Objective To explore the relationship between vitamin D and depression and the effects of chronic unpredictable mild stress (CUMS) plus sertraline on vitamin D metabolism in rat brain. Methods Male SD rats were randomly divided into normal control group,normal control + sertraline group,CUMS group and CUMS+sertraline group.CUMS was used to build the animal model of depression.After chronic exposure to CUMS or sertraline (8 mg·kg-1·d-1) for 6 weeks,behavioral response (sucrose preference test) and vitamin D metabolism in the prefrontal cortex were analyzed. Results Compared with normal control group,6 weeks of CUMS procedure induced the rats to a depression-like state,decreased weight and sucrose preference,and increased the expression of enzymes involved in vitamin D activation and catabolism (CYP27B1 and CYP24A1,respectively) and vitamin D receptor (VDR) in rat prefrontal cortex.As compared with CUMS group,CYP27B1,CYP24A1 and VDR were significantly decreased in CUMS+sertraline group (P<0.01 or P<0.05). Conclusion CUMS activates vitamin D signaling in the brain of the animal models of depression,while sertraline alleviates depressive behavior and relieves stress-induced activation of vitamin D signaling,indicating that vitamin D signaling may be involved in the stress-induced depression.
Fig.1
Comparison of weight gain and sucrose preference among four groups of rats (x̅±s,n=6) A.normal control group;B.normal control plus sertraline group;C.depression model group;D.depression plus sertraline group;Compared with normal control group, *1P<0.01; Compared with depression model group,*2P<0.05
Fig.2
Comparison of the protein expression of CYP27B1 and CYP24A1 in prefrontal cortex among four groups of rats (x̅±s,n=6) A.normal control group;B.normal control plus sertraline group;C.depression model group;D.depression plus sertraline group;Compared with normal control group, *1P<0.01; Compared with depression model group, *2P<0.01,*3P<0.05
Fig.3
Comparison of VDR expression in prefrontal cortex among four groups of rats (x̅±s,n=6) A.normal control group;B.normal control plus sertraline group;C.depression model group;D.depression plus sertraline group;Compared with normal control group, *1P<0.01; Compared with depression model group, *2P<0.05
Fig.4
Immunohistochemical staining of four groups of rats(×400) A.normal control group;B.normal control plus sertraline group;C.depression model group;D.depression plus sertraline group
JIANGP, ZHANG LH, CAI HL, et al.Neurochemical effects of chronic administration of calcitriol in rats[J]. , 2014, 6(12): 6048-6059.
Despite accumulating data showing the various neurological actions of vitamin D (VD), its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D) administration (50 ng/kg/day or 100 ng/kg/day). Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated 纬-aminobutyric acid (GABA) status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD) 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS) expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA) expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.
BIKLE DD.Vitamin D metabolism, mechanism of action, and clinical applications[J]. , 2014, 21(3): 319-329.
Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D). CYP2R1 is the most important 25-hydroxylase; CYP27B1 is the key 1-hydroxylase. Both 25OHD and 1,25(OH)2D are catabolized by CYP24A1. 1,25(OH)2D is the ligand for the vitamin D receptor (VDR), a transcription factor, binding to sites in the DNA called vitamin D response elements (VDREs). There are thousands of these binding sites regulating hundreds of genes in a cell-specific fashion. VDR-regulated transcription is dependent on comodulators, the profile of which is also cell specific. Analogs of 1,25(OH)2D are being developed to target specific diseases with minimal side effects. This review will examine these different aspects of vitamin D metabolism, mechanism of action, and clinical application.
BASITS.Vitamin D in health and disease: a literature review[J]. , 2013, 70(4): 161-72.
Vitamin D, a fat-soluble prohormone, is synthesised in response to sunlight. Vitamin D requires two metabolic conversions, 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney, to become active hormone. The active form, 1alpha,25-(OH)2D, binds to the vitamin D receptor (VDR) to modulate gene transcription and regulate mineral ion homeostasis. Vitamin D plays several roles in the body, influencing bone health as well as serum calcium and phosphate levels. Furthermore, vitamin D may modify immune function, cell proliferation, differentiation and apoptosis. Vitamin D deficiency has been associated with numerous health outcomes, including risk of rickets in children or osteomalacia in adults, increased risk of fractures, falls, cancer, autoimmune disease, infectious disease, type 1 and type 2 diabetes, hypertension and heart disease, and other diseases such as multiple sclerosis. Here, vitamin D physiology and metabolism, its genomic action and association of polymorphisms in vitamin D pathway genes with different diseases are reviewed by focusing on new findings published in the literature.
POLAK MA, HOUGHTON LA, REEDER AI, et al.Serum 25-hydroxyvitamin D concentrations and depressive symptoms among young adult men and women[J]. , 2014, 6(11): 4720-4730.
There has been an increased interest in the role of vitamin D in depression; however, there have been few studies conducted in younger population groups. Our aim was to investigate the association between vitamin D status and depressive symptoms in a non-clinical young adult sample living in Dunedin, New Zealand. A cross-sectional sample of 615 young adults completed a questionnaire including demographics and the Centre for Epidemiological Studies Depression Scale (CES-D). Height, weight and a blood sample for 25-hydroxyvitamin D [25(OH)D] was obtained. Serum 25(OH)D was used to predict depression scores, adjusting for potential confounders including time spent outdoors for 13 consecutive days, BMI, age, sex and ethnicity. Prevalence of low vitamin D was high even in this age group, and serum 25(OH)D was negatively associated with depression symptoms before and after adjustment. When investigating the relationship between the presence versus absence of depressive symptoms and quartiles of 25(OH)D, participants in the lowest quartile were more likely to report depressive symptoms compared with those in the highest quartile. Although our findings suggest that vitamin D is a predictor of depression symptomatology, even when controlling for time spent outdoors, a randomised controlled trial in this young adult target group is needed to confirm the association.
ANGLIN RE, SAMAANZ, WALTER SD, et al.Vitamin D deficiency and depression in adults: systematic review and meta-analysis[J]. , 2013, 202:100-107.
Background There is conflicting evidence about the relationship between vitamin D deficiency and depression, and a systematic assessment of the literature has not been available.Aims To determine the relationship, if any, between vitamin D deficiency and depression.Method A systematic review and meta-analysis of observational studies and randomised controlled trials was conducted.Results One case–control study, ten cross-sectional studies and three cohort studies with a total of 31 424 participants were analysed. Lower vitamin D levels were found in people with depression compared with controls (SMD = 0.60, 95% CI 0.23–0.97) and there was an increased odds ratio of depression for the lowest v . highest vitamin D categories in the cross-sectional studies (OR = 1.31, 95% CI 1.0–1.71). The cohort studies showed a significantly increased hazard ratio of depression for the lowest v . highest vitamin D categories (HR = 2.21, 95% CI 1.40–3.49).Conclusions Our analyses are consistent with the hypothesis that low vitamin D concentration is associated with depression, and highlight the need for randomised controlled trials of vitamin D for the prevention and treatment of depression to determine whether this association is causal.
BERTONE-JOHNSON ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence?[J]. , 2009, 67(8): 481-492.
While recent laboratory-based studies have substantially advanced our understanding of the action of vitamin D in the brain, much is still unknown concerning how vitamin D relates to mood. The few epidemiological studies of vitamin D and depression have produced inconsistent results and generally have had substantial methodological limitations. Recent findings from a randomized trial suggest th...
EYLES DW, BURNE TH, MCGRATH JJ.Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease[J]. , 2013, 34(1): 47-64.
Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer鈥檚 disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus.
BERTONE-JOHNSON ER, POWERS SI, SPANGLERL, et al. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women[J]. , 2011, 94(4): 1104-1112.
Vitamin D may plausibly reduce the occurrence of depression in postmenopausal women; however, epidemiologic evidence is limited, and few prospective studies have been conducted.We conducted a cross-sectional and prospective analysis of vitamin D intake from foods and supplements and risk of depressive symptoms.Study participants were 81,189 members of the Women's Health Initiative (WHI) Observational Study who were aged 50-79 y at baseline. Vitamin D intake at baseline was measured by food-frequency and supplement-use questionnaires. Depressive symptoms at baseline and after 3 y were assessed by using the Burnam scale and current antidepressant medication use.After age, physical activity, and other factors were controlled for, women who reported a total intake of 鈮800 IU vitamin D/d had a prevalence OR for depressive symptoms of 0.79 (95% CI: 0.71, 0.89; P-trend < 0.001) compared with women who reported a total intake of <100 IU vitamin D/d. In analyses limited to women without evidence of depression at baseline, an intake of 鈮400 compared with <100 IU vitamin D/d from food sources was associated with 20% lower risk of depressive symptoms at year 3 (OR: 0.80; 95% CI: 0.67, 0.95; P-trend = 0.001). The results for supplemental vitamin D were less consistent, as were the results from secondary analyses that included as cases women who were currently using antidepressant medications.Overall, our findings support a potential inverse association of vitamin D, primarily from food sources, and depressive symptoms in postmenopausal women. Additional prospective studies and randomized trials are essential in establishing whether the improvement of vitamin D status holds promise for the prevention of depression, the treatment of depression, or both.
HOANG MT, DEFINA LF, WILLIS BL, et al.Association between low serum 25-hydroxyvitamin D and depression in a large sample of healthy adults: the Cooper Center longitudinal study[J]. , 2011, 86(11): 1050-1055.
To investigate the association between serum vitamin D levels and depression in a large database of patients from the Cooper Clinic.We conducted a cross-sectional study of 12,594 participants seen at the Cooper Clinic from November 27, 2006, to October 4, 2010. Serum 25-hydroxyvitamin D [25(OH)D] was analyzed, and depression was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of 10 or more. Those with and those without a history of depression represented 2 distinct populations with respect to CES-D scores; accordingly, they were analyzed separately.In the total sample, higher vitamin D levels were associated with a significantly decreased risk [odds ratio, 0.92 (95% confidence interval, 0.87-0.97)] of current depression based on CES-D scores. The finding was stronger in those with a prior history of depression [odds ratio, 0.90 (95% confidence interval, 0.82-0.98)] and not significant in those without a history of depression [odds ratio, 0.95 (95% confidence interval, 0.89-1.02)].We found that low vitamin D levels are associated with depressive symptoms, especially in persons with a history of depression. These findings suggest that primary care patients with a history of depression may be an important target for assessment of vitamin D levels.
ANNWEILERC, ANNWEILERT, MONTERO-ODASSOM, et al.Vitamin D and brain volumetric changes: systematic review and meta-analysis[J]. , 2014, 78(1): 30-39.
Vitamin D has multiple functions in the nervous system. Our objective was to systematically review and quantitatively synthesize evidence on the location and nature of brain morphometric changes linked to vitamin D depletion or repletion. A Medline search was conducted in February 2014, without limit of date and language restriction, using the MeSH terms "Vitamin D" OR "Ergocalciferols" combined with "Brain Mapping" OR "Magnetic Resonance Imaging" OR "Tomography, X-ray Computed" OR "Tomography, Emission-Computed, Single-Photon" OR "Positron-Emission Tomography" OR "Nuclear Medicine" OR "Radionucleide Imaging". Of the 376 selected studies, nine observational studies - two animal and seven human studies - met the selection criteria. The number of participants ranged from 20 to 333 (40-79% female). Three studies were eligible for fixed-effects meta-analysis of bias-corrected effect size of the difference in lateral ventricle volume between cases with vitamin D depletion and controls. Results showed that vitamin D depletion was associated with lower brain volume, specifically larger lateral ventricles. The pooled effect size was 1.01 [95% CI: 0.62; 1.41], a 'large' effect size indicating that the ventricle volume was 1.01 SD higher with vitamin D depletion. Results on brain subvolumes were mixed, and indicated that brain atrophy with vitamin D depletion could be explained not by temporal lobe atrophy but rather by loss of matter at the cranial vertex, possibly in the precuneus cortex. In conclusion, despite increasing evidence arguing for an action of vitamin D in the brain, data is sparse regarding brain morphological changes related to vitamin D depletion. The retrieved association between vitamin D depletion and brain atrophy provides a scientific base for vitamin D replacement trials.
JIANGP, XUEY, LI HD, et al.Dysregulation of vitamin D metabolism in the brain and myocardium of rats following prolonged exposure to dexamethasone[J]. , 2014, 231(17): 3445-3451.
Rationale Chronic stress or hypercortisolism may increase the risks of depression, cardiac disorders, and osteoporosis, which are also associated with vitamin D (VD) deficiency. Both glucocorticoid receptor (GR) and vitamin D receptor (VDR) are widely distributed and affect many aspects of human physiology. The cross talk between the two steroids is pervasive, but the effect of glucocorticoids on circulating VD and local VD metabolism remains elusive. Objectives To fill this critical gap, we assessed the alterations of circulating VD and VD intracrine system in the brain and myocardium of rats treated with two different doses (0.2 and 2聽mg/kg/day, respectively) of dexamethasone ( Dex ). Results Daily treatment with 2聽mg/kg of Dex for 10聽days induced the rats to a depressive-like state and decreased the expression of both VDR and the cytochromes P450 enzymes involved in VD activation (CYP27B1) and catabolism (CYP24A1) in the prefrontal cortex and hippocampus. Meanwhile, the dose of 0.2聽mg/kg Dex increased the expression of VDR in the prefrontal cortex but inhibited CYP27B1/CYP24A1/VDR expression in the hippocampus. Similarly, in the myocardium, the rats treated with Dex showed significantly lower expression of CYP27B1/CYP24A1/VDR. Renal VD metabolism and serum VD status were unchanged in 0.2聽mg/kg Dex -treated rats. However, the higher dose suppressed the three key players involved in VD metabolism but did not alter serum VD levels. Conclusion These data provide new evidence that glucocorticoids could affect intracrine actions of VD in the brain and myocardium, which suggests the potential involvement of VD in the neural and cardiac dysfunctions induced by glucocorticoid excess.
BRUNONI AR, KEMP AH, DANTAS EM, et al.Heart rate variability is a trait marker of major depressive disorder: evidence from the sertraline vs. electric current therapy to treat depression clinical study[J]. , 2013, 16(9): 1937-1949.
Decreased heart rate variability (HRV) is a cardiovascular predictor of mortality. Recent debate has focused on whether reductions in HRV in () are a consequence of the disorder or a consequence of pharmacotherapy. Here we report on the impact of transcranial direct current stimulation (tDCS), a non-pharmacological intervention, vs. to further investigate this issue. The employed design was a double-blind, randomized, factorial, placebo-controlled trial. One hundred and eighteen moderate-to-severe, medication-free, low-cardiovascular risk depressed patients were recruited for this study and allocated to either active/sham tDCS (10 consecutive sessions plus two extra sessions every other week) or placebo/(50 mg/d) for 6 wk. Patients were age and gender-matched to healthy controls from a concurrent cohort study [the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)]. The impact of disorder, treatment and clinical response on HRV (root mean square of successive differences and high frequency) was examined. Our findings confirmed that patients displayed decreased HRV relative to controls. Furthermore, HRV scores did not change following treatment with either a non-pharmacological (tDCS) or pharmacological () intervention, nor did HRV increase with clinical response to treatment. Based on these findings, we discuss whether reduced HRV is a trait-marker for , which may predispose patients to a of conditions and disease even after response to treatment. Our findings have important implications for our understanding of pathophysiology and the relationship between , and mortality.
Heart rate variability is a trait marker of major depressive disorder: evidence from the sertraline vs. electric current therapy to treat depression clinical study