This is the first report of an association between vitamin D deficiency in adolescents and severity of mental illness, defined as presence of psychotic features. These findings are similar to a cross-sectional study also linking vitamin D deficiency and adult psychosis [13
]. In a study of over 1,000 adults from combined cohorts of a longitudinal evaluation of severe mental illness and a population-based sample from the Oslo Health Study, vitamin D levels and presence of psychosis were compared between native Norwegians and dark-complexion immigrants to Norway. Prevalence of vitamin D deficiency and insufficiency in immigrants with psychosis was 80%, similar to the 72% in our sample of severely mentally ill adolescents. Additionally, 43% of the Oslo community population with psychosis met criteria for vitamin D deficiency, also similar to the 40% of this teen sample with psychosis. In the adult epidemiologic sample, disorientation on the PANSS, weight loss, and lack of physical energy correlated with lower 25-OH D levels after controlling for major depression. Demographics, level of functioning, lifestyle habits, and BMI were not associated with vitamin D levels.
Our findings also agree with an unpublished 2011 report of a child and adolescent psychiatric population residing in the Pacific Northwest. Using the same definitions of deficiency, insufficiency, and normal ranges as in the current study, 21% of 67 youth with severe psychiatric symptoms residing in 2 Oregon residential treatment programs had vitamin D deficiency, vs. 14% of a comparable NHANES sample. For the children with psychotic disorders, the prevalence of vitamin D deficiency was 43% [14
]. The overall mean 25-OH D level was 28.9
ng/mL, with 2/3 of the patients falling below the normal range; mean 25-OHD in the youth with psychotic disorders was 26.47
ng/mL (SD12.42). Another group of psychiatric inpatient Parisian adolescents (N
136) were also found to be largely vitamin D-deficient (72.4%), with the mean 25-OHD value 15–16
ng/mL, lower in blacks and North Africans [15
]. No differences in mean levels were found between those taking or not taking antipsychotics, indicating that antipsychotics may not lower vitamin D absorption.
The prevalence of vitamin D deficiency in our sample of acutely mentally ill adolescents is also greater than the high rates observed in U.S. community adolescent populations (34% vs. NHANES 9%)[3
] and in Australian adult private psychiatric inpatients (vitamin D deficiency 11%, defined as <25
nmol/L, or 10
]. The latter study found a 29% difference between mean levels in patients vs. controls. Our higher prevalence rates of deficiency and insufficiency may be in part due to the latitude of Rochester, NY, 43.145 degrees N. Paris, France is 48.51
N, and Geelong, Australia 38.10
S. Except during summer months, skin makes negligible vitamin D from sunlight at latitudes above 37 degrees north or below 37 degrees south.
Potential causal mechanisms
Basic and preclinical animal studies provide clues as to how vitamin D may lower risk for psychosis, and how vitamin D deficiency may raise risk for psychosis and depression. These mechanisms include 25-OH vitamin D and calciferol, the renal metabolite of 25-OH D (1,25-OH D): 1) altering neurotrophic factors and monoamine levels [17
], resulting in vitamin D-related behavioral phenotypes similar to those for depression and psychosis [19
], 2) facilitating oxidative stress responses [20
], 3) changing multiple neuroendocrine transmitters [21
], and 4) regulating hormonal and serotonin pathway effects within the CNS [24
Race, ethnicity, dietary intake and sunlight exposure
Dietary intake and sunlight exposure as sources of vitamin D are influenced by race. The NHANES found poor dietary intake of vitamin D and lower exercise in older African American and female Hispanic adolescents. Although not fully comparable due to different methodologies, our mentally ill non-Caucasian population also demonstrates more vitamin D deficiency, and for Asians and biracial subjects a greater rate of psychosis, but not after adjusting for vitamin D level. Small clinical studies to date suggest potential for a causal link between low vitamin D and mood disorders [8
], necessitating that randomized controlled trials in carefully defined populations of interest be performed to better characterize the relationship between vitamin D deficiency and risk for depression and psychosis.
In addition to the possibility that vitamin D deficiency contributes to vulnerability to psychosis, other nutritional factors may play a role: adolescents eating a diet low in dairy products may also consume less of other nutrient-rich foods, including those with essential fatty acids. Adverse omega-3:omega-6 fatty acid ratios and/or other dietary micronutrient deficiencies that are commonly associated with vitamin D deficiency such as vitamin B12 may also contribute to emergence of psychotic symptoms.
Implications for future research in psychiatry
Effects on mental illness
If a prospective association between psychotic features and vitamin D deficiency is confirmed, outstanding issues include: 1) how vitamin D affects monoamine function and the HPA axis and immune responses to stress and symptom production, 2) whether supplementation can be protective against incident depression or psychosis and their recurrence, and 3) whether supplementation improves symptoms in those with clinically diagnosed depression or psychosis, especially in populations with darker skin [26
]. An open-label Swedish case-series suggests that depression is improved by vitamin D supplementation in adolescents [27
]. Prevention studies in high-risk offspring would be highly novel. Thus, future studies could target both prevention of mental and comorbid physical illness, focusing on disparity and somatic treatment augmentation.
Importance to overall health in psychiatric populations
Normalizing vitamin D levels warrants study in those with severe mental illness to determine whether, and at what dose, vitamin D helps protect against metabolic side effects from psychopharmacologic treatment or reduces the development of comorbid physical illnesses such as diabetes, cardiovascular disease, and osteoporosis. Low vitamin D is associated with greater BMI, insulin resistance, and systolic blood pressure, lower HDL-C in obese adolescents and adults, and lower final height in young adult women [3
]. Vitamin D status may be especially important in those with serious mental illness as they develop poorer metabolic health at earlier ages. Optimal vitamin D levels also may protect against several different cancers (breast, colon, pancreas, and prostate), and autoimmune disorders (lupus, multiple sclerosis, and Type I diabetes) [32
]. Molecular mechanisms of vitamin D that are protective against cancer include reducing cellular oxidative stress [33
]. Vitamin D supplementation may thus represent a low-cost population-based intervention capable of reducing utilization of more intensive physical and mental health treatments; multiple trials are underway assessing impact on a variety of physical health conditions including osteoporosis, insulin resistance, and cardiovascular risk. A large scale epidemiologic RCT (the Vitamin D and omega¬3 Trial; VITAL) is examining whether supplementation prevents chronic diseases (http://www.vitalstudy.org
Supplementation issues in adolescents
How should low vitamin D levels be corrected? Supplementation with over-the-counter or prescription vitamin D for those with low vitamin D is important, as natural dietary sources are few and include chiefly oily fish, irradiated mushrooms, egg yolks, and fortified milk, juices, cereal, and margarine (http://dietary¬supplements.info.nih.gov/factsheets/vitamind.asp
). Most adolescents, especially those who skip breakfast or are lactose intolerant, do not consume adequate amounts of these foods to maintain optimal vitamin D levels, and cannot meet their requirements through diet alone. Risk for developing vitamin D toxicity with supplements has been largely unsupported [34
]; studies giving as much as 14,000
IU per week of D3 to adolescents over one year’s time have shown no evidence of toxicity [35
]. A serum level of more than 200
ng/ml 25-OHD may be necessary for symptoms of toxicity to occur. The Institute of Medicine in 2010 raised its daily intake recommendations based on evidence for skeletal growth and maintenance; the current recommended dietary allowance (RDA) is 600
IU per day for 1–70
years of age with an upper level intake of 4,000
IU per day [36
]. The American Academy of Pediatrics had previously raised its recommended supplementation from 200
IU in 2003 to 400
IU per day in 2008 to prevent rickets in children and adolescents who do not obtain this goal through fortified foods [37
]. Additional initial supplementation to return deficient individuals to normal may be indicated as dietary reference intake amounts recommended by the IOM may still be insufficient for bone health maintenance in many individuals [38
]. The amount necessary to prevent breast and colon cancer, Type I diabetes, and multiple sclerosis has been speculated to be closer to 4,000-8,000
IU per day [32
]. The amount appropriate for maintenance of best mental and physical health is therefore controversial, and is unknown in the chronically mentally ill, who may metabolize vitamin D more quickly due to added oxidative stress burden.
This work is limited by a small sample size, cross-sectional method, inpatient sampling bias, and lack of formal research measures for diagnosis and severity of illness, family psychiatric history, sun exposure, and intake of Vitamin D and other dietary nutrients. No adolescents, however, were taking vitamin D supplementation. A winter sampling bias is present, potentially contributing to low rates of D-deficiency, however, this does not rule out that seasonal effects in illness severity and admission rates related to greater vitamin D deficiency may occur. Analysis of ultraviolet radiation for latitudes 0 to 80 degrees N found that for March through October, sites from 18 degrees to 44 degrees N (the majority of the continental United States) had equal amounts of vitamin D producing ultraviolet light; November through February only demonstrated decreases in vitamin D producing ultraviolet light [39
]. Additional limitations include that adolescents were not screened for osteomalacia; serum parathyroid hormone values were not routinely checked in those who were D-deficient; however, several performed clinically were within normal ranges. Many confidence intervals are wide; confirmation of these results awaits a large sample study and more rigorous design. Probing smaller enriched clinical samples may be useful in providing biologic signals of relevance in populations with depression, for example, using neurocognitive tasks. Descriptive differences in a clinical population compared with population norms may also provide direction for further investigation related to both interactive effects of mental illness and ancestry.