Association between Vitamin D Supplementation and Mental Health in Healthy Adults: A Systematic Review

Vitamin D is considered to be a crucial factor that influences symptoms of depression, negative emotions, and quality of life, but to date, no systematic review has been conducted with regard to its effect on other domains of mental health. The aim of the study was to evaluate the influence of vitamin D supplementation on mental health in healthy adults. The systematic review was registered in the PROSPERO database (CRD42020155779) and performed according to the PRISMA guidelines. The literature search was conducted in PubMed and Web of Science databases and included intervention studies published until October 2019. The human studies were included if the supplementation regimen involved the administration of a specified dosage of vitamin D to an adult sample. A total of 7613 records were screened and assessed independently by two researchers, based on their title, abstract, and full text sequentially. Finally, 14 studies were included, and their risk of bias was assessed using the Newcastle–Ottawa Scale (NOS). The studies were included if they presented the results of various doses of vitamin D, compared the supplementation results with the placebo effect, compared the outcome with no supplementation, or observed effect of specific dose applied. The assessed mental health outcomes mainly included depressive symptoms, or depression, well-being, quality of life, mood, general mental component, and anxiety, but single studies also included other parameters such as distress, impression of improvement, and fear of falling and flourishing. The results of the majority of studies did not confirm a positive influence of vitamin D supplementation. None of the high-quality studies (assessed using NOS), which evaluated outcomes other than depression, supported the hypothesis that vitamin D supplementation effectively ameliorates mental health issues, while they present conflicting evidence for depression. Some studies indicated that supplementation should be combined with physical activity to provide effective results, and that supplementation is less effective than vitamin D supply from food sources. The included studies were conducted in diverse populations and followed various doses and intervals of administration, so the results may be incomparable, which should be considered as a limitation. The conducted systematic review did not provide strong evidence for a positive effect of vitamin D supplementation on mental health in healthy adults.


Introduction
Vitamin D is considered to be a crucial nutrient for calcium absorption and homeostasis, thus influencing bone health and metabolism [1]. However, several investigations in the last few decades have revealed that this vitamin is associated with numerous extra-skeletal was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [25] for the systematic literature search, screening, inclusion, and reporting. The literature search was conducted based on PubMed and Web of Science databases, and it included intervention studies published until October 2019, as the search procedure was conducted in October 2019.

The Eligibility and Inclusion
The eligible studies were to present the intervention including vitamin D supplementation and its influence on mental health outcomes. Only studies published in English, in a peer-reviewed journal were allowed.
The inclusion criteria were formulated as follows: (1) Studied adult population; (2) Applied vitamin D supplementation of the specified dose; (3) Outcome including any mental health aspect assessed based on any method (including both subjective questionnaire and medical diagnosis).
The exclusion criteria were formulated as follows: (1) Studies conducted in animal models; (2) Studies conducted in a specific populations of individuals with any specific physical health problems (any physical symptom, disease, or disorder defining the studied group); (3) Studies conducted in subjects with intellectual disabilities; (4) Studies conducted in subjects with eating disorders; (5) Studies conducted in subjects with neurological disorders (e.g., Alzheimer's disease, epilepsy). (6) Studies assessing influence of combined multiple nutrients supplemented; (7) Studies assessing influence of maternal vitamin D supplementation on mental health in offspring.
No additional criteria, associated with the country, or population were formulated, and the patient, intervention/exposure, comparator, outcome, and study design (PICOS) criteria for inclusion and exclusion of studies are summarized in Table 1.

The Search Strategy
The applied detailed electronic search strategy for databases of PubMed and Web of Science is presented in Supplementary Table S1.
The identified studies were verified to remove duplicates, and they were assessed independently by 2 researchers, based on the title, to screen and assess studies for eligibility. This assessment was followed by the next step, which was conducted based on abstract, to assess studies for eligibility, which was also conducted independently by 2 researchers. If any disagreement appeared at any step, it was discussed with the other researcher. Afterwards, the full texts of the studies indicated as eligible were extracted, and if unavailable, the corresponding author was contacted to obtain full text. The full texts that were gathered were finally assessed by 2 researchers to confirm including them to a systematic review. If any disagreement appeared, it was discussed with the other researcher. The inclusion procedure is presented in Figure 1.

Study design
Peer-reviewed articles published in English, including: randomized controlled trials, randomized crossover trials, cohort studies, case-control studies, and cross-sectional studies Articles not published in English, reviews, meta-analyses, expert opinions, letters to editor, comments, studies in animal models, methodological articles, case reports, and conference reports

The Search Strategy
The applied detailed electronic search strategy for databases of PubMed and Web of Science is presented in Supplementary Table S1.
The identified studies were verified to remove duplicates, and they were assessed independently by 2 researchers, based on the title, to screen and assess studies for eligibility. This assessment was followed by the next step, which was conducted based on abstract, to assess studies for eligibility, which was also conducted independently by 2 researchers. If any disagreement appeared at any step, it was discussed with the other researcher. Afterwards, the full texts of the studies indicated as eligible were extracted, and if unavailable, the corresponding author was contacted to obtain full text. The full texts that were gathered were finally assessed by 2 researchers to confirm including them to a systematic review. If any disagreement appeared, it was discussed with the other researcher. The inclusion procedure is presented in Figure 1.

Procedure of Data Extraction
The procedure of data extraction was conducted independently by 2 researchers. If any information was unavailable in the article, the corresponding author was contacted to request additional information (referred to in the Results section as data provided on request). If any disagreement appeared, it was discussed with the other researcher. The extracted information included: study design and basic details of the studies included in the systematic review (country/location, studied group, time); characteristics of the

Procedure of Data Extraction
The procedure of data extraction was conducted independently by 2 researchers. If any information was unavailable in the article, the corresponding author was contacted to request additional information (referred to in the Results section as data provided on request). If any disagreement appeared, it was discussed with the other researcher. The extracted information included: study design and basic details of the studies included in the systematic review (country/location, studied group, time); characteristics of the groups studied (number of participants and of female participants, age, inclusion criteria/exclusion criteria); characteristics of the exposure and outcome studied (vitamin D measure, applied vitamin D supplementation, mental health outcome, psychological measure), and findings formulated (observations and conclusions as formulated by authors of the study).
According to the procedure recommended for the systematic reviews, the risk of bias resulting from methodological quality [26] was assessed while using the Newcastle-Ottawa Scale (NOS) [27]. The included studies were assessed for the selection (score of 0 to 4), comparability (score of 0 to 2), and exposure/outcome (score of 0 to 3). The final assessment was made within the following categories: very high risk of bias (total score of 0 to 3), high risk of bias (total score of 4 to 6), and low risk of bias (total score of 7 to 9) [28].
The summary of concluded association between vitamin D supplementation and mental health in adults, accompanied by the Newcastle-Ottawa Scale (NOS) total score for the studies included in the systematic review, is presented in Table 5. The findings for the studies included in the systematic review are presented in Supplementary Table S2. Among the included studies, seven were associated with a low risk of bias (NOS score of 7-9) [28], some reported protective effects of vitamin D [31,36], and some found no beneficial effects for this vitamin [32,35,37,38,40]. However, it should be noted that the majority of the studies did not provide strong evidence for a positive influence of vitamin D supplementation. Moreover, none of the high-quality studies (associated with low risk of bias), which assessed outcomes other than depression (mental well-being [32,35], quality of life/health-related quality of life [35,40], anxiety [37], fear of falling [35], flourishing [37], mood [37]) supported positive effects of vitamin D supplementation. On the contrary, highquality studies provided conflicting evidence for depression/depressive symptoms-either positive influence of vitamin D supplementation [30,36] or no such influence [37,38,40].           Table 5. The summary of concluded association between vitamin D supplementation and mental health in adults, accompanied by the Newcastle-Ottawa Scale (NOS) total score for the studies included in the systematic review. a Supporting-concluded positive influence of applied vitamin D supplementation on mental health; not supporting-concluded no positive influence of applied vitamin D supplementation on mental health; inconclusive-no clear association between applied vitamin D supplementation and mental health; b the Newcastle-Ottawa Scale (NOS) total score within the following categories: very high risk of bias (0-3 NOS points), high risk of bias (4-6 NOS points), and low risk of bias (7-9 NOS points) [28].

Discussion
The described inconsistent observations with regard to the effect of vitamin D supplementation on mental health are in agreement with the general controversies associated with the therapeutic use of vitamin D supplementation [43]. They are associated with no consistent recommendations of vitamin D intake [44], which for adults varies from 5 µg in Australia and New Zealand [45] to 20 µg in Germany, Austria, and Switzerland [46]. Similarly, there are also diverse opinions with regard to baseline levels of 25(OH)D in the serum, below which vitamin D deficiency occurs [47]. A threshold level of 30 nmol/L is specified by the United States (US) Institute of Medicine (IoM) [48] and the United Kingdom National Osteoporosis Society [49] and a level of 50 nmol/L by the US Endocrine Society [50] and European Food Safety Authority (EFSA) [51]. In addition, the vitamin D supplementation doses recommended by various authorities for the general population of adults also differ [52], ranging from daily supplementation limit of no more than 15 µg, recommended by IoM [53], to the maximum permissible level of 50 µg, recommended by US Endocrine Society [50].
The above-mentioned results show that little is known about the target 25(OH)D blood level, but also various recommendations of supplementation may be formulated, which in the studies included in the present systematic review ranged from 15 µg per day for at least 2 months [29] to 250 µg per day for 2 weeks [39]. Furthermore, some researchers did not apply daily vitamin D doses, but weekly [33,34,38], monthly [37,41], or even yearly doses [32]. However, the efficacy of vitamin D supplementation is dependent on the applied dosage [54] and time intervals proposed for this supplementation [55], so the results of the included studies may be incomparable. In addition, some countries have their national vitamin D fortification policy, which includes fortification of products such as milk (Finland, Sweden, and Iceland); nondairy milk alternatives, such as soy, rice, and oat drinks (Finland); fat spreads/margarines (Finland and United Kingdom) [56]. These products influence the vitamin D status in these populations and may also contribute to the differences in results between studies. However, if the dietary intake of vitamin D is not recorded within the study, it might not have been taken into account.
Bearing this in mind, it must be emphasized that the studies included in the systematic review were conducted in various populations, as well as various doses and intervals were followed for supplementation, so the results may have been incomparable, which is a limitation of the present analysis. Moreover, only studies published in English, in peerreviewed journals were included, which means that some interesting results may not have been taken into account. The other issue is associated with the diverse quality of the included studies accompanied by the relatively low number of studies randomized against placebo, which may be associated with the risk of bias. Last but not least, the presented study included articles published until October 2019, while the further ones were not screened, which also should be indicated as one of the limitations.
As described above, the results of the conducted systematic review did not provide explicit evidence to demonstrate a positive effect of vitamin D supplementation on mental health in a population of adults. Not only did the majority of the included studies not support it, but also, many reported inconclusive results. Only 36% of the studies were classified as supporting [29][30][31]36,42], and among them, some suggested that specific conditions need to be met in order to observe the positive influence of vitamin D supplementation. One study confirmed that vitamin D supplementation may be beneficial to overcome depression only when it is combined with physical activity [42], while another study recommended the dietary intake primarily through food sources that provided better results, while for supplementation, less consistent results were documented [31]. Considering these findings, it may be concluded that vitamin D supplementation may be not so effective as dietary intake, but also that it should be an element of a broader treatment program, also including behavioral therapy. In spite of this, it is generally stated that if taking dietary supplements to correct vitamin D deficiency improves mental well-being, it would be a simple and costeffective solution for patients at risk of depression and possibly other mental disorders [57]. However, the results of the conducted systematic review indicate that this solution may not be as effective as expected.
Although a majority of the high-quality studies indicate that vitamin D supplementation may have a positive impact on depression, other studies do not support the positive influence of vitamin D supplementation on other mental health problems. Therefore, vitamin D supplementation should not be treated as the only dietary intervention to be applied in the prevention and therapy of mental health disorders. The treatment protocol should not only include a broader dietary intervention, to ensure that an adequate amount of the vitamin D is obtained through the food sources, but should also include other dietary modifications. Such a modification should be based on the well-known association between diet and mental health, as indicated in the previous systematic reviews that determined the effects of fruit and vegetable intake [58] and various dietary patterns [59]. Moreover, physical activity should also be promoted as the confirmed factor associated with mental health [60], additionally supporting the positive influence of vitamin D.

Conclusions
The conducted systematic review did not confirm a positive influence of vitamin D supplementation on mental health in healthy adults. It was supported only by some studies, which mainly included depression and not other mental health problems. Some studies indicated that this supplementation should be combined with physical activity to produce effective results, while some studies revealed that supplementation is less effective than vitamin D supply from food sources.