The prevalence of vitamin D deficiency and associated factors in first‐episode psychosis

Vitamin D deficiency is prevalent in people with established psychotic disorders, but less is known about vitamin D levels in people with first‐episode psychosis (FEP). This study aimed to determine the prevalence of vitamin D deficiency in people with FEP and identify the factors associated with vitamin D status.

Vitamin D deficiency is predominantly caused by poor exposure to sunlight, as well as insufficient dietary intake of vitamin D (Holick, 1995).
Vitamin D deficiency is linked to the development of a number of physical health comorbidities, including cardiovascular disease, autoimmune disease, osteoporosis, metabolic diseases and some cancers (Nowson et al., 2012).Individuals with a diagnosis of schizophrenia are more likely to have vitamin D deficiency (Valipour et al., 2014;Zhu et al., 2020), and there is also a small number of studies demonstrating that this is evident in those diagnosed with first-episode psychosis (FEP) (Cui et al., 2021;Firth et al., 2018).This is particularly concerning, given the increased rates of metabolic syndrome of people experiencing an FEP independent of antipsychotic exposure (Garrido-Torres et al., 2021).This risk is only further compounded by the use of antipsychotics, which are known to have significant metabolic side effects in this population (Pramyothin & Khaodhiar, 2010).
Furthermore, given the evidence that vitamin D may be involved in the aetiology of psychotic disorders (Albiñana et al., 2021) and the aforementioned high prevalence of vitamin D deficiency in FEP populations (Cui et al., 2021), it is worth investigating whether vitamin D is associated with clinical symptoms in this population.
There is currently a paucity of vitamin D research in people with minimal antipsychotic exposure (Tsiglopoulos et al., 2021).Therefore, in a population of young people with an FEP with minimal antipsychotic medication exposure, this study aims to determine (i) the prevalence of vitamin D insufficiency and deficiency; (ii) the demographic and clinical features associated with vitamin D deficiency.

| Design
This was a prospective cohort study nested within a randomized controlled trial, specifically the Physical Health Assistance in Early Recovery of Psychosis (PHAstER) study (O'Donoghue et al., 2020).

| Setting and participants
Young people, aged 15-24, receiving treatment for an FEP at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia, between August 2018 and December 2020 were eligible.
Participants had less than 4 weeks of exposure to antipsychotic medication and had measures of serum vitamin D levels at baseline.

| Instruments and measures
Levels of serum 25-hydroxyvitamin D were determined by chemiluminescence immunoassay using the DiaSorin LIAISON ® 25 OH Vitamin D TOTAL Assay.Vitamin D deficiency was classified as <30 nmol/L, insufficiency as 30-50 nmol/L and sufficiency as >50 nmol/L (Nowson et al., 2012).For analysis of the present study, participants were divided into two groups: those who were vitamin D deficient (<30 nmol/L) and those who were not vitamin D deficient (>30 nmol/L) General psychopathology was measured using the Brief Psychiatric Rating Scale (BPRS), an 18-item measure (Rhoades & Overall, 1988).A BPRS psychosis subscale was devised from the four items: hallucinations, unusual thought content, conceptual disorganization and suspiciousness and the depression item of the BPRS was used to assess depressive symptoms.Negative symptoms were evaluated using the Schedule for Assessment of Negative Symptoms (SANS) (Andreasen, 1989) and cognition was assessed using the digit span item of the WAIS III (Wechsler Adult Intelligence Scale), which is known to be a reliable method of assessing working memory (De Paula et al., 2016).The level of functioning was rated according to the Social and Occupational Functioning Assessment Scale (SOFAS).

| Statistical methods
Statistical analysis was performed using IBM SPSS 26.A significance level of p < .05 was set.T-tests were used to determine whether differences existed between parametric continuous variables and chi-square statistics were used to determine whether there was a difference between two or more categorical variables.Bivariate correlations between vitamin D and clinical symptoms were measured with Spearman's rho.

| Ethical approval and consent procedure
This study was approved by the Melbourne Health HREC (HREC/18/ MH/77).All participants provided written informed consent.

| Demographics and prevalence of vitamin D deficiency
A total of 37 young people were included, and they had a mean serum vitamin D of 47.2 nmol/L (SD = 16.4;range = 14-85 nmol/L).The demographic details of the participants can be found in Table 1, 24% (n = 9) were vitamin D deficient, 30% (n = 11) were insufficient and 46% (n = 17) had sufficient levels of vitamin D (Table 1).

| Association between vitamin D levels and demographic characteristics
There was no statistical difference in the demographic factors between those who were vitamin D deficient and those who were either vitamin D insufficient or sufficient.A total of 33.3% of males were deficient, compared to 16.7% of females ( p = .25).Of those young people who were born in Australia, 22.6% were vitamin D deficient, compared to 33.3% of those who were migrants ( p = .57).
There was a trend association between vitamin D and season of sampling, particularly vitamin D deficiency and winter months ( p = .068).There was no difference in substance use between groups.

| Association between vitamin D levels and clinical characteristics
Vitamin D levels were not correlated with positive symptoms (p = .42),general psychopathology (p = .17),negative symptoms (p = .39)or social and occupational functioning (p = .42)(Table 2).When examined according to the categories of vitamin D deficient and not deficient, there were no differences in relation to: positive symptoms (p = .88);general psychopathology (p = .23);negative symptoms (p = .52),cognitive symptoms (p = 0.69), depressive symptoms (p = .34)or social and occupational functioning (p = .86)(Table 3).
The analysis was repeated with just comparing the vitamin D deficient group to the sufficient group and there was a statistically significant association between vitamin D and season of sampling (χ 2 = 11.73,df = 3, p = .008).There were no other significant differences to the initial analysis (Table S1).

| Comparison to previous literature
In the young people with an FEP, the mean vitamin D level was lower and there was a higher proportion of either vitamin D insufficiency or deficiency compared to a representative sample of young adults in Australia (54% compared to 32%) (Horton-French et al., 2021).The high prevalence of vitamin D deficiency in the early stages of a psychotic disorder could be due to social withdrawal in the prodromal stage of a psychotic disorder, which could result in less outdoor sunlight exposure (Larson et al., 2010).Alternatively, the high prevalence of vitamin D deficiency could be involved in the aetiology of the disorder, as opposed to a consequence of it.This is supported by studies which demonstrate neurotransmitter alterations common to schizophrenia and impaired cognition in animals with vitamin D deficiency (Cui et al., 2021).
The relationship between ethnicity and low vitamin D in this population has been established in previous studies (Crews et al., 2013;Graham et al., 2015;Lally et al., 2019;Nerhus et al., 2015) and therefore the lack of an association with migrant status in this study needs to be interpreted with caution, due to the very small number of migrants.Overall, the present study supports the findings of a recent randomized control trial, which found no improvement in psychopathological symptoms after vitamin D supplementation in people with FEP (Gaughran et al., 2021).The present study also supports some of the findings of a recent systemic review, which found no association between vitamin D and positive and depressive symptoms in people with FEP (Tsiglopoulos et al., 2021).However, the review found vitamin D to be inversely associated with negative symptoms and positively associated cognitive performance (Tsiglopoulos et al., 2021).

| Clinical implications
The high prevalence of vitamin D insufficiency and deficiency in our study, which replicates previous findings, highlights that individuals affected by psychotic disorders may be subject to the long-term consequences of low vitamin D (Nowson et al., 2012).A meta-analysis T A B L E 1 Baseline demographic, clinical and physical health characteristics of study participants.found high levels of vitamin D to be associated with a 43% reduction in risk of cardiometabolic disorders, including cardiovascular disease, type 2 diabetes and metabolic syndrome (Parker et al., 2010).This is important given that vitamin D is inversely proportional to the risk of developing metabolic syndrome in young adults (Fung et al., 2012), which may compound the known susceptibility of people with psychosis to poor physical health outcomes (Morgan et al., 2014).Furthermore, a review of randomized controlled trials and meta-analyses found vitamin D to be protective against the development of musculoskeletal disorders, infectious diseases, autoimmune diseases, some cancers, and an association between vitamin D deficiency and allcause mortality (Pludowski et al., 2013).Although there is a risk of over-investigating vitamin D levels in people presenting with FEP, given the high prevalence of vitamin D deficiency in this population, the known long-term benefits of vitamin D sufficiency and recommendation of supplementation of vitamin D deficient individuals in the general population, assessment of vitamin D status in this population is warranted (Pludowski et al., 2018).It is important to supplement individuals affected by psychotic disorders who are vitamin D deficient and the general guidelines for deficiency should still be followed for this cohort.

| Strengths and limitations
There are several limitations to this study.First, the study lacks power due to the relatively small sample size, which may have led to type II errors.Second, the study lacked a control group and it was also unable to control for a number of potential confounders, including levels of physical activity and time spent outdoors.
Correlations between serum vitamin D and clinical symptoms in study sample.
T A B L E 3 Comparison of demographic and clinical characteristics according to vitamin D status.Brief Psychiatric Rating Scale; SANS, Scale for the Assessment of Negative Symptoms, SOFAS, Social and Occupational Functioning Assessment Scale.
a Data available for 36 participants.b Data available for 35 participants.c Data available for 31 participants.d Data available for 14 participants.