Serum vitamin D and hippocampal gray matter volume in schizophrenia

Highlights

• Vitamin D deficiency might be one of the contributing factors in schizophrenia pathogenesis.

• Hippocampal abnormalities are established in schizophrenia.

• Hippocampus expresses high levels of vitamin D receptors.

• Serum vitamin D level correlated positively with hippocampus volume in schizophrenia patients.

Abstract

Disparate lines of evidence including epidemiological and case-control studies have increasingly implicated vitamin D in the pathogenesis of schizophrenia. Vitamin D deficiency can lead to dysfunction of the hippocampus – a brain region hypothesized to be critically involved in schizophrenia. In this study, we examined for potential association between serum vitamin D level and hippocampal gray matter volume in antipsychotic-naïve or antipsychotic-free schizophrenia patients (n=35). Serum vitamin D level was estimated using 25-OH vitamin D immunoassay. Optimized voxel-based morphometry was used to analyze 3-Tesla magnetic resonance imaging (MRI) (1-mm slice thickness). Ninety-seven percent of the schizophrenia patients (n=34) had sub-optimal levels of serum vitamin D (83%, deficiency; 14%, insufficiency). A significant positive correlation was seen between vitamin D and regional gray matter volume in the right hippocampus after controlling for age, years of education and total intracranial volume (Montreal Neurological Institute (MNI) coordinates: x=35, y=−18, z=−8; t=4.34 pFWE_Corrected=0.018). These observations support a potential role of vitamin D deficiency in mediating hippocampal volume deficits, possibly through neurotrophic, neuroimmunomodulatory and glutamatergic effects.

Introduction

Disparate lines of evidence have implicated vitamin D in the pathogenesis of schizophrenia. Infant cohort studies have revealed elevated risk for schizophrenia in infants with deficient vitamin D (McGrath et al., 2010) and reduced risk in those who had received supplementation (McGrath et al., 2004). Deficient serum levels of vitamin D have been observed in patients with first episode psychosis (Graham et al., 2014) as well as in patients with chronic schizophrenia (Humble et al., 2010). A recent meta-analysis on the relationship between vitamin D and psychosis reported a moderately significant reduction in serum levels of vitamin D in schizophrenia patients compared with healthy controls and a trend for lower levels compared with other psychoses (Belvederi Murri et al., 2013).

Following the discovery of vitamin D receptors (VDRs) in neurons and glial cells (Garcion et al., 2002), studies have increasingly demonstrated the importance of vitamin D in early brain development as well as in facilitating optimal brain function (Eyles et al., 2003). Vitamin D can cross the blood–brain barrier and stimulate a broad range of functions by binding to VDRs (Kalueff et al., 2006). The action of vitamin D in the brain is largely considered to be neuroprotective (Garcion et al., 2002). It is reported to be involved in the biosynthesis of neurotransmitters and neurotrophic factors like brain-derived neurotrophic factor (BDNF) (Kiraly et al., 2006). It is also implicated in the reduction of free radicals and reactive oxygen species, and hence confers neuroprotection (Garcion et al., 1997, Wang et al., 2001). Since deficient BDNF (Kalmady et al., 2013) and increased oxidative stress (Wu et al., 2013) have been associated with schizophrenia, these effects mediated by vitamin D through VDRs could be critical in this disorder.

Interestingly, both deficient BDNF (Erickson et al., 2010) and as excessive oxidative stress (Wang and Michaelis, 2010) can result in abnormalities of the hippocampus – a brain region that hypothetically plays a critical role in schizophrenia pathogenesis (Heckers and Konradi, 2010). Hippocampal abnormalities in schizophrenia manifest in the form of smaller hippocampal volume, altered number of neurons, reduced functional activity and abnormal functioning of genes expressed by the hippocampus (Harrison, 2004, Heckers and Konradi, 2010). Among these, smaller hippocampal volume in schizophrenia is a well-replicated finding in many studies (Steen et al., 2006, Heckers and Konradi, 2010). More importantly, the hippocampus is one of the brain regions with maximal concentrations of VDRs (Eyles et al., 2005); vitamin D has been shown to play a critical role in hippocampal cell survival through its neuroprotective effects (Langub et al., 2001).

All of these observations suggest that vitamin D deficiency in schizophrenia might be associated with hippocampal abnormalities. To date, no study has looked into the association between serum vitamin D and hippocampal volume in schizophrenia. In this study therefore, we examined the association between serum vitamin D level and hippocampal gray matter (GM) volume in antipsychotic-naïve or anti-sychotic-free schizophrenia patients. We hypothesized that hippocampal GM volume would positively correlate with serum vitamin D levels in schizophrenia patients.