The association between vitamin D and symptom domains in psychotic disorders: A systematic review
Introduction
Psychotic disorders have a complex aetiology involving genetic, environmental and social factors interacting during critical periods of neurodevelopment (Davis et al., 2016). The individual effect of environmental factors on the development of a psychotic disorder is significantly amplified when such factors act in concert at key neurodevelopmental milestones in genetically susceptible individuals (Davis et al., 2016). One such factor that has gained attention in the literature is developmental vitamin D. Developmental vitamin D deficiency was first implicated as a potential risk factor for schizophrenia based on epidemiological findings (McGrath et al., 2010). Initially, it was noticed that migrants and individuals born in winter-spring months have an increased incidence of schizophrenia (Ödegaard, 1932; Torrey, 1977). Since then, studies have supported these preliminary findings (O'Donoghue et al., 2020) and showed an increased incidence of psychosis in people residing at higher latitudes (Kinney et al., 2009; Saha et al., 2006), people with early life urban residence (Vassos et al., 2012) and in ethnic groups with dark coloured skin (Davis et al., 2016) – all factors that have been associated with low vitamin D (Holick, 1995). These findings paved the way for analytical epidemiological studies, which have since demonstrated a causal relationship between neonatal vitamin D and schizophrenia using repositories of dried neonatal blood spots (Cui et al., 2021). Most recently, a study found that neonates who were vitamin D deficient had a 44% increased risk of developing schizophrenia (Eyles et al., 2018).
There is a biologically plausible mechanism for the involvement of vitamin D in the aetiology and progression of psychotic disorders. Apart from its role in calcium homeostasis, vitamin D also acts as a neuroprotective secosteroid hormone involved in neurotransmitter expression and neurodevelopment (Cui et al., 2021). It has also been observed that brain alterations commonly seen in schizophrenia, including enlarged lateral ventricles and thinning of the cortex, were found in offspring of vitamin D deficient rodents (Eyles et al., 2013). Furthermore, the offspring of such rodents demonstrated specific endophenotypes and behaviours common to schizophrenia (Schoenrock and Tarantino, 2016). It is hypothesised that such changes are due to the interaction between vitamin D and dopamine neurons in the developing brain (Cui et al., 2021). Vitamin D deficiency is also associated with regions of the brain involved in the pathogenesis of psychotic disorders, including dysfunction of the hippocampus (Shivakumar et al., 2015), as well as with the levels of certain inflammatory markers found in chronic psychotic disorders (Chiang et al., 2016). Furthermore, preclinical studies have indicated that adult vitamin D deficiency may further impair cognitive function through its interactions with excitatory and inhibitory neurocircuits (Cui et al., 2021). Such findings suggest that postnatal vitamin D deficiency may also be an important risk factor in the progression of psychotic disorders, as well as in their aetiology.
The abovementioned associations suggest that vitamin D could be involved in the clinical presentation of psychotic disorders, and the correlation has been implicated in meta-analysis (Cui et al., 2021; Valipour et al., 2014; Zhu et al., 2020). Most recently, Cui et al. (2021) confirmed the findings of earlier meta-analyses that people with psychosis have an increased risk of vitamin D deficiency. The meta-analysis also replicates the finding by Firth et al. (2018) that the association exists as early as first onset of a psychotic disorder. The latter study investigated the relationship between FEP and a range of nutritional deficiencies – including vitamin D – and found worse mental health outcomes in people with low vitamin D in three studies (Firth et al., 2018). In terms of symptom associations, a systematic review assessed correlates of vitamin D in psychotic disorders and found no significant association between vitamin D and clinical symptoms (Adamson et al., 2017). However, a wide range of clinical and demographic correlates were examined in the review, such as age, gender, duration of illness, and only three of the included studies assessed the relationship between vitamin D and symptom domains of a psychotic disorder.
Vitamin D is a safe, cheap and well tolerated intervention that could form part of a primary prevention strategy for psychotic disorders. McGrath et al. (2010) argues that given the accessibility of vitamin D, the significant burden of disability associated with psychosis and the accumulating evidence linking vitamin D to psychotic disorders, further research in this field is warranted (McGrath, 2010).
The association between vitamin D and symptoms of psychotic disorders has not been reviewed independently. Hence, the aim of the present study was to conduct a systematic review of studies of the association between vitamin D and the symptom domains (positive and negative psychotic symptoms, total and general psychopathology, cognitive and depressive) of people with first-episode and enduring psychosis.
Section snippets
Methods
The systematic review was submitted to PROSPERO for registration on 3 March 2020 (ID CRD42020171759). There was a delay in registration due to the preferential registration of COVID-19-related registrations, and we initiated the review before registration was finalised. The registration record was eventually published by PROSPERO exactly as submitted.
Studies identified
In the initial search 1748 studies were identified. This was reduced to 1040 after 708 duplicates were removed. Following screening of titles and abstracts, 983 articles were excluded, leaving 59 articles for full-text screening. After full-text screening, 29 articles were eligible for inclusion (Fig. 1).
Results
The associations between vitamin D and clinical symptoms in people with psychosis are presented as the following five domains: negative symptoms, positive symptoms, total psychopathology and
Summary of evidence
The findings in both observational studies and interventional studies were heterogeneous for most of the outcomes assessed. Many of the included observational studies found an inverse association between vitamin D and negative psychotic symptoms (57%; 13/23); and that vitamin D was positively associated with cognitive performance and inversely associated with cognitive symptoms (63%; 5/8), although some significant findings were lost after controlling for other factors. No association between
Conclusion
This review, the first to specifically address the relationship between vitamin D and symptom domains of a psychotic disorder, lends support to the hypothesis that low levels of vitamin D are associated with more severe psychotic symptoms in some symptom domains, in particular negative psychotic symptoms and cognitive functioning. The association is complicated by heterogeneity between studies, and the inability to assert causality due to the observational study design of most included
CRediT authorship contribution statement
Jonathan Tsiglopoulos wrote the review and prepared the manuscript. Brian O'Donoghue was involved in the concept and review of the systematic review. Jonathan Tsiglopoulos, Nicholas Pearson and Brian O'Donoghue were involved in the screening process of the articles included. Nathan Mifsud and Kelly Allott revised the systematic review.
Role of funding source
No funding was received for this study.
Declaration of competing interest
None to declare.
Acknowledgements
None to declare.
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