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Vitamin D and schizophrenia: 20 years on - PubMed

Review

Vitamin D and schizophrenia: 20 years on

Xiaoying Cui et al. Mol Psychiatry. 2021 Jul.

Abstract

Many epidemiological studies have highlighted the link between vitamin D deficiency and schizophrenia. In particular, two prominent studies report an association between neonatal vitamin D deficiency and an increased risk of schizophrenia. In parallel, much has been learnt about the role of vitamin D in the developing central nervous system over the last two decades. Studies in rodent models of developmental vitamin D (DVD)-deficiency describe how brain development is altered leading to a range of neurobiological and behavioral phenotypes of interest to schizophrenia. While glutamate and gamma aminobutyric acid (GABA) systems have been little investigated in these models, alterations in developing dopamine systems are frequently reported. There have been far more studies reporting patients with schizophrenia have an increased risk of vitamin D deficiency compared to well controls. Here we have conducted a systematic review and meta-analysis that basically confirms this association and extends this to first-episode psychosis. However, patients with schizophrenia also have poorer general health, poorer diets, are frequently less active and also have an increased risk of other medical conditions, all factors which reduce circulating vitamin D levels. Therefore, we would urge caution in any causal interpretation of this association. We also summarize the inconsistent results from existing vitamin D supplementation trials in patients with schizophrenia. In respect to animal models of adult vitamin D deficiency, such exposures produce subtle neurochemical alterations and effects on cognition but do not appear to produce behavioral phenotypes of relevance to schizophrenia. We conclude, the hypothesis that vitamin D deficiency during early life may increase the risk of schizophrenia remains plausible and warrants ongoing research.

© 2021. Crown.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Timelines of vitamin D deficiency in preclinical studies is depicted along with reported alterations.

Red boxes depict the period of vitamin D deficiency. Yellow star indicates the time when the normal vitamin D containing diets were reintroduced. Preclinical studies of developmental vitamin D (DVD) deficiency show extensive alterations to developing dopamine (DA) neurons, neuronal differentiation, alterations to brain structure and behavioral phenotypes of interest to schizophrenia (green boxes). DVD deficiency reduces many DA-related genes. Multiple vitamin D response elements (VDREs) have been predicted in the promoters of all genes listed (in silico in black text) using the online software (MoloTool, Transcription Factor Motif Location Toolbox Version 11) [144]. Those genes listed in red have been functionally validated, i.e directly regulated by liganded VDR interacting with VDREs within their promoters. Preclinical studies of adult vitamin D (AVD) deficiency show a number of neurotransmitter alterations and impaired cognition (blue boxes). DVD deficiency developmental vitamin D deficiency, AVD deficiency adult vitamin D deficiency, E12–E18 embryonic days 12–18, p0–140 postnatal days 0–140, COMT Catechol-O-methyltransferase, GDNF glia-derived neurotrophic factor, cRET ret proto-oncogene, DRD2 dopamine receptor D2, NGF nerve growth factor, BDNF brain-derived neurotrophic factor, p75NTR neurotrophin receptor P75, TH tyrosine hydroxylase, Nurr1 nuclear receptor-related 1, p57kip2 cyclin-dependent kinase inhibitor 1C, p21 cyclin-dependent kinase inhibitor 1A, p27 cyclin-dependent kinase inhibitor 1B, USV ultrasonic vocalization, LTP long-term potentiation, DAT dopamine transporter, Grin2b glutamate ionotropic receptor NMDA type subunit 2B, GAD glutamate decarboxylase, PNN perineuronal net, GABA gamma-aminobutyric acid, DOPAC 3,4-Dihydroxyphenylacetic acid, HVA homovanillic acid (Color figure online).

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