- Email: [email protected]
Vitamin D and depression
Author’s Accepted Manuscript Vitamin D and Depression Gordon B. Parker, Heather Brotchie, Rebecca K. Graham
www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(16)30892-8 http://dx.doi.org/10.1016/j.jad.2016.08.082 JAD8563
To appear in: Journal of Affective Disorders Received date: 30 May 2016 Revised date: 18 July 2016 Accepted date: 27 August 2016 Cite this article as: Gordon B. Parker, Heather Brotchie and Rebecca K. Graham, Vitamin D and Depression, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2016.08.082 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Vitamin D and Depression Gordon B. Parkerab*, M.D, PhD, FRANZCP Heather Brotchie, MB BS, BA Rebecca K. Grahamab, BA. (Psych hons), PhD
a School b Black
*
of Psychiatry, University of New South Wales, Sydney, NSW, Australia
Dog Institute, Sydney, NSW, Australia
Corresponding author and reprints. G. Parker, Black Dog Institute. Hospital Rd, Prince of Wales
Hospital, Randwick, Sydney, Australia, 2031. E-mail address: [email protected]; Tel.: +61 293824372; fax: +61 29382434
Abstract Objective: To examine whether vitamin D deficiency or insufficiency is associated with depression and whether vitamin D supplementation is an effective treatment for depression. Method: Empirical papers published in recent years were identified using three search engines and online databases – PubMed, Google Scholar and Cochrane Database. Specific search terms used were ‘vitamin D’, ‘depression’ and ‘treatment’ and articles were selected that examined the association between vitamin D deficiency/insufficiency and depression, vitamin D supplementation and Vitamin D as a treatment for depression. Our review weighted more recent studies (from 2011), although also considered earlier publications. Results: Empirical studies appear to provide increasing evidence for an association between vitamin D insufficiency and depression, and for vitamin D supplementation and augmentation in those with clinical depression who are vitamin D deficient. Methodological limitations associated with many of the studies are detailed. Limitations: Articles were restricted to those in the English language while publication bias may have weighted studies with positive findings. Conclusions: There remains a need for empirical studies to move beyond cross-sectional designs to undertake more randomised controlled longitudinal trials so as to clarify the role of vitamin D in the pathogenesis of depression and its management, as well as to establish whether currently suggested associations are clinically significant and distinctive. 1
Keywords: vitamin D, depression, treatment, augmentation, supplementation.
1. Introduction There has been longstanding interest in the role of ‘natural’ treatments for depression, such as nutritional and dietary products. While many dietary factors have been implicated in the cause and treatment of depression, there has been a lack of scientific rigour in many of the reported studies. The principal dietary preparations so considered in journal reports include omega-3 fatty acids, vitamin D, the vitamin B group, minerals (e.g. zinc, magnesium and iron), antioxidants (e.g. vitamin C) and soy. In this paper we focus on vitamin D as changes in vitamin D receptors impact on various brain neurotransmitters, and thus suggest a potential role of vitamin D in causing and redressing mood disorders. While a role for vitamin D has been implicated in varying psychiatric and neurological conditions, the current review focuses solely on depression. The aim of this study was to extend a previous 2011 clinical review (Parker and Brotchie, 2011) and include more recent studies evaluating links between vitamin D and depression. In particular, to examine (i) the extent to which vitamin D deficiency and insufficiency is associated with depression, and (ii) whether vitamin D is an efficacious treatment for depression for those with vitamin D deficiency or insufficiency when given as a supplement or when augmenting an antidepressant drug. 2. Methods and material A literature search of relevant databases was performed (using PubMed, Cochrane Database of Systematic Reviews and Google Scholar) with papers selected that evaluated the association between vitamin D and depression. Specific search terms included “vitamin D” and “depression” – and with “treatment” included to identify studies related to whether vitamin D is an efficacious treatment for depression. In selecting studies, we prioritised those published in recent years (2011 – 2016) – while also including and overviewing earlier studies - that examined for links between vitamin D deficiency or insufficiency and depression, and as to whether vitamin D has antidepressant properties. 3. Results We first detail information regarding the process via which Vitamin D enters the body, consider sufficient and optimal levels in humans and detail the role of vitamin D in the human body. Study results (from the last five years) are considered together with data presented in the previous 2011 review. The section then overviews the empirical research on vitamin D and variable expressions of depression including Seasonal Affective Disorder. 3.1. Overview of vitamin D 2
Vitamin D can be accessed by humans from a variety of sources, including exposure to sunlight, general diet intake and dietary supplements (Holick, 2007). While there are two types of vitamin D obtained from dietary sources, D2 (or ergocalciferol) from plant sources (such as mushrooms and soy milk) and D3 (or cholecalciferol) from animal sources (such as raw fish, mackerel, eel, canned/smoked salmon), D3 is approximately three times stronger than D2. However, even from animal sources, it is difficult to obtain sufficient daily vitamin D from general dietary intake (Maxwell, 1994). The majority of vitamin D is produced in the body through the penetration of sunlight on the skin to ultraviolet B (UVB) radiation which involves a complex process involving solar UVB radiation converting 7-dehydrocholesterol to pre-vitamin D3, and then to vitamin D3. Once converted, Vitamin D enters the blood stream and is metabolised in the liver, forming 25-hydroxyvitamin D or 25 (OH) D and is then further metabolised in the kidneys to its active form (1,25-dihydroxyvitamin D). This process is illustrated graphically in Figure 1. It then binds to vitamin D receptors in target tissues to regulate gene transcription and to structures within cell membranes to mediate a number of non-genomic responses. Vitamin D receptors are present in most tissues and cells in the body, and within the brain show some specificity to the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus and substantia nigra (Eyles et al., 2005; Eyles et al., 2013). This is of relevance as many of those brain regions have been implicated in the physiology of depression (Drevets et al., 2008). Blood levels of 25 (OH) D are used to determine whether an individual has adequate levels of vitamin D and can be reported either as nanograms per millilitre (ng/ml) or as nanomoles per litre (nmol/L). While there is a lack of international consensus, it is generally conceded that the optimal range of 25 (OH) D is between 3060 ng/ml and with ‘insufficiency’ defined as levels between 21-29 ng/ml and ‘deficiency’ as < 20 ng/ml (Holick, 2007). For laboratories that measure in nmol/litre, < 50 nM is judged as the criterion for vitamin D deficiency. Recommendations from the Institute of Medicine of the National Academies (2011) for adequate daily vitamin D levels are 600 IU for children and adults up to 70 years of age, and 800 for adults over 70 years of age. If there is evidence of vitamin D deficiency, the recommended daily supplement is 1000 IU to correct the deficiency and to then maintain adequate levels. It has been estimated that approximately one billion people have insufficient levels of vitamin D or are vitamin D deficient. There are a multitude of reasons for vitamin deficiency, even in warm and sunny climates where vitamin D in the form of sunlight is freely available for most of the year. The season, time of day and latitude affects the amount of solar radiation reaching the skin as the number of solar UVB photons reaching the earth depends on the zenith angle of the sun. Current lifestyle factors also play a role, as the majority of people spend their working hours unexposed to sunshine (Joshi et al., 2010). The elderly may be at particular risk for low levels if housebound or living in nursing homes. Other important factors include ageing, darker skin tones (melanin absorbs more UVB radiation) and sunscreen use – which, while playing an important role in preventing skin cancers, also absorbs UVB radiation. 3
Decreased vitamin D can also occur (i) as a consequence of liver failure and chronic renal diseases, (ii) decreased bioavailability (due to factors such as malabsorption and obesity) and (iii) increased catabolism (due to certain medications, such as anticonvulsants and glucocorticoids). 3.2. Vitamin D and the human body The potential effects of extended vitamin D deficiency on the human body are vast and varied, and spread across most of the lifespan. In utero and during childhood, vitamin D deficiency can cause growth retardation and skeletal deformities, and may increase the risk of hip fracture in later adulthood. Vitamin D is considered essential for bone health, and with deficiency potentially leading to calcium deficiency and reduced bone density which can lead to conditions such as osteopenia and osteoporosis. Vitamin D also plays an important role in immunity and in destroying various infectious agents and is judged to have the potential to prevent certain cancers (e.g. breast, colon and prostate). It can also have effects on blood pressure, body circulation and blood sugar control (Holick, 2007). Eyles et al. (2013) reviewed the biology of vitamin D in the developing and adult brain and the links between low levels of vitamin D and neuropsychiatric diseases. The active form of vitamin D, calcitriol, plays a role in activating the gene expression of an enzyme (tyrosine hydroxylase) which is considered to be the rate-limiting step in the synthesis of the catecholamines. These neurotransmitters (namely, dopamine, noradrenaline and adrenaline) are implicated in the pathophysiology of mood disorders. If there is a causal relationship whereby vitamin D insufficiency or deficiency provides a risk to later depression, suggested possible mechanisms include compromised nerve growth factor synthesis and an impact on various neurotransmitter targets. 3.3. Studies examining for links between vitamin D levels and depression An overview of the empirical studies examining for an association between vitamin D and depression is now presented, with results described separately for (1) crosssectional studies, (2) longitudinal studies and (3) randomised controlled trials. The section is concluded by considering a specific subtype of depression - seasonal affective disorder (or SAD) - characterised by depressive symptoms that occur at the darkest time of the year and where it is hypothesised that light deficiency is causal. 3.3.1. Cross-sectional studies The numerous cross-sectional studies reported in the last decade have generated contrasting findings. A population-based cohort study of those aged 65 years or older in the Netherlands (Hoogendijk et al., 2008) reported that 25 (OH) D levels were 14% lower in both those diagnosed with minor depression (n = 169) and with major depression (n = 26). Lower 25 (OH) D levels were linked with greater depression severity, and with the association remaining significant after controlling for age, gender, body mass index (BMI), smoking status and a number of medical conditions. Conversely, 4
a population-based cross-sectional study in China (Pan et al., 2009) examined 3,262 middle-aged and elderly Chinese community residents and failed to find any evidence linking depressive symptoms with 25 (OH) D levels. Bertone-Johnson (2009) overviewed and considered reasons for the contrasting conclusions in relation to any links between 25 (OH) D levels and both depression and depression severity. For example, the studies noting ‘positive’ results often failed to consider other potential explanations such that depressed individuals may be at greater risk of lower vitamin D levels as a consequence of spending less time outdoors, being less physically active and with any decreased appetite leading to dietary changes. Thus, as lower vitamin D levels may be an antecedent or a consequence of depression, prospective studies are required to assess changes in mood over time to determine causality. Some cross-sectional community studies have evaluated – and rejected – any contribution from such lifestyle factors. For example, a large United Kingdom epidemiological study of 3,369 men with a mean age of 60 years (Lee et al., 2011) reported an inverse relationship between 25 (OH) D levels and depression levels but with their analyses largely failing to find a contribution from several lifestyle and health factors. In another report, Zhao et al. (2010) conducted a large cross-sectional study amongst adults of all ages. They failed to show a significant association between vitamin D deficiency and depression after adjusting for potential confounders (e.g. the degree of sun exposure, the level of physical activity, diet, age and BMI). Other studies have reported weak associations with lifestyle factors. For example, Black et al. (2014) undertook a cross-sectional study of young adults recruited from the Western Australian Pregnancy Cohort Study, investigating the relationship between serum 25(OH)D concentrations and symptoms of depression, anxiety and stress. After adjusting for confounding factors (i.e. age, race, BMI and physical activity), an increase in serum 25(OH)D of 10 nmol/L was associated with an 8% decrease in depression subscale scores in males (not females) – but there were no significant associations with symptoms of stress and anxiety. While many of these studies have reported a positive association between vitamin D deficiency and depression in elderly patients, there is less empirical support for this association in younger samples. The other key problem with cross-sectional studies is that any clarification of causality requires a longitudinal design. Thus, while crosssectional designs allow for an examination of the association between two variables (e.g. vitamin D deficiency and depression), they fail to specify the direction of these effects (e.g. Do low vitamin D levels lead to depression, or does depression lead to low vitamin D levels?). This is salient as depressed individuals often isolate themselves indoors and/or their associated reduced appetite may lead to dietary changes that then reduce their vitamin D levels. 3.3.2. Longitudinal studies Few studies examining for an association between vitamin D and depression using a longitudinal design have been published. Milaneschi et al. (2010) examined the association between vitamin D levels at baseline and subsequent depression in their 65
year prospective study with 954 adults aged 65 years or older. They reported that individuals with low 25 (OH) D3 levels at baseline (i.e. <50 nM or <20 ng/ml) had significantly higher depression scores at the two follow-up periods (3 and 6 years) compared to those with high levels at baseline – and with the association being more distinctive for women than for men. Milaneschi et al. (2013) investigated the association between 25 (OH) D levels and depressive disorders in a large cohort aged 18-65 years from the Netherlands Study of Depression and Anxiety. While mainly cross-sectional, the study had longitudinal elements, and comprised 1,102 subjects with current depressive disorders, 790 with remitted depressive disorders (according to DSM-IV criteria) and 495 healthy controls. Compared with healthy controls, lower 25 (OH) D levels were quantified in participants with current clinical depression, particularly in those with the most severe symptoms. In the currently depressed sub-set, 25 (OH) D was inversely associated with symptom severity - suggesting a dose-response gradient – and, in relation to the longitudinal component, with a greater risk of having a depressive disorder at the two-year follow up. The authors suggested that low vitamin D levels may represent an underlying biological vulnerability to depression. This study had the advantage of including those with a clinical diagnosis of depression, and also adjusting for potential confounding factors in the assessment of 25(OH) D levels, including a measure of actual sunlight irradiation. Almeida et al. (2015) undertook an observational study examining for retrospective, cross-sectional and prospective associations between vitamin D concentration and depressed mood in a community-derived sample of 3,105 older men. Plasma concentration of 25(OH) D was measured at the time of the study and a history of ‘past depression’ measured through direct questioning and administrative health linkage data. ‘Current depression’ was assessed via a geriatric depression scale and ‘incident depression’ by a health questionnaire score or by administrative health data linkage during the 6-year follow up period. A vitamin D concentration of < 50nmol/L was associated with greater odds of current, but not past, depression. Of the 2,740 men with neither a past nor a current history of depression, 81 developed clinically significant symptoms during the follow-up period. The adjusted hazard ratio of incident depression for men with plasma vitamin D <50 nmol/L was 1.03. The authors interpreted their results as not supporting a role for vitamin D as a cause of depression. 3.3.3 Meta-analytic results A systematic review and meta-analysis conducted by Anglin et al. (2013) evaluated the relationship between depression and hypovitaminosis D including pooled data from one case study, 10 cross-sectional studies and three longitudinal cohort studies. They reported a positive association between low vitamin D levels and depression. Specifically, they quantified lower vitamin D levels in individuals with depression compared with controls and, in the cross-sectional studies, an increased odds ratio of depression for the lowest versus the highest vitamin D categories. In addition, the cohort studies showed a significantly increased hazard ratio of depression for the 6
lowest versus highest vitamin D categories. This data base was later re-analysed by Annweiler et al. (2013) using a new random-effects meta-analysis. Their analysis quantified a probability of about 65% that an individual with depression would have a lower 25(OH) D concentration than an individual without depression, if both individuals were chosen at random. 3.4. Randomised controlled trials evaluating vitamin D as a treatment factor While randomised controlled trials (or RCTs) are important to determine whether vitamin D supplementation is an effective treatment for depression, those studies have yielded inconsistent results. This may reflect design limitations (e.g. varying study criteria such as sample size, age range of subjects, vitamin D dosage and method of administration, depression measures used and the assessment of outcome). Such limitations make it difficult to generalise findings across studies. The majority of the studies report on the effect of vitamin D supplementation (comparing individuals receiving only vitamin D with a placebo group) while there has become a more recent focus on the possible role of vitamin D augmentation (comparing individuals receiving an antidepressant and vitamin D supplementation to those receiving only an antidepressant). 3.4.1. Vitamin D supplementation In a recent study, Li et al. (2014) undertook a systematic review of RCT’s evaluating the efficacy of vitamin D use in comparison with placebo in those with depression. They selected parallel RCTs investigating adults at risk of depression, those with depressive symptoms and those with a primary diagnosis of depression, and employed a classical and Bayesian random effects meta-analysis of six RCTS – with five studies sampling adults at risk of depression and one study of depressed patients. Their analysis found no significant effect of vitamin D supplements on post-intervention depression scores. They noted that factors such as varying vitamin D3 dosages, a range in duration of treatment (from weeks to years) and various measures used to measure depression may have confounded interpretation. They concluded, however, that there is insufficient evidence to support the efficacy of vitamin D supplementation in those with depressive symptoms. Spedding (2014) undertook a systematic review and meta-analysis of 15 randomised controlled trials (RCTs) that examined the efficacy of vitamin D supplements for those with depression, variably measured by depression severity and whether clinical criteria (for major depression) were met. They noted that previous meta-analyses of such studies had failed to demonstrate efficacy and appraised the methodological quality and biological flaws (i.e. limitations in the design of primary studies which preclude the research hypothesis being tested) in relation to both the hypotheses and study designs. Of the 15 RCTs, results from the eight studies with ‘biological flaws’ were inconclusive, while the seven without such flaws showed statistically significant improvement in depression (i.e. Arvold et al. 2009; Gloth et al. 1999; Jorde et al. 2008; Khoraminya et al. 2013; Landsdowne & Provost 1998; Veith et 7
al. 2004; Zhang et al. 2011). Based on those studies lacking methodological flaws, Spedding concluded that vitamin D supplementation of 800 mg or more daily was of benefit in the management of depression and when vitamin D levels were raised by supplementation. His detailing of ‘biological flaws’ highlights that supplementation studies must require participants to be vitamin D deficient at baseline and to receive an adequate dose of vitamin D to achieve vitamin D sufficiency status during the trial criteria not met by many of the RCTs. One of these studies judged to be without ‘biological flaws’ (i.e. Jorde et al. 2008), involved a large sample of overweight or obese individuals aged 21-70 years, and whose depression severity scores were higher one year later in those with insufficient levels of 25 (OH) D. However, levels of 25 (OH) D were not found to correlate with depression severity scores. Those randomly allocated to receive vitamin D supplementation of either 40,000 or 20,000 IU each week showed an improvement in depression scores 12 months later, which did not occur in those receiving the placebo. There were, nevertheless, several study limitations, such as the use of a community sample with low rates of clinical depression. Schaffer et al. (2014) reviewed the effects of vitamin D supplementation on depressive symptoms in published RCTs. Of the seven trials meeting study inclusion criteria, results indicated that vitamin D supplementation had no overall effect on depressive symptoms. Subgroup analyses, however, revealed a moderate and statistically significant effect for participants in two (of the seven) studies and which involved subjects with clinically significant depressive symptoms or a depressive disorder (Mozaffari-Khosravi et al. 2013; Khoraminya et al. 2013). There was a small non-significant effect in the five studies involving those without clinically significant depression. Schaffer et al. concluded that vitamin D supplementation may be effective for reducing depressive symptoms in patients with clinically significant depression but that further high quality research is needed to target depressed patients, assess baseline levels of vitamin D and also consider appropriate vitamin D dosing and method of delivery. Such nuances are highlighted in a clinical trial by Mozarffari-Khozravi et al. (2013) that followed 120 patients with a Beck Depression Inventory (BDI) score of 17 or more and who were assessed as vitamin D deficient. Subjects were randomly assigned to three groups (n = 40 in each), with one group receiving a single intramuscular dose of 300,000 IU vitamin D, the second receiving a single intramuscular dose of 150,000 IU vitamin D, and the third receiving no intervention. After three months, the depression state and serum vitamin D were remeasured. In the group that received 300,000 IU vitamin D there was a significant correction of vitamin D deficiency, and it was only this group that showed a significant improvement in BDI depression scores compared to the group that received no vitamin D intervention. The authors concluded that the correction of the vitamin D deficiency improved the depression state and that 300,000 IU of vitamin D was safe and more effective than a 150,000 IU dose. Sepehrmanesh et al. (2015) reported a RCT study in patients with Major Depressive Disorder (MDD) and with all being vitamin D deficient (with serum 25(OH) D < 20ug/l) to assess whether vitamin D supplementation can reduce symptoms of depression, and 8
measured metabolic profiles, serum high-sensitivity C-reactive protein (hs-CRP) and biomarkers of oxidative stress. Forty patients aged 18-65 years were assigned to receive a single capsule of 50,000 IU vitamin D per week or a placebo for eight weeks and with serum 25(OH) D levels measured at baseline and again at eight weeks. For those receiving vitamin D supplementation, there was a greater change in levels compared to those who did not receive vitamin D at week 8 (20.4 ug/L +/or -5.5 ug/L compared to a decrease of 0.9ug/L +/or -3.5 ug/L in the placebo group). This study showed that, after controlling for age and baseline BMI, vitamin D supplementation was associated with a significant decrease in Beck Depression Inventory (BDI) scores, in addition to improvements in glucose homeostasis and oxidative stress compared to the placebo group, although with no significant changes in serum calcium concentrations, lipid profiles, fasting plasma glucose (FPG), insulin sensitivity check index (QUICKI) or hs-CRP concentrations. 3.4.2. Vitamin D augmentation with an antidepressant In addition to pure vitamin D supplementation (which presumes vitamin D being prescribed alone) there has been increased interest in vitamin D as an augmenter of antidepressant medication. The adjunctive use of standardized pharmaceutical grade nutrients (or ‘nutraceuticals’), has the potential to modulate specific neurochemical pathways implicated in depression. A clinical study by Khoraminya et al. (2013) was the first randomized, double-blind, placebo-controlled trial specifically designed to determine the effects of vitamin D augmentation in patients with major depressive disorder (MDD). Forty two outpatients with a DSM-IV diagnosis of MDD without psychotic features were randomly assigned to receive 500 IU of vitamin D plus one 20 mg capsule of fluoxetine or, alternatively, a vitamin D placebo tablet and the fluoxetine capsule daily for eight weeks. Fasting levels of 25 (OH) D levels were taken at the start of the trial and depression severity assessed every two weeks. Results indicated that the vitamin D plus fluoxetine combination was significantly superior to fluoxetine alone in patients with MDD and who were vitamin D deficient. While studies are slowly developing in this area, there is a need for more specialized systematic reviews or meta-analyses. Sarris et al. (2016) conducted a systematic review based on 40 world-wide clinical trials (up to December, 2015) that used nutraceuticals to treat clinical depression in combination with formal antidepressant medications. Primarily positive results were found for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethylEPA), and vitamin D (results based on only two studies), with positive isolated studies for creatine, folinic acid, and an amino acid combination. Based on their findings, the authors concluded that the current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms. 3.5. Seasonality, vitamin D and depression
9
The process via which vitamin D affects mood may be particularly pertinent for those depressive disorders with seasonal patterns and where variations in UVB exposure may result in vitamin D deficiency. For example, Seasonal Affective Disorder (or SAD) is a depressive subtype characterised by depressive symptoms that occur at the darkest time of the year and where light deficiency is viewed as causal. Characteristic symptoms are hypersomnia, hyperphagia, anergia, mood worsening in the evening, and with symptoms lessoning in the spring and summer due to the increase in levels of light. The specific mechanism involved is believed to be the shorter daily photoperiod of winter, with suboptimal light input to retinal photoreceptors disturbing the optimal functioning of the suprachiasmatic nucleus (SCN) and its interactions with the pineal gland and secretion of melatonin. While there has been some success in treatment via phototherapy, such studies have produced inconsistent findings. It has been suggested that light and the circadian regulation of the SCN are closely related to the pathophysiology of SAD, with serotonin dysfunction implicated in the process (Humble, 2010). The association between vitamin D deficiency and SAD is suggested by its higher prevalence at increased latitude where there is reduced exposure to UVB radiation and we now consider some salient studies. 3.5.1. Cross sectional studies on seasonality, vitamin D and depression A community-based observational study in Japan (Nanri et al. 2011) involving 527 participants (aged between 21 and 67 years) found no association between 25 (OH) D3 and depressive symptoms – although there was a trend for vitamin D to have a protective effect on depression in late autumn (when there are low levels of sunshine) compared to the summer season. A national community study in England (Stewart & Hirani, 2010) of 2,070 older people (over 65 years) reported that vitamin D deficiency was associated with severe (but not milder) depression in northern latitudes, but that this association was not modified by season of examination. Such findings correspond to the results found in an Amsterdam study (Hoogendijk et al. 2008) - although those authors reported that lower 25 (OH) D levels were associated with both major and minor depression – but again with season of data acquisition having no effect on the association. In a study by Stewart and Hirani (2010), seasonality did not influence the association between low 25 (OH) D and depression. Such data are indirect as there are currently no known published longitudinal studies on vitamin D and depression for individuals with SAD. 3.5.2. RCTs related to SAD and vitamin D A small double-blind intervention study (Gloth et al. 1999) randomly assigned eight patients with seasonal affective disorder (SAD) to receive 100,000 IU of daily vitamin D and seven to receive phototherapy. The authors reported that vitamin D supplementation was associated with a greater improvement on depression measures, and with such improvement significantly correlated with the increase in 25 (OH) D levels. There have been several small RCTs examining the effect of vitamin D supplementation in those with seasonal mood changes, and with many reporting 10
positive effects. Lansdowne and Provost (1998) randomised 44 healthy participants to receive varying doses of vitamin D3 for five days over winter, and with supplementation associated with improvements in positive affect and with decreased negative affect. Another larger trial randomised 82 adults with vitamin D deficiency into two groups receiving varying doses of vitamin D supplementation for two winters (600 and 4000 IU) and found some improvement on depression scores after two months in the group receiving the higher dosage (Vieth et al. 2004). An RCT by Dumville et al. (2006), however, found no significant improvement in mental health scores of elderly women who received supplementation with 800 IU of vitamin D over a six-month winter period, although only small doses of vitamin D were used and 25(OH)D was not assessed in this study. Bertone-Johnston (2009) reviewed these studies and concluded that there is only “modest support” for the effective treatment of SAD symptoms with vitamin D supplementation. 4. Discussion While our understanding of the basic physiology of the function of vitamin D in the brain is steadily increasing, there is a need for more sophisticated studies to gain a greater understanding of the processes, especially vitamin D ligand distribution and receptor function. Human studies using MRI brain scanning techniques and animal modelling studies (Eyles et al. 2013) may be of relevance in advancing this understanding. The available research evidence indicates that adequate levels of vitamin D intake are required for normal brain neuropsychiatric functioning, with meta-analyses from cross-sectional and longitudinal studies suggesting an association between low levels of vitamin D and some expressions of ‘depression’. The caveat here is that some studies have examined ‘depression’ dimensionally on depression severity measures (and thus including those who would not meet formal depression ‘caseness’ criteria) while others limit consideration to individuals meeting clinical criteria for depression, with the latter group perhaps the most important. Few studies have examined for the multiple salient confounding factors that may create non-causal associations, while not all studies have limited intervention to those who are formally deficient or insufficient in vitamin D. Turning to the second key issue – is vitamin D supplementation of benefit for those with depression – there is again support from several systematic reviews and metaanalyses for the proposal but also a number of caveats. Benefit or not may reflect the type and severity of ‘depression,’ whether vitamin D is prescribed alone or in conjunction with an antidepressant drug – and with benefit likely to be restricted to those who were vitamin D deficient prior to intervention. As summarised by GlickmanSimon and Pettit (2015), clarifying whether there is any therapeutic role will require large randomised, placebo-controlled trials that (i) enrol only depressed patients deficient in vitamin D, (ii) administer a standardized oral dosage (those authors suggesting 1,000 IU of cholecalciferol and (iii) measure post-treatment vitamin D levels to ensure that vitamin D levels are then within the normal range. We would include additional criteria, such that assessments examine improvement in relation to both 11
formalised clinical depressive disorders and to depression severity. Further, that studies evaluate vitamin D supplementation alone as against its use as an antidepressant augmentor, as it is likely that many of the published studies assessing vitamin D supplementation included patients who were already in receipt of an antidepressant medication for their depression. The recent systematic review by Sarris et al. (2016) is one of the first to suggest that vitamin D (among other nutraceuticals) is recommended for use with antidepressant medications in effectively treating depression, but as this review considered only two clinical trials, that conclusion cannot be viewed as definitive. In relation to seasonal affective disorder (SAD), it would appear that vitamin D deficiency is unlikely to contribute to its aetiology but some evidence to indicate that those experiencing SAD may benefit from Vitamin D augmentation. 5. Limitations The main limitations of the current analysis include only reviewing publications in the English language, and the necessary inclusion of only published material which may be limited to positive findings and thus risk artificial inflation of results. 6. Conclusion We conclude, from both the cross-sectional and longitudinal studies, that there is increasing evidence of an increased risk of depression in those who are vitamin D deficient and that vitamin D supplementation is of benefit for depressed individuals who are vitamin D deficient. Acknowledgments This study was supported by an NHMRC Program Grant (1037196). There are no relevant conflicts to disclose. References Almeida, O.P., Hankey, G.J., Yeap, B.B., Golledge, J., Flicker, L., 2015. Vitamin D concentration and its association with past, current and future depression in older men: The Health in Men Study. Maturitas. 81, 36-41. Anglin, R.E.S., Samaan, Z., Walter S.D., McDonald, S.D., 2013. Vitamin D deficiency and depression in adults: systemic review and meta-analysis. Br. J. Psych. 202, 100117. Annweiler, C., Rastmanesh, R., Richard-Devantoy, S., Beauchet, O., 2013. ASCP Corner: The role of vitamin D in depression: From a curious idea to a therapeutic option. J. Clin. Psychiatry. 74(11), 1121-1122. Arvold, D., Odean, M., Dornfeld, M., Regal, R., Arvold, J., Karwoski, G., Mast, D., Sanford, P., Sjoberg, R., 2009. Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial. Endocrine Practice. 15(3), 203-212. 12
Bertrone-Johnson, E.R., 2009. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr. Rev. 67, 481-492. Bertone-Johnson, E. R., Powers, S. I., Spangler, L., Brunner, R. L., Michael, Y. L., Larson, J. C., Millen, A.E., Bueche, M.N., Salmoirago-Blotcher, E., Liu, S., Wassertheil-Smoller, S., 2011. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am. J. Clin. Nutr. 94(4), 1104-1112. Black, L.J., Jacoby, P., Allen, K.L., Trapp, G.S., Hart, P.H., Byrne, S.M., Mori, T.A., Beilin, L.J., Oddy, W.H., 2014. Low vitamin D levels are associated with symptoms of depression in young adults. Aust. NZ. J. Psychiatry. 48(5), 464-471. de Koning, E., van Schoor, N.M., Pennix, B.W.J.H., Elders, P.J.M., Heijboer, A.C., Smit, J.H., Bet, P.M., van Tulder, M.W., den Heijer, M., van Marwijk, H.W.J., Lips, P., 2015. Vitamin D supplementation to prevent depression and poor physical function in older adults: study protocol of the D-Vitaal study, a randomized placebocontrolled clinical trial. BMC. Geriatrics. 15(1), 1. Drevets, W.C., Price, J.L., Purey, M.L., 2008. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain. Struct. Funct. 213, 93-118. Dumville, J.C., Miles, J.N., Porthouse, J., Cockayne, S., Saxon, L., King, C., 2006. Can vitamin D supplementation pkrevent winter-time blues? A randomised trial among older women. J. Nutr. Health. Aging. 10, 151-153. Eyles, D.W., Smith, S., Kinobe, R., Hewison, M., McGrath, J.J., 2005. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J. Chem. Neuroanat. 29, 21-30. Eyles, D.W., Burne, T.H.J., McGrath, J.J., 2013. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front. Neuroendocrinol. 34, 47-64. Glickman-Simon ,P., and Pettit, J., 2015. There is currently insufficient evidence to determine the effectiveness of vitamin D supplementation for depression. Explore. 11(3), 223. Gloth, F.M., Alum, W., Hollis, B., 1999. Vitamin D vs. broad spectrum phototherapy in the treatment of seasonal affective disorder. J. Nutr. Health. Aging. 3, 5-7. Holick, M.F., 2007. Vitamin D deficiency. N. Engl. J. Med. 357, 266-281. Hoogendijk, W.J.G., Lips, P., Dik, MG., Deeg, D.J.H., Beekman, A.T.F., Penninz, W.J.H., 2008. Depression is associated with decreased 25-hydroxyVitamin D and increased parathyroid hormone levels in older adults. Arch. Gen. Psychiatry. 65, 508-512. Humble, M.B., 2010. Vitamin D, light and mental health. J. Photochem. Photobiol. B. 10, 142-149. Institute of Medicine of the National Academies. Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D., 2011. Chapter 5: Dietary reference intakes for adequacy: calcium and vitamin D. National Academies Press, 291-340. Jorde, R., Sneve, M., Figenschau, Y., Svartberg, J., Waterloo, K., 2008. Effects of Vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J. Intern. Med. 263, 599-609. 13
Joshi, D., Center, J.R., Eisman, J.A., 2010. Vitamin D deficiency in adults. Aust. Prescr. 33, 103–106. Khoraminya, N., Tehrani-Doost, M., Jazayeri, S., Hosseini, A., Djazayery, A., 2013. Therapeutic effects of Vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust. NZ. J. Psychiatry. 47, 271-275. Lansdowne, A. T., Provost, S. C., 1998. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology. 135(4), 319-323. Lee, D. M., Tajar, A., O’Neill, T. W., O’Connor, D. B., Bartfai, G., Boonen, S., Bouillon, R., Casanueva, F.F., Finn, J.D., Forti, G., Giwercman, A., 2011. Lower vitamin D levels are associated with depression among community-dwelling European men. J. Psychopharmacol. 25(10), 1320-1328. Li, G., Mbuagbaw, L., Samaan, Z., Falavigna, M., Zhang, S., Adachi, J.D., Cheng, J., Papaionnou, A., Thabane, L., 2014. Efficacy of Vitamin D supplementation in depression in adults: a systematic review. J. Clin. Endocrinol. Metab. 99(3), 757767. Maxwell, J.D., 1994. Seasonal variation in Vitamin D. Proc. Nutr. Soc. 53, 533-543. Milaneschi, Y., Shardell, M., Corsi, A.M., Vazzana,R., Bandinelli,S., Gurainik, J.M., Ferrucci,L., 2010. Serum 25-hydroxyVitamin D and depressive symptoms in older women and men. J. Clin. Endocrinol. Metab. 95, 3225-3233. Milaneschi,Y., Hoogendijk, W., Heijboer, A.C., Schoevers,R., van Hemert, A.M., Beekman, T.T.F., Smit, J.H., Penninx, B.W.J.H., 2013. The association between low vitamin D and depressive disorders. Mol. Psychiatry. 19, 444-451. Mozaffari-Khosravi, H., Nabizade, L., Yassini-Ardakani, S.M., Hadinedoushan, H., Barzegar, K., 2013. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J. Clin. Psychopharmacol. 33(3), 378-85. Nanri, A., Foo, L. H., Nakamura, K., Hori, A., Poudel-Tandukar, K., Matsushita, Y., Mizoue, T., 2011. Serum 25-hydroxyvitamin D concentrations and season-specific correlates in Japanese adults. J. Epidemiol. 21(5), 346-353. Pan, A., Lu, L., Franco, O.H., Yu, Z., Li, H., Lin, X., 2009. Association between depressive symptoms and 25-hydroxyVitamin D in middle-aged and elderly Chinese. J. Affect. Disord. 118, 240-243. Parker, G., Brotchie, H., 2011. ‘D’ for depression: any role for vitamin D? ‘Food for Thought’ II. Acta. Psychiatr. Scand. 124, 243-249. Sarris, J., Murphy, J., Mischoulon, D., Papakostas, G. I., Fava, M., Berk, M., & Ng, C. H., 2016. Adjunctive Nutraceuticals for Depression: A Systematic Review and MetaAnalyses. Am. J. Psychiatry. Sepehrmanesh, Z., Kolahdooz, F., Abedi, F., Mazroii, N., Assarian, A., Asemi, Z., Esmaillzadeh, A., 2015. Vitamin D Supplementation affects the Beck Depression Inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: A randomised, controlled clinical trial. J. Nutr. First. published ahead of print Nov 25, 2015 as doi: 10.3945/jn.115.218883.
14
Shaffer, J.A., Edmondson, D., Taggart Wasson, L., Falzon, L., Homma, K., Ezeokoli, N., Li, P., Davidson, K.W., 2014. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom. Med. 76(3), 190 – 196. Spedding, S., 2014. Review: Vitamin D and Depression: A systematic review and metaanalysis comparing studies with and without biological flaws. Nutrients. 6, 15011518. Stewart, R., Hirani, V., 2010. Relationship between Vitamin D levels and depressive symptoms in older residents from a national survey population. Psychosom. Med. 72, 608-612. Vieth, R., Kimball, S., Ju, A., Walfish, P.G., 2004. Randomised comparison of the effects of vitamin D3, adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr. J. 3 (1), 1. Zhang, M., Robitaille, L., Eintracht, S., Hoffer, L. J., 2011. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. 27(5), 530-533. Zhao, G., Ford, E.S., Li, C., and Balluz, L.S., 2010. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression amongst US adults. Br. J. Nutr. 104, 1696-1702.
Fig. 1. The metabolism of vitamin D to its active form.
Highlights
15
There is adequate evidence for a positive association between vitamin D deficiency and depression. If a depressed individual is deficient, Vitamin D supplementation/augmentation can be an effective treatment. The current evidence base is limited by methodological flaws. There is a need for further randomised controlled longitudinal studies.
16
www.elsevier.com/locate/jad
PII: DOI: Reference:
S0165-0327(16)30892-8 http://dx.doi.org/10.1016/j.jad.2016.08.082 JAD8563
To appear in: Journal of Affective Disorders Received date: 30 May 2016 Revised date: 18 July 2016 Accepted date: 27 August 2016 Cite this article as: Gordon B. Parker, Heather Brotchie and Rebecca K. Graham, Vitamin D and Depression, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2016.08.082 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Vitamin D and Depression Gordon B. Parkerab*, M.D, PhD, FRANZCP Heather Brotchie, MB BS, BA Rebecca K. Grahamab, BA. (Psych hons), PhD
a School b Black
*
of Psychiatry, University of New South Wales, Sydney, NSW, Australia
Dog Institute, Sydney, NSW, Australia
Corresponding author and reprints. G. Parker, Black Dog Institute. Hospital Rd, Prince of Wales
Hospital, Randwick, Sydney, Australia, 2031. E-mail address: [email protected]; Tel.: +61 293824372; fax: +61 29382434
Abstract Objective: To examine whether vitamin D deficiency or insufficiency is associated with depression and whether vitamin D supplementation is an effective treatment for depression. Method: Empirical papers published in recent years were identified using three search engines and online databases – PubMed, Google Scholar and Cochrane Database. Specific search terms used were ‘vitamin D’, ‘depression’ and ‘treatment’ and articles were selected that examined the association between vitamin D deficiency/insufficiency and depression, vitamin D supplementation and Vitamin D as a treatment for depression. Our review weighted more recent studies (from 2011), although also considered earlier publications. Results: Empirical studies appear to provide increasing evidence for an association between vitamin D insufficiency and depression, and for vitamin D supplementation and augmentation in those with clinical depression who are vitamin D deficient. Methodological limitations associated with many of the studies are detailed. Limitations: Articles were restricted to those in the English language while publication bias may have weighted studies with positive findings. Conclusions: There remains a need for empirical studies to move beyond cross-sectional designs to undertake more randomised controlled longitudinal trials so as to clarify the role of vitamin D in the pathogenesis of depression and its management, as well as to establish whether currently suggested associations are clinically significant and distinctive. 1
Keywords: vitamin D, depression, treatment, augmentation, supplementation.
1. Introduction There has been longstanding interest in the role of ‘natural’ treatments for depression, such as nutritional and dietary products. While many dietary factors have been implicated in the cause and treatment of depression, there has been a lack of scientific rigour in many of the reported studies. The principal dietary preparations so considered in journal reports include omega-3 fatty acids, vitamin D, the vitamin B group, minerals (e.g. zinc, magnesium and iron), antioxidants (e.g. vitamin C) and soy. In this paper we focus on vitamin D as changes in vitamin D receptors impact on various brain neurotransmitters, and thus suggest a potential role of vitamin D in causing and redressing mood disorders. While a role for vitamin D has been implicated in varying psychiatric and neurological conditions, the current review focuses solely on depression. The aim of this study was to extend a previous 2011 clinical review (Parker and Brotchie, 2011) and include more recent studies evaluating links between vitamin D and depression. In particular, to examine (i) the extent to which vitamin D deficiency and insufficiency is associated with depression, and (ii) whether vitamin D is an efficacious treatment for depression for those with vitamin D deficiency or insufficiency when given as a supplement or when augmenting an antidepressant drug. 2. Methods and material A literature search of relevant databases was performed (using PubMed, Cochrane Database of Systematic Reviews and Google Scholar) with papers selected that evaluated the association between vitamin D and depression. Specific search terms included “vitamin D” and “depression” – and with “treatment” included to identify studies related to whether vitamin D is an efficacious treatment for depression. In selecting studies, we prioritised those published in recent years (2011 – 2016) – while also including and overviewing earlier studies - that examined for links between vitamin D deficiency or insufficiency and depression, and as to whether vitamin D has antidepressant properties. 3. Results We first detail information regarding the process via which Vitamin D enters the body, consider sufficient and optimal levels in humans and detail the role of vitamin D in the human body. Study results (from the last five years) are considered together with data presented in the previous 2011 review. The section then overviews the empirical research on vitamin D and variable expressions of depression including Seasonal Affective Disorder. 3.1. Overview of vitamin D 2
Vitamin D can be accessed by humans from a variety of sources, including exposure to sunlight, general diet intake and dietary supplements (Holick, 2007). While there are two types of vitamin D obtained from dietary sources, D2 (or ergocalciferol) from plant sources (such as mushrooms and soy milk) and D3 (or cholecalciferol) from animal sources (such as raw fish, mackerel, eel, canned/smoked salmon), D3 is approximately three times stronger than D2. However, even from animal sources, it is difficult to obtain sufficient daily vitamin D from general dietary intake (Maxwell, 1994). The majority of vitamin D is produced in the body through the penetration of sunlight on the skin to ultraviolet B (UVB) radiation which involves a complex process involving solar UVB radiation converting 7-dehydrocholesterol to pre-vitamin D3, and then to vitamin D3. Once converted, Vitamin D enters the blood stream and is metabolised in the liver, forming 25-hydroxyvitamin D or 25 (OH) D and is then further metabolised in the kidneys to its active form (1,25-dihydroxyvitamin D). This process is illustrated graphically in Figure 1. It then binds to vitamin D receptors in target tissues to regulate gene transcription and to structures within cell membranes to mediate a number of non-genomic responses. Vitamin D receptors are present in most tissues and cells in the body, and within the brain show some specificity to the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus and substantia nigra (Eyles et al., 2005; Eyles et al., 2013). This is of relevance as many of those brain regions have been implicated in the physiology of depression (Drevets et al., 2008). Blood levels of 25 (OH) D are used to determine whether an individual has adequate levels of vitamin D and can be reported either as nanograms per millilitre (ng/ml) or as nanomoles per litre (nmol/L). While there is a lack of international consensus, it is generally conceded that the optimal range of 25 (OH) D is between 3060 ng/ml and with ‘insufficiency’ defined as levels between 21-29 ng/ml and ‘deficiency’ as < 20 ng/ml (Holick, 2007). For laboratories that measure in nmol/litre, < 50 nM is judged as the criterion for vitamin D deficiency. Recommendations from the Institute of Medicine of the National Academies (2011) for adequate daily vitamin D levels are 600 IU for children and adults up to 70 years of age, and 800 for adults over 70 years of age. If there is evidence of vitamin D deficiency, the recommended daily supplement is 1000 IU to correct the deficiency and to then maintain adequate levels. It has been estimated that approximately one billion people have insufficient levels of vitamin D or are vitamin D deficient. There are a multitude of reasons for vitamin deficiency, even in warm and sunny climates where vitamin D in the form of sunlight is freely available for most of the year. The season, time of day and latitude affects the amount of solar radiation reaching the skin as the number of solar UVB photons reaching the earth depends on the zenith angle of the sun. Current lifestyle factors also play a role, as the majority of people spend their working hours unexposed to sunshine (Joshi et al., 2010). The elderly may be at particular risk for low levels if housebound or living in nursing homes. Other important factors include ageing, darker skin tones (melanin absorbs more UVB radiation) and sunscreen use – which, while playing an important role in preventing skin cancers, also absorbs UVB radiation. 3
Decreased vitamin D can also occur (i) as a consequence of liver failure and chronic renal diseases, (ii) decreased bioavailability (due to factors such as malabsorption and obesity) and (iii) increased catabolism (due to certain medications, such as anticonvulsants and glucocorticoids). 3.2. Vitamin D and the human body The potential effects of extended vitamin D deficiency on the human body are vast and varied, and spread across most of the lifespan. In utero and during childhood, vitamin D deficiency can cause growth retardation and skeletal deformities, and may increase the risk of hip fracture in later adulthood. Vitamin D is considered essential for bone health, and with deficiency potentially leading to calcium deficiency and reduced bone density which can lead to conditions such as osteopenia and osteoporosis. Vitamin D also plays an important role in immunity and in destroying various infectious agents and is judged to have the potential to prevent certain cancers (e.g. breast, colon and prostate). It can also have effects on blood pressure, body circulation and blood sugar control (Holick, 2007). Eyles et al. (2013) reviewed the biology of vitamin D in the developing and adult brain and the links between low levels of vitamin D and neuropsychiatric diseases. The active form of vitamin D, calcitriol, plays a role in activating the gene expression of an enzyme (tyrosine hydroxylase) which is considered to be the rate-limiting step in the synthesis of the catecholamines. These neurotransmitters (namely, dopamine, noradrenaline and adrenaline) are implicated in the pathophysiology of mood disorders. If there is a causal relationship whereby vitamin D insufficiency or deficiency provides a risk to later depression, suggested possible mechanisms include compromised nerve growth factor synthesis and an impact on various neurotransmitter targets. 3.3. Studies examining for links between vitamin D levels and depression An overview of the empirical studies examining for an association between vitamin D and depression is now presented, with results described separately for (1) crosssectional studies, (2) longitudinal studies and (3) randomised controlled trials. The section is concluded by considering a specific subtype of depression - seasonal affective disorder (or SAD) - characterised by depressive symptoms that occur at the darkest time of the year and where it is hypothesised that light deficiency is causal. 3.3.1. Cross-sectional studies The numerous cross-sectional studies reported in the last decade have generated contrasting findings. A population-based cohort study of those aged 65 years or older in the Netherlands (Hoogendijk et al., 2008) reported that 25 (OH) D levels were 14% lower in both those diagnosed with minor depression (n = 169) and with major depression (n = 26). Lower 25 (OH) D levels were linked with greater depression severity, and with the association remaining significant after controlling for age, gender, body mass index (BMI), smoking status and a number of medical conditions. Conversely, 4
a population-based cross-sectional study in China (Pan et al., 2009) examined 3,262 middle-aged and elderly Chinese community residents and failed to find any evidence linking depressive symptoms with 25 (OH) D levels. Bertone-Johnson (2009) overviewed and considered reasons for the contrasting conclusions in relation to any links between 25 (OH) D levels and both depression and depression severity. For example, the studies noting ‘positive’ results often failed to consider other potential explanations such that depressed individuals may be at greater risk of lower vitamin D levels as a consequence of spending less time outdoors, being less physically active and with any decreased appetite leading to dietary changes. Thus, as lower vitamin D levels may be an antecedent or a consequence of depression, prospective studies are required to assess changes in mood over time to determine causality. Some cross-sectional community studies have evaluated – and rejected – any contribution from such lifestyle factors. For example, a large United Kingdom epidemiological study of 3,369 men with a mean age of 60 years (Lee et al., 2011) reported an inverse relationship between 25 (OH) D levels and depression levels but with their analyses largely failing to find a contribution from several lifestyle and health factors. In another report, Zhao et al. (2010) conducted a large cross-sectional study amongst adults of all ages. They failed to show a significant association between vitamin D deficiency and depression after adjusting for potential confounders (e.g. the degree of sun exposure, the level of physical activity, diet, age and BMI). Other studies have reported weak associations with lifestyle factors. For example, Black et al. (2014) undertook a cross-sectional study of young adults recruited from the Western Australian Pregnancy Cohort Study, investigating the relationship between serum 25(OH)D concentrations and symptoms of depression, anxiety and stress. After adjusting for confounding factors (i.e. age, race, BMI and physical activity), an increase in serum 25(OH)D of 10 nmol/L was associated with an 8% decrease in depression subscale scores in males (not females) – but there were no significant associations with symptoms of stress and anxiety. While many of these studies have reported a positive association between vitamin D deficiency and depression in elderly patients, there is less empirical support for this association in younger samples. The other key problem with cross-sectional studies is that any clarification of causality requires a longitudinal design. Thus, while crosssectional designs allow for an examination of the association between two variables (e.g. vitamin D deficiency and depression), they fail to specify the direction of these effects (e.g. Do low vitamin D levels lead to depression, or does depression lead to low vitamin D levels?). This is salient as depressed individuals often isolate themselves indoors and/or their associated reduced appetite may lead to dietary changes that then reduce their vitamin D levels. 3.3.2. Longitudinal studies Few studies examining for an association between vitamin D and depression using a longitudinal design have been published. Milaneschi et al. (2010) examined the association between vitamin D levels at baseline and subsequent depression in their 65
year prospective study with 954 adults aged 65 years or older. They reported that individuals with low 25 (OH) D3 levels at baseline (i.e. <50 nM or <20 ng/ml) had significantly higher depression scores at the two follow-up periods (3 and 6 years) compared to those with high levels at baseline – and with the association being more distinctive for women than for men. Milaneschi et al. (2013) investigated the association between 25 (OH) D levels and depressive disorders in a large cohort aged 18-65 years from the Netherlands Study of Depression and Anxiety. While mainly cross-sectional, the study had longitudinal elements, and comprised 1,102 subjects with current depressive disorders, 790 with remitted depressive disorders (according to DSM-IV criteria) and 495 healthy controls. Compared with healthy controls, lower 25 (OH) D levels were quantified in participants with current clinical depression, particularly in those with the most severe symptoms. In the currently depressed sub-set, 25 (OH) D was inversely associated with symptom severity - suggesting a dose-response gradient – and, in relation to the longitudinal component, with a greater risk of having a depressive disorder at the two-year follow up. The authors suggested that low vitamin D levels may represent an underlying biological vulnerability to depression. This study had the advantage of including those with a clinical diagnosis of depression, and also adjusting for potential confounding factors in the assessment of 25(OH) D levels, including a measure of actual sunlight irradiation. Almeida et al. (2015) undertook an observational study examining for retrospective, cross-sectional and prospective associations between vitamin D concentration and depressed mood in a community-derived sample of 3,105 older men. Plasma concentration of 25(OH) D was measured at the time of the study and a history of ‘past depression’ measured through direct questioning and administrative health linkage data. ‘Current depression’ was assessed via a geriatric depression scale and ‘incident depression’ by a health questionnaire score or by administrative health data linkage during the 6-year follow up period. A vitamin D concentration of < 50nmol/L was associated with greater odds of current, but not past, depression. Of the 2,740 men with neither a past nor a current history of depression, 81 developed clinically significant symptoms during the follow-up period. The adjusted hazard ratio of incident depression for men with plasma vitamin D <50 nmol/L was 1.03. The authors interpreted their results as not supporting a role for vitamin D as a cause of depression. 3.3.3 Meta-analytic results A systematic review and meta-analysis conducted by Anglin et al. (2013) evaluated the relationship between depression and hypovitaminosis D including pooled data from one case study, 10 cross-sectional studies and three longitudinal cohort studies. They reported a positive association between low vitamin D levels and depression. Specifically, they quantified lower vitamin D levels in individuals with depression compared with controls and, in the cross-sectional studies, an increased odds ratio of depression for the lowest versus the highest vitamin D categories. In addition, the cohort studies showed a significantly increased hazard ratio of depression for the 6
lowest versus highest vitamin D categories. This data base was later re-analysed by Annweiler et al. (2013) using a new random-effects meta-analysis. Their analysis quantified a probability of about 65% that an individual with depression would have a lower 25(OH) D concentration than an individual without depression, if both individuals were chosen at random. 3.4. Randomised controlled trials evaluating vitamin D as a treatment factor While randomised controlled trials (or RCTs) are important to determine whether vitamin D supplementation is an effective treatment for depression, those studies have yielded inconsistent results. This may reflect design limitations (e.g. varying study criteria such as sample size, age range of subjects, vitamin D dosage and method of administration, depression measures used and the assessment of outcome). Such limitations make it difficult to generalise findings across studies. The majority of the studies report on the effect of vitamin D supplementation (comparing individuals receiving only vitamin D with a placebo group) while there has become a more recent focus on the possible role of vitamin D augmentation (comparing individuals receiving an antidepressant and vitamin D supplementation to those receiving only an antidepressant). 3.4.1. Vitamin D supplementation In a recent study, Li et al. (2014) undertook a systematic review of RCT’s evaluating the efficacy of vitamin D use in comparison with placebo in those with depression. They selected parallel RCTs investigating adults at risk of depression, those with depressive symptoms and those with a primary diagnosis of depression, and employed a classical and Bayesian random effects meta-analysis of six RCTS – with five studies sampling adults at risk of depression and one study of depressed patients. Their analysis found no significant effect of vitamin D supplements on post-intervention depression scores. They noted that factors such as varying vitamin D3 dosages, a range in duration of treatment (from weeks to years) and various measures used to measure depression may have confounded interpretation. They concluded, however, that there is insufficient evidence to support the efficacy of vitamin D supplementation in those with depressive symptoms. Spedding (2014) undertook a systematic review and meta-analysis of 15 randomised controlled trials (RCTs) that examined the efficacy of vitamin D supplements for those with depression, variably measured by depression severity and whether clinical criteria (for major depression) were met. They noted that previous meta-analyses of such studies had failed to demonstrate efficacy and appraised the methodological quality and biological flaws (i.e. limitations in the design of primary studies which preclude the research hypothesis being tested) in relation to both the hypotheses and study designs. Of the 15 RCTs, results from the eight studies with ‘biological flaws’ were inconclusive, while the seven without such flaws showed statistically significant improvement in depression (i.e. Arvold et al. 2009; Gloth et al. 1999; Jorde et al. 2008; Khoraminya et al. 2013; Landsdowne & Provost 1998; Veith et 7
al. 2004; Zhang et al. 2011). Based on those studies lacking methodological flaws, Spedding concluded that vitamin D supplementation of 800 mg or more daily was of benefit in the management of depression and when vitamin D levels were raised by supplementation. His detailing of ‘biological flaws’ highlights that supplementation studies must require participants to be vitamin D deficient at baseline and to receive an adequate dose of vitamin D to achieve vitamin D sufficiency status during the trial criteria not met by many of the RCTs. One of these studies judged to be without ‘biological flaws’ (i.e. Jorde et al. 2008), involved a large sample of overweight or obese individuals aged 21-70 years, and whose depression severity scores were higher one year later in those with insufficient levels of 25 (OH) D. However, levels of 25 (OH) D were not found to correlate with depression severity scores. Those randomly allocated to receive vitamin D supplementation of either 40,000 or 20,000 IU each week showed an improvement in depression scores 12 months later, which did not occur in those receiving the placebo. There were, nevertheless, several study limitations, such as the use of a community sample with low rates of clinical depression. Schaffer et al. (2014) reviewed the effects of vitamin D supplementation on depressive symptoms in published RCTs. Of the seven trials meeting study inclusion criteria, results indicated that vitamin D supplementation had no overall effect on depressive symptoms. Subgroup analyses, however, revealed a moderate and statistically significant effect for participants in two (of the seven) studies and which involved subjects with clinically significant depressive symptoms or a depressive disorder (Mozaffari-Khosravi et al. 2013; Khoraminya et al. 2013). There was a small non-significant effect in the five studies involving those without clinically significant depression. Schaffer et al. concluded that vitamin D supplementation may be effective for reducing depressive symptoms in patients with clinically significant depression but that further high quality research is needed to target depressed patients, assess baseline levels of vitamin D and also consider appropriate vitamin D dosing and method of delivery. Such nuances are highlighted in a clinical trial by Mozarffari-Khozravi et al. (2013) that followed 120 patients with a Beck Depression Inventory (BDI) score of 17 or more and who were assessed as vitamin D deficient. Subjects were randomly assigned to three groups (n = 40 in each), with one group receiving a single intramuscular dose of 300,000 IU vitamin D, the second receiving a single intramuscular dose of 150,000 IU vitamin D, and the third receiving no intervention. After three months, the depression state and serum vitamin D were remeasured. In the group that received 300,000 IU vitamin D there was a significant correction of vitamin D deficiency, and it was only this group that showed a significant improvement in BDI depression scores compared to the group that received no vitamin D intervention. The authors concluded that the correction of the vitamin D deficiency improved the depression state and that 300,000 IU of vitamin D was safe and more effective than a 150,000 IU dose. Sepehrmanesh et al. (2015) reported a RCT study in patients with Major Depressive Disorder (MDD) and with all being vitamin D deficient (with serum 25(OH) D < 20ug/l) to assess whether vitamin D supplementation can reduce symptoms of depression, and 8
measured metabolic profiles, serum high-sensitivity C-reactive protein (hs-CRP) and biomarkers of oxidative stress. Forty patients aged 18-65 years were assigned to receive a single capsule of 50,000 IU vitamin D per week or a placebo for eight weeks and with serum 25(OH) D levels measured at baseline and again at eight weeks. For those receiving vitamin D supplementation, there was a greater change in levels compared to those who did not receive vitamin D at week 8 (20.4 ug/L +/or -5.5 ug/L compared to a decrease of 0.9ug/L +/or -3.5 ug/L in the placebo group). This study showed that, after controlling for age and baseline BMI, vitamin D supplementation was associated with a significant decrease in Beck Depression Inventory (BDI) scores, in addition to improvements in glucose homeostasis and oxidative stress compared to the placebo group, although with no significant changes in serum calcium concentrations, lipid profiles, fasting plasma glucose (FPG), insulin sensitivity check index (QUICKI) or hs-CRP concentrations. 3.4.2. Vitamin D augmentation with an antidepressant In addition to pure vitamin D supplementation (which presumes vitamin D being prescribed alone) there has been increased interest in vitamin D as an augmenter of antidepressant medication. The adjunctive use of standardized pharmaceutical grade nutrients (or ‘nutraceuticals’), has the potential to modulate specific neurochemical pathways implicated in depression. A clinical study by Khoraminya et al. (2013) was the first randomized, double-blind, placebo-controlled trial specifically designed to determine the effects of vitamin D augmentation in patients with major depressive disorder (MDD). Forty two outpatients with a DSM-IV diagnosis of MDD without psychotic features were randomly assigned to receive 500 IU of vitamin D plus one 20 mg capsule of fluoxetine or, alternatively, a vitamin D placebo tablet and the fluoxetine capsule daily for eight weeks. Fasting levels of 25 (OH) D levels were taken at the start of the trial and depression severity assessed every two weeks. Results indicated that the vitamin D plus fluoxetine combination was significantly superior to fluoxetine alone in patients with MDD and who were vitamin D deficient. While studies are slowly developing in this area, there is a need for more specialized systematic reviews or meta-analyses. Sarris et al. (2016) conducted a systematic review based on 40 world-wide clinical trials (up to December, 2015) that used nutraceuticals to treat clinical depression in combination with formal antidepressant medications. Primarily positive results were found for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethylEPA), and vitamin D (results based on only two studies), with positive isolated studies for creatine, folinic acid, and an amino acid combination. Based on their findings, the authors concluded that the current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms. 3.5. Seasonality, vitamin D and depression
9
The process via which vitamin D affects mood may be particularly pertinent for those depressive disorders with seasonal patterns and where variations in UVB exposure may result in vitamin D deficiency. For example, Seasonal Affective Disorder (or SAD) is a depressive subtype characterised by depressive symptoms that occur at the darkest time of the year and where light deficiency is viewed as causal. Characteristic symptoms are hypersomnia, hyperphagia, anergia, mood worsening in the evening, and with symptoms lessoning in the spring and summer due to the increase in levels of light. The specific mechanism involved is believed to be the shorter daily photoperiod of winter, with suboptimal light input to retinal photoreceptors disturbing the optimal functioning of the suprachiasmatic nucleus (SCN) and its interactions with the pineal gland and secretion of melatonin. While there has been some success in treatment via phototherapy, such studies have produced inconsistent findings. It has been suggested that light and the circadian regulation of the SCN are closely related to the pathophysiology of SAD, with serotonin dysfunction implicated in the process (Humble, 2010). The association between vitamin D deficiency and SAD is suggested by its higher prevalence at increased latitude where there is reduced exposure to UVB radiation and we now consider some salient studies. 3.5.1. Cross sectional studies on seasonality, vitamin D and depression A community-based observational study in Japan (Nanri et al. 2011) involving 527 participants (aged between 21 and 67 years) found no association between 25 (OH) D3 and depressive symptoms – although there was a trend for vitamin D to have a protective effect on depression in late autumn (when there are low levels of sunshine) compared to the summer season. A national community study in England (Stewart & Hirani, 2010) of 2,070 older people (over 65 years) reported that vitamin D deficiency was associated with severe (but not milder) depression in northern latitudes, but that this association was not modified by season of examination. Such findings correspond to the results found in an Amsterdam study (Hoogendijk et al. 2008) - although those authors reported that lower 25 (OH) D levels were associated with both major and minor depression – but again with season of data acquisition having no effect on the association. In a study by Stewart and Hirani (2010), seasonality did not influence the association between low 25 (OH) D and depression. Such data are indirect as there are currently no known published longitudinal studies on vitamin D and depression for individuals with SAD. 3.5.2. RCTs related to SAD and vitamin D A small double-blind intervention study (Gloth et al. 1999) randomly assigned eight patients with seasonal affective disorder (SAD) to receive 100,000 IU of daily vitamin D and seven to receive phototherapy. The authors reported that vitamin D supplementation was associated with a greater improvement on depression measures, and with such improvement significantly correlated with the increase in 25 (OH) D levels. There have been several small RCTs examining the effect of vitamin D supplementation in those with seasonal mood changes, and with many reporting 10
positive effects. Lansdowne and Provost (1998) randomised 44 healthy participants to receive varying doses of vitamin D3 for five days over winter, and with supplementation associated with improvements in positive affect and with decreased negative affect. Another larger trial randomised 82 adults with vitamin D deficiency into two groups receiving varying doses of vitamin D supplementation for two winters (600 and 4000 IU) and found some improvement on depression scores after two months in the group receiving the higher dosage (Vieth et al. 2004). An RCT by Dumville et al. (2006), however, found no significant improvement in mental health scores of elderly women who received supplementation with 800 IU of vitamin D over a six-month winter period, although only small doses of vitamin D were used and 25(OH)D was not assessed in this study. Bertone-Johnston (2009) reviewed these studies and concluded that there is only “modest support” for the effective treatment of SAD symptoms with vitamin D supplementation. 4. Discussion While our understanding of the basic physiology of the function of vitamin D in the brain is steadily increasing, there is a need for more sophisticated studies to gain a greater understanding of the processes, especially vitamin D ligand distribution and receptor function. Human studies using MRI brain scanning techniques and animal modelling studies (Eyles et al. 2013) may be of relevance in advancing this understanding. The available research evidence indicates that adequate levels of vitamin D intake are required for normal brain neuropsychiatric functioning, with meta-analyses from cross-sectional and longitudinal studies suggesting an association between low levels of vitamin D and some expressions of ‘depression’. The caveat here is that some studies have examined ‘depression’ dimensionally on depression severity measures (and thus including those who would not meet formal depression ‘caseness’ criteria) while others limit consideration to individuals meeting clinical criteria for depression, with the latter group perhaps the most important. Few studies have examined for the multiple salient confounding factors that may create non-causal associations, while not all studies have limited intervention to those who are formally deficient or insufficient in vitamin D. Turning to the second key issue – is vitamin D supplementation of benefit for those with depression – there is again support from several systematic reviews and metaanalyses for the proposal but also a number of caveats. Benefit or not may reflect the type and severity of ‘depression,’ whether vitamin D is prescribed alone or in conjunction with an antidepressant drug – and with benefit likely to be restricted to those who were vitamin D deficient prior to intervention. As summarised by GlickmanSimon and Pettit (2015), clarifying whether there is any therapeutic role will require large randomised, placebo-controlled trials that (i) enrol only depressed patients deficient in vitamin D, (ii) administer a standardized oral dosage (those authors suggesting 1,000 IU of cholecalciferol and (iii) measure post-treatment vitamin D levels to ensure that vitamin D levels are then within the normal range. We would include additional criteria, such that assessments examine improvement in relation to both 11
formalised clinical depressive disorders and to depression severity. Further, that studies evaluate vitamin D supplementation alone as against its use as an antidepressant augmentor, as it is likely that many of the published studies assessing vitamin D supplementation included patients who were already in receipt of an antidepressant medication for their depression. The recent systematic review by Sarris et al. (2016) is one of the first to suggest that vitamin D (among other nutraceuticals) is recommended for use with antidepressant medications in effectively treating depression, but as this review considered only two clinical trials, that conclusion cannot be viewed as definitive. In relation to seasonal affective disorder (SAD), it would appear that vitamin D deficiency is unlikely to contribute to its aetiology but some evidence to indicate that those experiencing SAD may benefit from Vitamin D augmentation. 5. Limitations The main limitations of the current analysis include only reviewing publications in the English language, and the necessary inclusion of only published material which may be limited to positive findings and thus risk artificial inflation of results. 6. Conclusion We conclude, from both the cross-sectional and longitudinal studies, that there is increasing evidence of an increased risk of depression in those who are vitamin D deficient and that vitamin D supplementation is of benefit for depressed individuals who are vitamin D deficient. Acknowledgments This study was supported by an NHMRC Program Grant (1037196). There are no relevant conflicts to disclose. References Almeida, O.P., Hankey, G.J., Yeap, B.B., Golledge, J., Flicker, L., 2015. Vitamin D concentration and its association with past, current and future depression in older men: The Health in Men Study. Maturitas. 81, 36-41. Anglin, R.E.S., Samaan, Z., Walter S.D., McDonald, S.D., 2013. Vitamin D deficiency and depression in adults: systemic review and meta-analysis. Br. J. Psych. 202, 100117. Annweiler, C., Rastmanesh, R., Richard-Devantoy, S., Beauchet, O., 2013. ASCP Corner: The role of vitamin D in depression: From a curious idea to a therapeutic option. J. Clin. Psychiatry. 74(11), 1121-1122. Arvold, D., Odean, M., Dornfeld, M., Regal, R., Arvold, J., Karwoski, G., Mast, D., Sanford, P., Sjoberg, R., 2009. Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial. Endocrine Practice. 15(3), 203-212. 12
Bertrone-Johnson, E.R., 2009. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr. Rev. 67, 481-492. Bertone-Johnson, E. R., Powers, S. I., Spangler, L., Brunner, R. L., Michael, Y. L., Larson, J. C., Millen, A.E., Bueche, M.N., Salmoirago-Blotcher, E., Liu, S., Wassertheil-Smoller, S., 2011. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am. J. Clin. Nutr. 94(4), 1104-1112. Black, L.J., Jacoby, P., Allen, K.L., Trapp, G.S., Hart, P.H., Byrne, S.M., Mori, T.A., Beilin, L.J., Oddy, W.H., 2014. Low vitamin D levels are associated with symptoms of depression in young adults. Aust. NZ. J. Psychiatry. 48(5), 464-471. de Koning, E., van Schoor, N.M., Pennix, B.W.J.H., Elders, P.J.M., Heijboer, A.C., Smit, J.H., Bet, P.M., van Tulder, M.W., den Heijer, M., van Marwijk, H.W.J., Lips, P., 2015. Vitamin D supplementation to prevent depression and poor physical function in older adults: study protocol of the D-Vitaal study, a randomized placebocontrolled clinical trial. BMC. Geriatrics. 15(1), 1. Drevets, W.C., Price, J.L., Purey, M.L., 2008. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain. Struct. Funct. 213, 93-118. Dumville, J.C., Miles, J.N., Porthouse, J., Cockayne, S., Saxon, L., King, C., 2006. Can vitamin D supplementation pkrevent winter-time blues? A randomised trial among older women. J. Nutr. Health. Aging. 10, 151-153. Eyles, D.W., Smith, S., Kinobe, R., Hewison, M., McGrath, J.J., 2005. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J. Chem. Neuroanat. 29, 21-30. Eyles, D.W., Burne, T.H.J., McGrath, J.J., 2013. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front. Neuroendocrinol. 34, 47-64. Glickman-Simon ,P., and Pettit, J., 2015. There is currently insufficient evidence to determine the effectiveness of vitamin D supplementation for depression. Explore. 11(3), 223. Gloth, F.M., Alum, W., Hollis, B., 1999. Vitamin D vs. broad spectrum phototherapy in the treatment of seasonal affective disorder. J. Nutr. Health. Aging. 3, 5-7. Holick, M.F., 2007. Vitamin D deficiency. N. Engl. J. Med. 357, 266-281. Hoogendijk, W.J.G., Lips, P., Dik, MG., Deeg, D.J.H., Beekman, A.T.F., Penninz, W.J.H., 2008. Depression is associated with decreased 25-hydroxyVitamin D and increased parathyroid hormone levels in older adults. Arch. Gen. Psychiatry. 65, 508-512. Humble, M.B., 2010. Vitamin D, light and mental health. J. Photochem. Photobiol. B. 10, 142-149. Institute of Medicine of the National Academies. Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D., 2011. Chapter 5: Dietary reference intakes for adequacy: calcium and vitamin D. National Academies Press, 291-340. Jorde, R., Sneve, M., Figenschau, Y., Svartberg, J., Waterloo, K., 2008. Effects of Vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J. Intern. Med. 263, 599-609. 13
Joshi, D., Center, J.R., Eisman, J.A., 2010. Vitamin D deficiency in adults. Aust. Prescr. 33, 103–106. Khoraminya, N., Tehrani-Doost, M., Jazayeri, S., Hosseini, A., Djazayery, A., 2013. Therapeutic effects of Vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust. NZ. J. Psychiatry. 47, 271-275. Lansdowne, A. T., Provost, S. C., 1998. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology. 135(4), 319-323. Lee, D. M., Tajar, A., O’Neill, T. W., O’Connor, D. B., Bartfai, G., Boonen, S., Bouillon, R., Casanueva, F.F., Finn, J.D., Forti, G., Giwercman, A., 2011. Lower vitamin D levels are associated with depression among community-dwelling European men. J. Psychopharmacol. 25(10), 1320-1328. Li, G., Mbuagbaw, L., Samaan, Z., Falavigna, M., Zhang, S., Adachi, J.D., Cheng, J., Papaionnou, A., Thabane, L., 2014. Efficacy of Vitamin D supplementation in depression in adults: a systematic review. J. Clin. Endocrinol. Metab. 99(3), 757767. Maxwell, J.D., 1994. Seasonal variation in Vitamin D. Proc. Nutr. Soc. 53, 533-543. Milaneschi, Y., Shardell, M., Corsi, A.M., Vazzana,R., Bandinelli,S., Gurainik, J.M., Ferrucci,L., 2010. Serum 25-hydroxyVitamin D and depressive symptoms in older women and men. J. Clin. Endocrinol. Metab. 95, 3225-3233. Milaneschi,Y., Hoogendijk, W., Heijboer, A.C., Schoevers,R., van Hemert, A.M., Beekman, T.T.F., Smit, J.H., Penninx, B.W.J.H., 2013. The association between low vitamin D and depressive disorders. Mol. Psychiatry. 19, 444-451. Mozaffari-Khosravi, H., Nabizade, L., Yassini-Ardakani, S.M., Hadinedoushan, H., Barzegar, K., 2013. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J. Clin. Psychopharmacol. 33(3), 378-85. Nanri, A., Foo, L. H., Nakamura, K., Hori, A., Poudel-Tandukar, K., Matsushita, Y., Mizoue, T., 2011. Serum 25-hydroxyvitamin D concentrations and season-specific correlates in Japanese adults. J. Epidemiol. 21(5), 346-353. Pan, A., Lu, L., Franco, O.H., Yu, Z., Li, H., Lin, X., 2009. Association between depressive symptoms and 25-hydroxyVitamin D in middle-aged and elderly Chinese. J. Affect. Disord. 118, 240-243. Parker, G., Brotchie, H., 2011. ‘D’ for depression: any role for vitamin D? ‘Food for Thought’ II. Acta. Psychiatr. Scand. 124, 243-249. Sarris, J., Murphy, J., Mischoulon, D., Papakostas, G. I., Fava, M., Berk, M., & Ng, C. H., 2016. Adjunctive Nutraceuticals for Depression: A Systematic Review and MetaAnalyses. Am. J. Psychiatry. Sepehrmanesh, Z., Kolahdooz, F., Abedi, F., Mazroii, N., Assarian, A., Asemi, Z., Esmaillzadeh, A., 2015. Vitamin D Supplementation affects the Beck Depression Inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: A randomised, controlled clinical trial. J. Nutr. First. published ahead of print Nov 25, 2015 as doi: 10.3945/jn.115.218883.
14
Shaffer, J.A., Edmondson, D., Taggart Wasson, L., Falzon, L., Homma, K., Ezeokoli, N., Li, P., Davidson, K.W., 2014. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom. Med. 76(3), 190 – 196. Spedding, S., 2014. Review: Vitamin D and Depression: A systematic review and metaanalysis comparing studies with and without biological flaws. Nutrients. 6, 15011518. Stewart, R., Hirani, V., 2010. Relationship between Vitamin D levels and depressive symptoms in older residents from a national survey population. Psychosom. Med. 72, 608-612. Vieth, R., Kimball, S., Ju, A., Walfish, P.G., 2004. Randomised comparison of the effects of vitamin D3, adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr. J. 3 (1), 1. Zhang, M., Robitaille, L., Eintracht, S., Hoffer, L. J., 2011. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. 27(5), 530-533. Zhao, G., Ford, E.S., Li, C., and Balluz, L.S., 2010. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression amongst US adults. Br. J. Nutr. 104, 1696-1702.
Fig. 1. The metabolism of vitamin D to its active form.
Highlights
15
There is adequate evidence for a positive association between vitamin D deficiency and depression. If a depressed individual is deficient, Vitamin D supplementation/augmentation can be an effective treatment. The current evidence base is limited by methodological flaws. There is a need for further randomised controlled longitudinal studies.
16