Vitamin D deficiency and psychotic features in mentally ill adolescents: A cross-sectional study

Vitamin D deficiency is endemic across the life span and in diverse populations throughout the world [1]. Contributing factors are lack of exposure to sunlight and insufficient dietary intake; individuals with darker skin are at higher risk due to low cutaneous synthesis and dairy-poor diets. In a study of healthy Northeastern US adolescents, more than 90% of African American teens and 55% of all teens had low vitamin D [2]. The National Health and Nutritional Examination Survey (NHANES 2001–2004) found an overall US prevalence of vitamin D insufficiency in adolescents of 61%, with 9% deficient [3].

Vitamin D is well recognized as essential for intestinal calcium absorption, serum calcium homeostasis, optimal skeletal development, and the prevention of rickets and osteoporosis [4]. The importance of vitamin D to the CNS in both healthy and psychiatric populations is less well-appreciated and is vastly understudied compared to its known impact on bone health. Vitamin D receptors are present throughout the brain, and D-deficiency is associated with negative CNS effects in animal studies [5]. Vitamin D receptors and activating enzymes are particularly prominent in the hypothalamus and substantia nigra, and are involved in glucocorticoid signaling in hippocampal cells. Depletion models show maternal offspring with abnormal brain shape, cell number, and reduced neurotropic factors and receptors. Vitamin D receptor animal knock-out models show increased anxiety, decreased activity, and muscular and motor impairments, resembling phenotypic models of depression. Vitamin D is neuroprotective to hippocampal cells, through regulating calcium ion channels and activating PKC and mapPK pathways.

Clinical studies reinforce the significance of this basic work. A Finnish cohort supplemented with prenatal and infant vitamin D demonstrated reduced adult risk for schizophrenia [6]. Low vitamin D levels were found to correlate with major depression [7] and premenstrual mood symptoms in women [8], and mood disorders and cognitive impairment in older adults [9]. Two randomized controlled trials (RCT) have shown that raising vitamin D levels improved depression. The first study examined phototherapy vs. vitamin D supplementation for seasonal affective disorder, and found a positive effect for vitamin D via either supplementation or phototherapy within one month [10]. Another RCT of overweight and obese subjects, at greater risk for low vitamin D than those of normal weight, found higher levels of depression with low vitamin D; supplementation resulted in significant improvement in depressive symptoms after one year [11]. To the best of our knowledge, there have been no published studies examining vitamin D deficiency and the presence of psychosis in adolescents.

We hypothesized that, in severely mentally ill adolescents, defined as adolescents requiring either inpatient or partial hospitalization, 1) rates of vitamin D insufficiency and deficiency would be greater than those documented in general US populations, and 2) lower vitamin D levels would be associated with mental illness severity, defined as presence of psychotic features.

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 ng/mL) [16]. 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.

Vitamin D deficiency is highly prevalent in this descriptive sample of acutely mentally ill adolescents, especially in African-American and Asian teens, and appears related to psychotic symptoms. This work is the first to report an association between psychosis and vitamin D deficiency in psychiatrically hospitalized adolescents [40] and confirms this association found previously in an adult population [13]. Our study also expands on similar deficiency findings from a Parisian inpatient adolescent cohort [15], providing clinical diagnoses of mood disorders in the great majority of inpatient teens with vitamin D deficiency, and further, finding lower risk for psychosis in the presence of antidepressant treatment. Both support the possibility that heightened vulnerability to psychotic features occurs in the substantial proportion of teens with mood disorders who are vitamin D deficient. Prospective trials of vitamin D supplementation are needed to address targeted mental health symptom domains as well as metabolic health variables in D-deficient severely mentally ill adolescents and adults, focusing on dose-finding and tolerability. Calls have been made for clinical monitoring in patients with psychiatric illness as well as randomized trials of vitamin D for depression [41, 42]. Clinical screening for vitamin D deficiency in severely mentally ill adolescents is justified by their high risk for both chronic mental illness and early onset of cardiometabolic comorbidities, especially as vitamin D deficiency at mid-life appears a strong independent predictor of all-cause mortality (odds ratios 2.64, 95% CI 1.901 to 3.662. p < 0.0001) [43]. A key clinical question raised by our work and supported by known safety data is whether psychiatrically hospitalized dark-complected adolescents, including African-Americans, Asians, and Muslim females in traditional covered dress, should be routinely supplemented with vitamin D until proven otherwise.