Vitamin D, Folate and the Intracranial Volume in Schizophrenia and Bipolar Disorder and Healthy Controls
Scientific Reports volume 8, Article number: 10817 (2018)
Tiril P. Gurholt, Kåre Osnes, Mari Nerhus, Kjetil N. Jørgensen, Vera Lonning, Akiah O. Berg, Ole A. Andreassen, Ingrid Melle & Ingrid Agartz
Seem to lack a consensus in the literature
- Less vitamin D, bigger brain - humans and animals - Jan 2015
- Schizophrenia and smaller hippocampus both associated with low vitamin D – June 2015
- Schizophrenia associated with low vitamin D (97 percent) and smaller right hippocampus – Aug 2015
Overview Schizophrenia and Vitamin D contains the following summary
Many reasons to think that schizophrenia is associated with low vitamin D
1) 97% of patients with schizophrenia are vitamin D deficient
2) Schizophrenia varies with latitude (UVB) by 10X (controversy)
3) Schizophrenia is more common in those with dark skin (when away from the equator)
4) Schizophrenia is associated with low natal vitamin D
5) Schizophrenia has been increasing around the world when vitamin D has been decreasing (controversy)
6) Schizophrenia is associated with low birth rate, which is associated with low vitamin D
7) Schizophrenia is associated with Autism which is associated with low vitamin D
8) Schizophrenia Bulletin Editorial (Jan 2014) speculated that Vitamin D could be a major player
9) Schizophrenia 2X more likely if low vitamin D - meta-analysis
10) Schizophrenia increased 40 % for Spring births after Danes stopped vitamin D fortification
11) Schizophrenia is associated with season of birth
12) Schizophrenia is associated with poor Vitamin D Receptor genes
13) Schizophrenia risk is decreased if give Vitamin D after birth
14) Schizophrenia symptoms reduced when Vitamin D levels are restored
Vitamin D and folate deficiency are considered risk factors for schizophrenia and bipolar disorders, but it is unknown how vitamin D and folate influence the growing brain, cranium or the clinical phenotype. Serum vitamin D and folate levels are in part genetically regulated. We investigated whether adult vitamin D and folate levels are associated with the intracranial volume (ICV) under the hypothesis that developmental vitamin D or folate levels influence neurodevelopment and that current levels are associated with ICV. Ninety patients with severe mental disorders and 91 healthy controls underwent 3 T magnetic resonance imaging and serum sampling. Multiple linear regression was used to assess the contribution of serum vitamin D, folate and patient-control status on ICV. We show that vitamin D levels were within lower range for patients and controls (48.8 ± 22.1 nmol/l and 53.4 ± 20.0 nmol/l, respectively). A significant positive association was found between vitamin D and ICV (p = 0.003, r = 0.22), folate was trend-significantly associated with ICV. Folate and vitamin D were significantly associated (p = 0.0001, r = 0.28). There were nonsignificant patient-control differences and no interaction effects. The results suggest that Vitamin D is associated with ICV as detected in the adult. Further studies are warranted for replication and to investigate possible mechanisms and genetic associations.
The main finding of this study was that S-25(OH)D was positively associated with ICV in patients with severe mental disorders and in healthy controls. There was also a positive trend-significant association between S-folate and ICV in patients and controls, but when including both S-25(OH)D and S-folate in the same model, only S-25(OH)D was significantly associated with ICV. For both patients and controls, height was positively associated with ICV as expected due to the genetic overlap40 and there were expected sex differences (women < men). In line with a recent meta-analysis in bipolar disorder5, but contrary to the results from meta-analyses for schizophrenia3,4, the patients were not found to have smaller ICV than healthy controls. There were no interaction effects.
Further investigations showed a significant positive association between S-25(OH)D and S-folate, and there was also an expected significant increase in S-25(OH)D levels during summer. Non-Caucasian ethnicity was significantly associated with having lower S-25(OH)D as previously indicated in reports from Oslo, Norway49,57. The association between S-25(OH)D and S-folate is interpreted to explain the trending association between S-folate and ICV, although based on the results it cannot be ruled out that S-folate has an independent association with ICV.
This is, to our knowledge, the first study to report independent and positive associations of S-25(OH)D on ICV in both patients with severe mental disorders and healthy controls. However, these results are contrary to two previous studies that indicate an inverse association between S-25(OH)D and ICV in healthy female students 22 and in older adults with memory complaints 23. The discrepancy in the findings could be due to nonlinearity; The two previous studies had several participants with S-25(OH)D > 100 nmol/l, while the current study only had three above 100 nmol/l. In the scientific literature, there are indications of a nonlinear relation between neonatal S-25(OH)D and the risk for schizophrenia13 and between S-25(OH)D and other disease outcomes36. Thus, it is not unlikely that the S-25(OH)D association could be nonlinear and that this nonlinearity explains the discrepancy in the findings. Due to few study participants with higher S-25(OH)D measures nonlinearity was not investigated in this study.
Prenatal or childhood S-25(OH)D measures were not available for study. Adult measurements could, considering the genetic influence on S-25(OH)D35,36, hypothetically reflect premorbid S-25(OH)D with potential effect on the brain and cranial development and/or disease risk as detected in the adult.
Developmental vitamin D levels13 have been associated with increased risk for schizophrenia and animal models indicate altered gene expression following developmental vitamin D deficiency20,21. Thus, it is plausible that altered gene expression also occurs in humans with developmental vitamin D deficiencies. One could speculate that induced gene expression changes from micronutrient deficiency could influence the development of both the brain and cranium. Hypothetically, this could also be a precursor to the development of severe mental disorders although the data in this study does not support a significant patient effect on ICV. Such hypotheses warrant further investigation e.g. through studying neonatal S-25(OH)D or related gene expressions for morphological brain changes in childhood, adolescence or adulthood.
Although we have interpreted the observed association between S-25(OH)D and ICV along a genetic pathway, other factors beyond the genetic realm could also explain the association. It is possible that the observed association between S-25(OH)D and ICV is due to other factors not accounted for and that these factors are correlated with both S-25(OH)D and ICV in adults. Potentially, the association between S-25(OH)D and ICV could be mediated by lifestyle factors such as a sedentary indoors lifestyle, socioeconomic status, or education attainment. For instance, obesity in adolescence and adulthood have been associated with negative structural brain changes41. A recent meta-analysis reported that obesity was associated with higher prevalence of S-25(OH)D deficiency at all ages58. Thus, factors such as obesity could influence the cranium’s development, in addition to being associated with deficiencies. However, we did not observe an association between weight and S-25(OH)D levels although weight was found negatively associated with ICV. Lower socioeconomic status, a reported risk factor for schizo- phrenia46, has also been shown to influence brain structure in children negatively45, which in turn could influence the development of the cranium. These and other lifestyle related factors could have the potential to influence, or be influenced by, brain development and ICV as measured in the adult.
Unexpectedly, we also found a positive association between S-folate and S-25(OH)D levels which, to our knowledge, has not been previously reported. One possible explanation is through gastrointestinal health. There are indications that S-25(OH)D may influence intestinal permeability59. Vitamin D receptors are important for intestinal health 60, their genetic expression has been associated with microbiome diversity61 and have together with 1,25-dihydroxyvitamin D been associated with increased intestinal folate absorption in ex-vivo rats 62. Folate is synthetized by the intestinal microbiome 24 and in one study folate was associated with intestinal vitamin D metabolism in mice63. Thus, S-25(OH)D could potentially influence S-folate, or vice versa, positively through improved functioning of the intestinal microbiome and/or absorption. Replication is warranted as it could also be a spurious finding or related to diet.