**8. Neuropsychiatric diseases**

Beside neurodegenerative disorders also neuropsychiatric diseases affect the nervous system, and therefore we would like to give a brief summary of recent studies analyzing a possible influence of vitamin D on autism spectrum disorders (ASD), depression, and schizophrenia. Epidemiological studies demonstrated an elevated prevalence for ASD in children born at higher latitudes [151] and in offspring of highly pigmented women [152] as well as lower vitamin D levels of children with autism [153]. Furthermore maternal, gestational hypovitaminosis D is associated with a higher ASD risk [154, 155]. Recent findings of strong associations of ASD with polymorphisms in the VDR or other genes involved in vitamin D3 metabolism [156, 157] hypothesize vitamin D3 as environmental and genetic factor influencing ASD [158]. On the molecular level, cellular processes like oxidative stress or neuroinflammation were shown to play a role in ASD [159], and they could present a potential contact point for vitamin D3. In line with the abovementioned link between ASD and vitamin D, a vitamin D-deficient rat model revealed broad behavioral similarities between vitamin D-deficient models and ASD-associated behavior [160]. Treatment of an ASD rat model with high-dose vitamin D revealed significant protective effects [161]. In contrast to supplementation in animal trials, the first randomized controlled clinical study analyzing the daily supplementation of 300 IU vitamin D3/kg for 4 months on 109 children with ASD, resulting in significant improvement of autism symptoms, was retracted 1 month ago [162]. This lets us conclude that vitamin D3 can be suggested as possible preventive treatment for the prevention of ASD, but more studies supplementing pregnant women and their children with adequate levels of vitamin D3 have to be performed.

A potential link between vitamin D3 and depression is subject of current research, and for more detailed information about the potential role of vitamin D on major depressive disorder, we recommend a review from Casseb et al. [163]. A meta-analysis from Parker and colleagues concluded that there are increasing evidences for an influence of vitamin D on depression [164], and in line with this, another review also postulated hypovitaminosis D as risk factor for late-life depression [165]. Consistently, a very recent meta-analysis reported a negative association of serum 25(OH)D3 levels with the risk of depression [166].

A following cross-sectional study including 100 women in reproductive age also shows that the depression score inverse correlated with the vitamin D serum level [167]. Contradictorily, a supplementation with 1200 IU vitamin D for 12 months failed to have an influence on the prevention of depression in a very recent, randomized clinical trial including 155 participants having clinically relevant depressive symptoms [168]. Furthermore, a recent MR study from Libuda and colleagues indicates no causal relationship between both depressive symptoms and broad depression and vitamin D levels due to a missing association of six vitamin D-related SNPs with depression [169]. In summary, the current research investigating the role of vitamin D3 in depression is much less clear than other neurological disorders.

In respect to the chronic mental illness schizophrenia, it could be shown that hypovitaminosis D is common in patients [170]. This fits to the environmental risk factors that have been described for schizophrenia, like season of birth [171] and latitude [172]. Also a link between neonatal vitamin D levels and the schizophrenia risk was reported [173]. A recent randomized, placebo-controlled study from Krivoy and colleagues examined psychosis severity, mood, cognition, and metabolic profile in 47 schizophrenia patients during an 8-week supplementation of 14,000 IU vitamin D/week. The authors described no significant effects on psychosis, mood, or metabolic status, but a trend to an improved cognitive function accompanied by significant elevated vitamin D levels in the supplemented group. A possible explanation for these findings, given by the authors, could be that a medical score that measures the symptom severity in schizophrenia patients decreased during the study in the placebo as well as in the treated group and could thereby veil the influence of supplemented vitamin D [174]. An actual study reported beneficial effects of supplementation of vitamin D3 in combination with probiotics in schizophrenia patients [175]. Addressing the underlying molecular mechanism, vitamin D could perform its suggested beneficial actions via modulation of immune system and inflammation processes since it was reported that patients with chronic schizophrenia have significantly elevated levels of TNF-α and IL-6 [176]. Furthermore, it could be shown that the expression of genes involved in the metabolism of vitamin D3 (*VDR*, *CYP27B1*, *CYP24A1)* is significantly elevated in peripheral blood of schizophrenic patients [177], indicating a potential causal relationship between vitamin D3 and schizophrenia, which should be the aim of future research.
