed to compare vitamin D levels between first-episode psychosis (FEP) and MEP and to
investigate the correlations between vitamin D levels and symptoms in FEP patients. The participants were adults aged 18-45 years
who presented with affective and non-affective FEP to an early intervention team in Portugal. Depression was assessed using the
Beck Depression Inventory, and positive and negative symptoms and general psychopathology were measured with the Positive and
Negative Syndrome Scale. Blood samples were analyzed for 25-hydroxyvitamin D (25OHD). Thirty-three patients completed the
study in the FEP group and 33 in the MEP group. FEP patients had low levels of 25OHD (18.16 ± 7.48 ng/mL), with no significant
differences from MEP patients. Low 25OHD was significantly correlated with high severities of depressive (r=-0.484, p=0.004)
and negative (r=-0.480, p=0.005) symptoms as well as general psychopathology (r=-0.569, p=0.001) in FEP patients. Multiple
regression revealed an inverse association between general psychopathology and vitamin D level (p=0.027). More investigation
of the association of vitamin D and schizophrenia is needed, namely, using a nonpatient control group and trying to clarify possible
causality between vitamin D and psychiatric symptoms.

1. Introduction 1,25(OH)2D are transported in the circulation by vitamin

D-binding protein, which is a water-soluble carrier protein.
Vitamin D deficiency is traditionally associated with mus- Only 1% of the metabolites bind weakly to albumin to freely
culoskeletal consequences [1]. In recent years vitamin D has circulate in the bloodstream, and it is the free fraction of the
been associated with psychiatric disorders [2]. hormone that is the biologically active component [7].
Vitamin D is primarily produced by skin exposure to Vitamin D levels in the general population are higher
ultraviolet B sunlight with diet contributing with a small in men than in women, they decrease with increasing age
percentage (a maximum of 20%) [3]. Vitamin D levels vary [8], and because vitamin D is fat soluble and stored in
seasonally with lower levels occurring during the late winter adipose tissue, those with obesity have lower circulating
and early spring that reflect the levels of ambient sunlight [4]. levels [9]. There is also a relationship between low levels
People with pigmented skin need more sunlight to produce of vitamin D and tobacco [10], because tobacco increases
vitamin D, and lower levels of vitamin D are observed in hepatic cytochrome enzyme activity and consequently alters
Black and Asian populations [5]. Serum 25-hydroxyvitamin vitamin D metabolism [11].
D (25OHD) is considered the optimal vitamin D status Vitamin D is involved in several brain processes, includ-
indicator [6], and its hydroxylation in the kidneys pro- ing neurodevelopment, neurotrophic activities, and growth
duces 1,25-dihydroxyvitamin D (1,25(OH)2D), which is the factor regulation, and vitamin D also has a neuroprotective
active metabolite. Approximately 85-90% of 25OHD and role [12]. Several studies have suggested that vitamin D levels
2 Psychiatry Journal

are related to the development of psychosis [2]; namely, substance abuse or dependence, organic psychosis, presence
a correlation between low early life vitamin D levels and of major medical/neurological disease, and an inability to
schizophrenia has been suggested [13, 14]. There is also understand and complete the assessments.
evidence of increased prevalence of schizophrenia in urban The subjects were provided full information about the
environments, among dark-skinned migrants, among those nature and purpose of the study and were informed of the
with winter births and those at higher latitudes [15, 16]. It has possibility of terminating their participation at any time.
been hypothesized that vitamin D could be responsible for This study was conducted in accordance with the ethical
these results [15]. Vitamin D deficiency could be a modifiable principles contained in the Declaration of Helsinki. The
risk factor for psychotic disorders. Published studies have research protocol was approved by Hospital Vila Franca de
mainly included patients with established and chronic psy- Xira Ethics Committee, and written informed consent was
chotic disorders and populations living at high latitudes with obtained from all participants.
significant seasonal periods [2]. Few studies exist regarding
the early phases of psychosis and involving those living 2.2. Methods. At program entry, a trained consultant psy-
in low/medium latitude countries. Indeed, the published chiatrist collected detailed sociodemographic and clinical
research does not clarify the main question: is vitamin D data as part of the initial routine clinical care of FEP
deficiency the cause and/or consequence of psychosis [17]? patients. The clinical data included the duration of untreated
Several studies have demonstrated an inverse correla- psychosis (DUP), depressive symptoms, positive symptoms,
tion between vitamin D levels and positive, negative and negative symptoms, general psychopathology, and adherence
depressive symptoms in chronic psychosis [17, 18]. Few to medication.
studies have researched vitamin D in first-episode psychosis The duration of untreated psychosis was determined
(FEP) patients [19–23]. Only two studies have evaluated the using the Nottingham Onset Schedule (NOS) [25] and
association between vitamin D and symptoms in FEP. In was defined as the period of time from the onset of
Singapore, Yee et al. (2016) found an association between psychotic symptoms to treatment with antipsychotic med-
low levels of bioavailable vitamin D and negative symptoms ication. The diagnoses were established using the Opera-
in FEP patients [23]. Additionally, in North Carolina, USA, tional Criteria Checklist for Psychotic Illness and Affective
Graham et al. (2015) found that a greater severity of negative Illness (OPCRIT+) [25, 26]. The OPCRIT+ is a checklist
symptoms was correlated with lower vitamin D status in first- that includes items related to psychiatric history and psy-
episode schizophrenia patients [20]. Also, some published chopathology. The checklist ratings are entered into the
studies indicate that anticonvulsant medication could have a OPCRIT+ software, which generates a diagnosis for the main
negative effect on vitamin D levels [24]. categories of affective and psychotic disorders as defined
The aims of the present study were as follows: (1) to according to major classification systems including the DSM-
investigate vitamin D levels in affective and non-affective FEP IV. The OPCRIT+ has been demonstrated to have good
in a medium latitude country (40∘ N) that provides significant reliability when used by different raters. The rater was an
sunlight exposure during the entire year, (2) to compare experienced consultant psychiatrist who was trained in the
vitamin D levels in FEP subjects with those in chronic use of the OPCRIT+.
multiepisode psychosis (MEP) subjects, and (3) to examine Positive and negative symptoms and general
the relationship between vitamin D levels and symptom psychopathology were assessed with the Positive and
severity (positive, negative, and depressive symptoms and Negative Syndrome Scale (PANSS) [27]. This scale is
general psychopathology) in FEP. We hypothesized that FEP composed of three subscales that evaluate positive symptoms,
patients would have low levels of vitamin D that do not differ negative symptoms, and general psychopathology in
from those in MEP patients, which would reflect the early schizophrenia. Each item is scored from 1 (absent) to 7
presence of vitamin D deficiency in psychotic disorders. We (extreme). The positive subscale includes 7 items about
also hypothesized that FEP patients would exhibit negative positive symptoms (e.g., delusions, hallucinatory behavior,
correlations of vitamin D with general, negative, and depres- and hostility), and the total score varies between 7 and 49.
sive symptoms similar to the results that have been found in The negative subscale includes items related to negative
previous studies of MEP. symptoms (e.g., blunted affect, poor rapport, or difficulty in
abstract thinking), and the total score varies between 7 and
2. Material and Methods 49. The general psychopathology subscale includes a variety
of items related to psychopathology other than positive and
2.1. Subjects. All participants were part of a larger prospective negative symptoms, including anxiety, depression, somatic
study of FEP at the First-Episode Psychosis Program (PPEP) concern, lack of judgment and insight, and poor impulse
in Vila Franca de Xira, Portugal. The PPEP is a special- control. The total score for the general psychopathology
ized early intervention program that provides medical and subscale varies between 16 and 112.
psychosocial treatment and follow-up for affective and non- Depressive symptoms were evaluated with the Beck
affective FEP patients to a catchment area with a population of Depression Inventory (BDI) [28]. This instrument is a 21-
245,000. Patients aged 18 to 45 from the local catchment area question, multiple-choice, and self-report inventory that is
who were consecutively admitted between January 2016 and used to evaluate the incidence and severity of depression
March 2017 were eligible for participation in the study. The symptoms with a total score between 0 and 63. The version
exclusion criteria were the following: a primary diagnosis of of the BDI scale that had been translated into the Portuguese
Psychiatry Journal 3

language and validated for the Portuguese population was with antipsychotic alone, 6 (18.18%) with antipsychotic
used [28, 29]. To examine attitude and adherence behavior plus antidepressant, and 2 (6.06%) with mood stabi-
towards antipsychotic treatment, the Medication Adherence lizer/anticonvulsivant plus antipsychotic. There was no evi-
Rating Scale (MARS) was applied [30]. This scale has 10 dence of the effect of medication on vitamin D levels,
yes or no questions about medication and behavior toward including anticonvulsivant medication. Only two patients on
medication and results in a total score that ranges from 0 FEP group (mean vitamin D level 14.45 ng/mL) and four
to 10; higher scores indicate better adherence. The Global on MEP group (mean vitamin D level: 20.95 ng/mL) were
Assessment of Functioning Scale (GAF) was used to evaluate prescribed anticonvulsants, all with valproic acid.
general functioning [31]. The GAF subjectively evaluates
social, occupational, and psychological functioning, and the 3.2. Correlation Analysis. The 25OHD level was inversely
final score ranges from 1 (severely impaired) to 100 (extremely correlated with negative symptom (r=-0.480, p=0.005) and
high functioning). general psychopathology (r=-0.569, p=0.001) scores on
Blood collection was performed between 8.00 and 9.00 the PANSS and with the depressive symptom (r=-0.484,
am upon entry to the study. Blood was withdrawn by p=0.004) scores as evaluated with the BDI in the FEP group.
venipuncture into tubes containing SST for the collection of No correlation was found between 25OHD level and positive
the serum. The optimal vitamin D status indicator, i.e., 25- symptoms (Table 2) in the FEP sample. Also, no significant
hydroxyvitamin D (25OHD), was obtained by chemilumi- correlations were found between vitamin D levels and DUP,
nescent immunoassay. The 25OHD levels were classified as MARS, and GAF scores. Multiple linear regression analysis
sufficient if the value was ≥30 ng/mL and insufficient if the examining the associations of positive, negative, general
value was <30 ng/mL. psychopathology, and depressive symptoms (independent
variables) with 25-hydroxyvitamin D (dependent variable)
2.3. Statistical Analysis. The data were analyzed using IBM revealed an inverse correlation with general psychopathology
SPSS Statistics version 24. The descriptive statistics are (p=0.027).
reported as the means and standard deviations for continuous
measurements and as the frequencies and proportions for cat- 4. Discussion
egorical measurements. Demographic and clinical variables
were compared between groups with independent Student’s This study examined vitamin D levels in minimally treated
t-tests or chi-squared tests (or Fisher’s exact tests) for con- FEP patients in comparison with MEP in a medium lat-
tinuous and categorical variables, respectively. Correlation itude country. We also assessed the clinical symptoms in
analyses were performed with Pearson correlation coeffi- FEP and the correlations of vitamin D concentrations with
cients. The Kolmogorov-Smirnov test was used to confirm positive, negative, and depressive symptoms and general
the normal distributions of the variables. Multiple linear psychopathology. Our main findings were the following:
regression was used to assess the relationships between the (1) we found no significant difference in vitamin D levels
independent variables (the depressive, positive, and negative between the FEP and MEP samples; (2) even in a country with
symptoms and general psychopathology) and the dependent a significant exposure to sunlight, both the FEP and MEP
variable (25-hydroxyvitamin D). Clinical assessments were groups exhibited low levels of vitamin D; and (3) vitamin D
performed on the same day as blood sampling. All evalua- levels were inversely correlated with general psychopathology
tions were performed when the clinical picture of FEP had in FEP.
sufficient stability to warrant collaboration by the patient. A To our knowledge, only two other studies have examined
p value <0.05 was considered to be statistically significant. the correlation between vitamin D and psychotic and/or
affective symptoms in FEP. Graham et al. (2015) found that
3. Results greater severities of negative symptoms are correlated with
lower vitamin D levels but not with depressive or overall
3.1. Comparison of the Demographics and Vitamin D Levels symptoms in first-episode schizophrenia patients in North
between the Samples. Overall, 33 patients with FEP and 33 Carolina, USA [20]. There was no significant difference in the
patients with MEP were enrolled. Only 1 patient in FEP group mean vitamin D level between patients with schizophrenia
was excluded because the diagnosis of organic psychosis and healthy controls [20]. More recently, Yee et al. (2016)
was made. Descriptions of the participants and comparisons found an association between low bioavailable vitamin D and
between the two groups are summarized in Table 1. There negative symptoms in FEP in Singapore [23]. We did not
were no significant differences in gender, ethnicity, tobacco find correlations in the multiple linear regression between
use, diagnoses, body mass index (BMI), or blood collection vitamin D and negative symptoms as reported in these two
season between the two groups. previously mentioned studies. It is possible that our results
As expected, the FEP sample was significantly younger were limited by the lower levels of vitamin D compared
than the MEP sample (mean 31.21 vs. 41.15 years; p<0.001). with those observed in the study published by Graham and
The mean vitamin D levels were similar between the two colleagues [20].
groups (mean 18.16 ± 7.48 ng/mL for the FEP group Moreover, studies of chronic schizophrenia patients
and 16.20 ± 11.29 ng/mL for the MEP group; p=0.409). revealed associations of vitamin D with depressive and nega-
On the FEP group, 25 (75.75%) patients were medicated tive symptoms. Positive associations of low levels of vitamin
4 Psychiatry Journal

Table 1: Demographic and clinical characteristics of the study samples.

FEP (n=33) MEP (n=33) P

Age (years), mean (SD) 31.21 (10.03) 41.15 (9.88) <0.001†
Gender, n (%)
Male 23 (69.70%) 23 (69.70%) 1.000‡
Female 10 (69.30%) 10 (69.30%)
Ethnicity, n (%)
White 32 (96.97%) 32 (96.97%) 1.000‡
Black 1 (3.03%) 1 (3.03%)
Education (years), mean (SD) 10.28 (3.40)
Marital status, n (%)
Single/divorced 7 (21.21%) 7 (21.21%) 1.000‡
Married/partner 26 (78.78%) 26 (78.78%)
Blood collection season, n (%)
Summer season 16 (48.48%) 11 (33.33%) 0.211‡
Winter season 17 (51.51%) 22 (66.66%)
Tobacco, n (%)
Yes 14 (42.42%) 19 (57.57%) 0.218‡
No 19 (57.57%) 14 (42.42%)
Weight (kg), mean (SD) 70.86 (14.37) 74.86 (14.11) 0.257†
BMI (kg/m2), mean (SD) 23.85 (4.12) 25.08 (3.92) 0.221†
Diagnosis, n (%)
Schizophrenia 12 (36.36%) 19 (57.58%) 0.148§
Delusional disorder 5 (15.15%) 2 (6.06%)
Psychosis NOS 7 (21.21%) 1 (3.03%)
Bipolar disorder 2 (6.06%) 4 (12.12%)
Psychotic depression 4 (12.12%) 2 (6.06%)
Cannabis induced psychosis 2 (6.06%) 3 (9.09%)
Schizo-affective disorder 1 (3.03%) 2 (6.06%)
Cannabis use, n (%)
Yes 6 (18.18%)
Duration of untreated psychosis (DUP) (days), mean (SD) 450.54 (952.64)
Global Assessment Functioning (GAF), mean (SD) 59.21 (9.44)
Medication Adherence Rating Scale (MARS), Mean (SD) 6.40 (2.14)
Depressive symptom score (BDI), Mean (SD) 12.42 (9.10)
Positive symptom subscale score (PANSS), Mean (SD) 12.84 (3.57)
Negative symptom subscale score (PANSS), Mean (SD) 16.09 (7.27)
General psychopathology subscale score (PANSS), Mean (SD) 31.59 (7.43)
†
Student’s t-test
‡
Chi-squared test
§
Fisher’s exact test

Table 2: Correlations between vitamin D levels and clinical variables in first-episode psychosis.

25-Hydroxyvitamin D
Simple Multiple
correlation linear regression
r P ß P
Positive Symptoms -0.165 0.358 0.045 0.793
Negative symptoms -0.480 0.005∗ -0.269 0.178
General psychopathology -0.569 0.001∗ -0.538 0.027∗∗
Depressive symptoms -0.484 0.004∗ 0.225 0.257
∗significant at p<0.01; ∗∗significant at p<0.05.
Psychiatry Journal 5

D with negative [17, 18, 31, 32] and depressive symptoms [18] a randomized open-label trial that includes patients with
have been found in chronic psychotic patients, particularly schizophrenia and schizo-affective disorder and low levels of
those with schizophrenia. vitamin D (<30 ng/mL) who will be treated with vitamin D
The results of our research demonstrate that vitamin D supplementation. Unfortunately, there is no ongoing trial that
deficiency is present in psychotic disorders even in the early includes first-episode psychosis patients. Currently, there is
phases of the disorder and in countries with regular sunlight not sufficient evidence to support vitamin D screening and
exposure throughout the year. The main question persists: supplementation for psychotic patients.
is vitamin D deficiency the cause and/or consequence of Several limitations of our study exist. First, the relatively
the psychotic disorder? Our results indicate that vitamin D small sample size could limit the generalization of the data,
could have an etiological role in some psychopathological even though our sample is larger than those of previously
symptoms of psychosis, and thus its deficiency is present published papers in this field of knowledge. Second, the cross-
in the early stages of the disorder. For example, due to sectional design precludes the ability to provide evidence of
the neuroprotective function of vitamin D that prevents a causal relationship between low levels of vitamin D and
oxidative stress in the central nervous system, there is a symptoms in FEP. Third, we did not control for confounding
hypothesis that suggests that oxidative stress resulting from factors (e.g., daily calcium intake or sun exposure), which
vitamin D deficiency causes negative symptoms due to an might have influenced our findings. Fourth, the self-report
imbalance in glutamate-GABA responses [33, 34]. Vitamin nature of some of the scales and data, namely, the socially
D is also associated with depression because it is a regulator undesirable behaviors, such as cannabis use or tobacco smok-
of serotonin synthesis [35]. In the current research, we only ing, may be subject to reporting bias. Moreover, the informa-
found a negative correlation between vitamin D status and tion regarding the self-reported psychiatric symptoms (e.g.,
the general psychopathology subscale of the PANSS. This depressive symptoms) may not have been accurate. Fifth,
subscale includes a variety of psychiatric symptoms, such as we did not include a healthy control group, which would
depressive, anxious, and physical symptoms. Contrary to the have helped to differentiate whether low levels of vitamin
previously mentioned studies, we did not find any significant D are mainly found in patients with psychiatric disorders
correlation between vitamin D and negative symptoms in or if they are also found in the general population. Sixth,
FEP. Independently of the type of symptoms found to be asso- the generalization of our findings to countries of different
ciated, vitamin D deficiency has been found to be associated latitudes and consequently different levels of sun exposure
with severe psychiatric symptoms in all studies, including and different vitamin D levels must be performed cautiously.
ours. Some authors also speculate that patient behaviors that
result from negative symptoms and are present in all phases
of the disorder, including the prodrome, originate from long 5. Conclusion
periods of time spent indoors without sunlight exposure that
In conclusion, there is evidence demonstrating that there
result in low levels of vitamin D [36].
are low levels of vitamin D in psychotic disorders begin-
Recently a published article from Eyles and colleagues
ning in the early stages and that vitamin D could have a
studied the association between neonatal vitamin D status
pathophysiological role in psychosis. The results of research,
and risk of schizophrenia in a large Danish case-control study,
including ours, demonstrate the correlation between low
including 2602 neonates [37]. Results showed that those in
levels of vitamin D and high severity of psychiatric symptoms
the lowest quintile (<20.4noml/L) had an increased risk of
in all stages of psychotic disorders. There are ongoing trials
schizophrenia. This is an argument in line with the neu-
that are evaluating vitamin D as a possible adjuvant treatment
rodevelopment hypothesis of schizophrenia, where vitamin
in chronic multiepisode psychotic patients with low levels of
D deficiency in early phases of life could also represent a risk
vitamin D. In the future, these trials should also include first-
factor for schizophrenia later.
episode psychosis patients.
Research indicates the existence of a preliminary evidence
that certain vitamin and mineral supplements may reduce
psychiatry symptoms in some people with schizophrenia Data Availability
[38]. This includes vitamin B supplementation, but not
vitamin D yet. Based in our results, vitamin D deficiency The SPSS data used to support the findings of this study are
could represent a modifiable factor of psychopathology in available from the corresponding author upon request.
psychosis and could condition the clinical picture. Vitamin D
as an add-on treatment could be recommended for patients
with low levels. Evidence in favor of this treatment might Disclosure
soon be provided by the final results of the two trials (Clin-
All costs relating to the completion of this study were covered
icalTrials.gov Identifiers: NTC01759485 and NCT01169142).
by personal funds from both authors.
One is a randomized, double blind placebo-controlled trial
of which the main objective is to evaluate the effect of
vitamin D supplementation on the mental states of clozapine- Conflicts of Interest
treated patients with chronic schizophrenia and vitamin
D deficiency (20-30 ng/mL) and the relation of disease The authors declare that there are no conflicts of interest
severity with serum vitamin D level. The second study is regarding the publication of this paper.
6 Psychiatry Journal

Acknowledgments [16] J. J. McGrath, “The surprisingly rich contours of schizophrenia

epidemiology,” Archives of General Psychiatry, vol. 64, no. 1, pp.
The authors are grateful for the collaboration of Dr. Luis Silva, 14–16, 2007.
Director of the Pathology Department of the Hospital Vila [17] R. N. Yüksel, N. Altunsoy, B. Tikir et al., “Correlation between
Franca de Xira, for his contribution to this research project. total vitamin D levels and psychotic psychopathology in
patients with schizophrenia: therapeutic implications for add-
on vitamin D augmentation,” Therapeutic Advances in Psy-
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