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Mind & Brain, the Journal of Psychiatry

years, mean age 60 years) who participated in a multinational European epidemiologic study.40 An association was found between vitamin D level and a measure of executive function, the Digit Symbol Substitution Test, but not with other measures, including memory tests and figure copying.

The risk for cognitive decline was assessed in another

large epidemiologic trial, the InCHIANTI trial, in which 858 elderly persons above age 65 years were followed for 3 years with periodic cognitive assessments.41 Subjects with serious vitamin D deficiency (B10 ng/mL) had a greater risk of having a 3-point poorer score on the MMSE (1.60; 1.192.00 95% CI) than those with a serum level of at least 75 ng/mL and had a higher probability of scoring much worse on the Trail-Making Test B (1.31; 1.031.51 95% CI), but not Test A. Individuals with inadequate vitamin D levels had a 0.3-point/ year worse mean MMSE scores than those with sufficient levels.

The National Health and Examination study, an epidemio-

logic investigation of 4809 persons over 60 years, did not observe a relationship between cognitive function and serum vitamin D concentration.42 However, only a single memory test, in which persons were asked recall questions after being read a story, was given.

VITAMIN D AND DEPRESSION There is increasing evidence that vitamin D may be involved

in the pathogenesis of depression, as is the case with cognitive impairment.20 Although there have not been specific research studies outlining how lack of vitamin D might cause depression, hypotheses have been proposed.43 The pathogenesis of depression is a complex and incomple- tely understood subject, but one possibility is that it results from the lack of monoamine transmitters. Vitamin D increases expression of the gene for tyrosine hydroxylase, a monoamine that is converted into serotonin and norepi- nephrine.43,44 Vitamin D has been found to be protective to animal neurons in vitro against dopaminergic toxins.43

Another theory posits that depression is a consequence of

stress on steroid regulatory hormones in the brain.43,44 Vitamin D can be more properly termed a steroid hormone rather than a vitamin. Vitamin D can be metabolized by neurons in the hippocampus, which contains both steroid and vitamin D receptors. It is possible that an interaction between these two receptors occurs.43

A number of epidemiologic studies have detailed the relationship between vitamin D and depression. Depression was assessed in the Longitudinal Aging Study Amsterdam (LASA), which comprised 1282 individuals, age range 6595 years.45 Although the average serum vitamin D level was quite low (21 ng/mL), individuals who were diagnosed with either major or minor depression had a mean vitamin D concentration that was 14% less than that of other subjects. Vitamin D level was inversely related to the severity of symptoms (pB0.03). A temporal relationship between vitamin D and depressive symptoms was observed in 531 participants who were at least 65 years old and were part of

M&B 2011; 2:(1). July 2011 18

the InCHIANTI study for 6 years.46 Women who started with serum vitamin D levels of below 20 ng/mL had twice the risk for depression (indicated by a score of 16 or greater on the Center for Epidemiological Studies-Depression Scale [CES-D]) as those with higher levels, and men had 1.6 times the risk. A relationship was found between severe vitamin D deficiency (B10 ng/mL) and depression in 2070 individuals who took part in the 2005 Health Survey for England. There was an inverse correlation between vitamin D levels and number of positive answers on the Geriatric Depression Scale (r0.14, pB0.001). In 7358 patients with cardiovascular diseases who were at least 50 years old (mean age 73.1 years), subjects with ‘‘very low’’ serum vitamin D levels B15 ng/mL were 2.70 (95% CI 1.352.70; p0.005), those with vitamin D levels between 16 ng/mL and 30 ng/mL were 2.15 (95% CI 1.104.21; p0.03) more likely to be depressed than those with a vitamin D level of 50 ng/mL.47

The association between vitamin D and depression was further detailed in two other epidemiological investigations from the Far East. In China, one study initially observed an inverse correlation among 3262 community-dwelling individuals from 50 to 75 years of age.48 However, when this result was adjusted for other covariates such as socio- economic level, age, sex, smoking, geographic location, and marital status, the correlation disappeared. Japanese city government workers between 21 and 67 years old also had vitamin D levels and depressive symptoms measured in another investigation.49 When vitamin D levels were obtained in November, there was an inverse relationship between symptoms and levels. However, in a month of greater sunlight exposure, July, the relationship was no longer observed.

Other studies have explored a possible season association between vitamin D levels and symptoms of depression in small groups of women. In a yearlong trial in nine women with vitamin D deficiency (B16 ng/mL), an association was observed between scores on indices of depressive symptoms and variation of serum vitamin D concentrations by season.50

Several treatment trials attempted to treat seasonal mood disorders with vitamin D. However, most used rather small doses of supplementation. In an open trial, 250 women, aged 4372 years, were given 400 IU cholecalciferol a day after their depression symptom scores were logged during the winter.51 Unfortunately, vitamin D failed to improve symp- toms. In Britain, 2117 women who age 70 years or older with seasonal affective disorder took either 6 months of a 800 IU supplement or a placebo, but vitamin D again did not resolve symptoms, although vitamin D levels were not measured for adequacy of treatment.52 Vitamin D was compared to phototherapy for seasonal effective disorder in another study in which eight individuals were treated with one dose of 100 000 IU, and another seven were provided phototherapy.53 Serum vitamin concentrations rose in the supplement group from a mean of 11.0 ng/mL to 19.1 ng/mL (pB0.003) and from 13.7 ng/mL to 18.6 ng/mL (pB0.007) in the phototherapy group. Recipients of vitamin D (74% response, pB0.005) significantly raised their depression

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