- Email: [email protected]
Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease
Clinical Nutrition xxx (2015) 1e8
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease Caroline S. Stokes a, *, Frank Grünhage a, Crystal Baus b, Dietrich A. Volmer c, Stefan Wagenpfeil d, Matthias Riemenschneider b, Frank Lammert a a
Department of Medicine II, Saarland University Medical Center, Homburg, Germany Department of Psychiatry and Psychotherapy, Saarland University Medical Center, Homburg, Germany Institute of Bioanalytical Chemistry, Saarland University, Saarbrücken, Germany d Institute of Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Campus Homburg, Germany b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 9 March 2015 Accepted 8 July 2015
Background and aims: Vitamin D deficiency and depression frequently occur in patients with chronic liver diseases (CLD). Depression has recently been inversely associated with vitamin D in a meta-analysis, and vitamin D receptor is expressed in brain. This pilot study investigates whether vitamin D replacement ameliorates depressive symptoms in CLD patients and consists of a cross-sectional and an interventional analysis. Methods: Overall, 111 patients with CLD were included in the cross-sectional analysis. The Beck Depression Inventory II (BDI-II) was used to assess depression. Chemiluminescence immunoassay and LC-MS/MS quantified serum 25-hydroxyvitamin D levels. For the interventional analysis, 77 patients with inadequate vitamin D concentrations received 20,000 IU vitamin D per week for six months. The final follow-up was carried out six months post supplementation. Results: In the cross-sectional analysis, 81% of patients (median age 55 years, 47% women) had inadequate baseline vitamin D levels (<30 ng/ml), and 31% presented with depressive symptoms (BDI-II score 14). Depression severity correlated inversely with vitamin D level in depressed patients (b ¼ 0.483, P ¼ 0.004). Depression scores improved significantly from baseline in depressed patients after three and six months (P ¼ 0.003 and P ¼ 0.004, respectively) of supplementation, with vitamin D levels increasing to normal (P < 0.0001). Subgroup analyses revealed this anti-depressant effect of vitamin D to occur predominantly in women. The final follow-up showed increases in median BDI-II scores in the setting of decreased vitamin D levels. Conclusions: Vitamin D levels correlated with BDI-II scores, and vitamin D replacement significantly improved depressive symptoms in women with CLD. Adjuvant vitamin D may be considered in these patients. Registration No: DRKS00007782 German Clinical Trials Registry (DRKS) © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Beck Depression Inventory Cirrhosis Mood Supplementation Women 25-Hydroxyvitamin D
1. Introduction Chronic liver diseases (CLD) are often associated with vitamin D deficiency, which contributes to the manifestation of metabolic bone disease and other systemic complications [1,2]. This might be, in part, attributed to the involvement of the liver in the metabolism
* Corresponding author. Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany. Tel.: þ49 6841 16 23222; fax: þ49 6841 16 23267. E-mail address: [email protected] (C.S. Stokes).
of vitamin D. The first vitamin D hydroxylation step occurs in the liver, yielding 25-hydroxyvitamin D (the primary circulating form and accepted marker of vitamin D status). The second oxidation step in kidney produces the most biologically active vitamin D metabolite, 1,25-dihydroxyvitamin D, which subsequently enters all target cells, exerting its functions mainly through the vitamin D nuclear receptor (VDR) [3]. Given the broad expression of VDR in many organs, numerous non-skeletal benefits for vitamin D have been observed. In brain, vitamin D binds to VDR in many areas implicated in depression pathophysiology, such as neurons and glial cells of the limbic
http://dx.doi.org/10.1016/j.clnu.2015.07.004 0261-5614/© 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
2
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
system [4]. Indeed, VDR gene variants are reported to influence susceptibility to depressive symptoms [5]. Neurosteroidal effects of vitamin D have recently been illustrated in an experimental study, in which adult mice displayed behavioural and brain alterations upon the induction of vitamin D deficiency [6]. In humans, crosssectional studies have shown serum 25-hydroxyvitamin D concentrations to be inversely correlated with the severity of depressive symptoms [7]. A recent meta-analysis by Anglin and coworkers underscored this relationship [8]. Co-morbid depression often affects patients with CLD, with a reported prevalence of approximately 30% [9,10]. Standard antidepressant therapy, however, is not always feasible. Certain antidepressant medications are contraindicated in advanced CLD due to their side effects. Selective serotonin reuptake inhibitors, for instance, can induce gastrointestinal bleeding, possibly because of increased gastric acidity or via defective platelet aggregation due to reduced platelet serotonin [11]. Moreover, patients might be dissuaded by treatments for depression because of unwanted sideeffects, namely fatigue and the aggravation of features of the metabolic syndrome, such as weight gain and dyslipidemia [12]. Consequently, non-pharmacological options warrant further investigation, particularly if they are free from major side effects and also deliver additional health benefits. Vitamin D supplementation may fulfil these criteria and has previously been reported to ameliorate depressive symptoms in overweight subjects [13]. Whether vitamin D has direct benefits on depressive symptoms in patients with CLD has to date not been investigated. The primary aim here was to assess for antidepressant effects of vitamin D in CLD patients. We hypothesised that depressive symptoms can be mitigated by correcting inadequate vitamin D concentrations in these patients. 2. Patients and methods 2.1. Study patients We prospectively recruited adult patients attending the Hepatology Outpatient Clinic (Department of Medicine II, Saarland University Medical Center). Patients with CLD (diagnosed six months previously) were invited to participate, unless they had any of the following exclusion criteria: severe hepatic encephalopathy as quantified by Critical Flicker Frequency (CFF; HEPAtonorm analyzer; Accelab, Kusterdingen, Germany) and defined by CFF <35 Hz [14]; current interferon therapy; and specifically for the intervention phase: presence of hypercalciuria (urinary calcium >8.0 mmol/d); hypercalcaemia (any value above the upper normal limit, serum calcium >2.7 mmol/l), alone or in combination with hyperparathyroidism (parathyroid hormone [PTH] >65.0 pg/ml) [15]; history of calcium-containing kidney stones; allergy or hypersensitivity to any of the supplement ingredients (gelatine, peanuts, soy); sarcoidosis; stage IV or V chronic kidney disease (as defined by the National Kidney Foundation [16]), or pregnancy. Patients with adequate serum 25-hydroxyvitamin D levels (30 ng/ ml) did not receive vitamin D but were monitored during the intervention. The local research ethics committee approved the € study protocol (Arztekammer des Saarlandes, Ref. 57/11), which conforms with the declaration of Helsinki. All patients provided written informed consent. 2.2. Study design Eligible patients were included in a cross-sectional analysis assessing the association of vitamin D with depression. Patients with serum 25-hydroxyvitamin D concentrations <30 ng/ml then received six-month replacement therapy. This consisted of an oral
dose of 20,000 IU cholecalciferol/vitamin D3 (Dekristol®, Jenapharm, Jena, Germany) contained in one capsule, daily for the first seven days, then weekly thereon. Patients were further stratified into subgroups based on whether depressive symptoms were present. All patients were followed up after three (T1) and six months (T2), after which vitamin D supplementation was stopped. A final follow-up took place 12 months from baseline (T3) after a six-month pause from vitamin D. Compliance was determined from increases in serum 25-hydroxyvitamin D concentrations, together with the discrete interval pill-count method. Patients abstained from taking other nutritional supplements during the study, unless medically indicated. Patients on anti-depressant therapy were only recruited if their dose had remained stable for the preceding eight weeks, and were instructed to inform the study coordinator immediately upon any dosage or medication changes. 2.3. Study procedures Serum 25-hydroxyvitamin D analyses were conducted by chemiluminescence immunoassay LIAISON® 25-OH Vitamin D TOTAL Assay (DiaSorin, MN, USA). A subset of samples was validated by liquid chromatography-tandem mass spectrometry (LCMS/MS), 96-well micro-extraction (AC Extraction Plate, Tecan, €nnedorf, Switzerland), 25-hydroxyvitamin D isotope calibration Ma and quality control kits (Recipe, Munich, Germany) and 5500 QTRAP electrospray ionisation LC-MS/MS (Sciex, Concord, ON, Canada), as previously reported [17]. Other standard biochemical analyses in our central clinical laboratory included: calcium, phosphate, creatinine, urea, PTH as well as standard liver function tests (LFTs): alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), and gamma glutamyl transpeptidase (g-GT) activities, bilirubin, albumin, international normalised ratio (INR), and urinary calcium and phosphate concentrations. We monitored plasma and 24-h urine calcium levels and renal function at three-month intervals or more frequently, as indicated. Clinical examinations included lifestyle and health indicators. Bioelectrical impedance analysis assessed body composition (Tanita BC-418 MA, Sindelfingen, Germany). Physical activity was documented through self-report questions enabling classification into one of four physical activity index groups (inactive; moderately inactive; moderately active; active) as per the European Prospective Investigation into Cancer and Nutrition (EPIC) study questionnaires [18]. Patients completed the Alcohol Use Disorders Identification Test (AUDIT) to evaluate alcohol intake [19]. Diagnosis of depression and assessment of depressive symptoms was conducted using the International Classification of Diseases (ICD-10) system [20] and the validated German version of the revised Beck Depression Inventory II (BDI-II) [21]. This self-report instrument comprises 21 questions on a four-point likert scale. Final scores range from 0 (no depression) to 63 (severe depression); scores 14 represent the cut-off for depression. In addition, patients were asked whether any traumatic event may have occurred to significantly influence their score. 2.4. Outcome parameters The primary outcome assessed absolute changes in depressive symptoms after three and six months of vitamin D supplementation. In contrast to depression, no formal recommendations for interpreting the BDI-II in CLD patients exist, however a consensus statement from IMMPACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials [22]) suggests a reduction of five points as being clinically meaningful based on their systematic analysis of BDI in chronic pain studies. This recommendation was
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
also endorsed by other researchers [23]. We therefore interpreted a change (reduction) of five points on the BDI-II scale as being clinically meaningful, enabling the classification of a patient as ‘responder’. Secondary outcomes included liver biochemistry changes after vitamin D supplementation. 2.5. Statistical analyses Statistical analyses were performed with SPSS 20.0 (IBM, Ehningen, Germany). Non-parametric statistics were used, since the primary outcome variable was not normally distributed. We evaluated differences between categorical variables with c2 tests and the ManneWhitney U test was employed for continuous unpaired variables. Differences between blood parameters and clinical characteristics were examined using Kruskall-Wallis or ManneWhitney tests, where appropriate. We examined the association of season sampling on both vitamin D levels and depressive symptoms by comparing patients with blood taken during summer and autumn months with winter and spring months. Serum 25hydroxyvitamin D concentrations were further categorised based on thresholds reflecting clinical cut-offs for vitamin D inadequacy (<30 ng/ml), deficiency (<20 ng/ml) and severe deficiency (<10 ng/ ml) [24]. We investigated whether 25-hydroxyvitamin D levels were associated with depression severity using uni- and multivariate analyses after adjusting for possible confounders including age, sex, body mass index (BMI), season of blood sampling, physical activity or presence of cirrhosis. The presence of depressive symptoms was dichotomised and defined as clinically relevant for BDI-II 14 and was included as the dependent variable in all analyses. Significant variables (P value set to 0.1) in univariate analysis were included in the multivariate model with backward logistic regression (cross-checked with forward logistic regression, and only reported the results if they differed). Non-significant covariates with an established influence on depression (BMI, season) were also included in this multivariate model. Related samples (e.g. pre and post-intervention BDI-II scores) were analysed using Wilcoxon signed rank test. Given that both increasing age and women have a higher predisposition to depression, we carried out subgroup analyses excluding patients over 65 years of age, and comparing men with women. For the intervention study data, we used per-protocol analysis in addition to intention-to-treat analysis (ITT), where the last observation carried forward method was implemented to compare absolute changes in depression scores (a zero value was imputed for change score in drop-outs). Patients who returned for the first or second follow-up were retained in the per-protocol analysis. A two-sided P value < 0.05 was set as the threshold for statistical significance, and significant results are indicated with an asterisk. Results are presented as medians and ranges as well as absolute and relative frequencies, unless stated otherwise. 3. Results 3.1. Cross-sectional results 3.1.1. Patient characteristics Table 1 summarises the main characteristics of the outpatient cohort (n ¼ 111), for which the median age was 55 years and 52 were women. CLD resulted from chronic viral hepatitis in over half of the cohort with 40% of patients (n ¼ 41) having a normal BMI (<25 kg/m2). The remainder were either overweight (40%, BMI 25.0e29.9 kg/m2) or obese (20%, BMI 30 kg/m2). All but two patients had a normal AUDIT score assessing alcohol intake. A third of patients had developed liver cirrhosis, classified as Child-Pugh stages A (n ¼ 30) or B (n ¼ 5). Inadequate vitamin D serum
3
Table 1 Baseline characteristics of the cross-sectional study population. Entire cohort Sociodemographic N (male/female) 111 (59/52) Age, years, median (range) 55 (20e81) Lifestyle and health indicators (%) 13/27/26/34 PAI (inactive/moderately inactive/moderately active/active) BMI, kg/m2, median (range) 26.1 (17.0e54.5) Indicators of CLD Primary liver disease, n (%) Chronic hepatitis C 39 (35) virus infection Chronic hepatits B 21 (19) virus infection Autoimmune hepatitis 10 (9) Alcoholic liver disease 8 (7) NAFLD 12 (11) Other 21 (19) Liver cirrhosis, n (%) 35 (32) Depression based on BDI-II category, n (%) None (0e13 points) 77 (69) Mild (14e19 points) 18 (16) Moderate (20e28 points) 11 (10) Severe (29e63 points) 5 (5) BDI-II score, median (range) 10 (0e41) Biochemical serum markers, median (range) 25-hydroxyvitamin D (ng/ml) 16.9 (4.0e49.4) Calcium (mmol/l) 2.4 (2.0e2.7) Phosphate (mg/dl) 3.2 (1.3e4.5) PTH (pg/ml) 40 (14e90) AST (U/l) 37.5 (15.0e263.0) ALT (U/l) 39.5 (8.0e340.0) g-GT (U/l) 63.0 (12.0e914.0) AP (U/l) 84 (36e303) Creatinine (mg/dl) 0.8 (0.5e1.9) Urea (mg/dl) 31.0 (4.6e77.0)
Depression
No depression
34 (14/20) 56 (30e77)
77 (45/32) 54 (20e81)
18/18/37/27
10/31/22/37
27.1 (17.0e36.0)
25.1 (18.5e54.5)*
14 (41)
25 (33)
4 (12)
17 (22)
1 (3) 4 (12) 4 (12) 7 (20) 17 (50)**
9 (12) 4 (5) 8 (10) 14 (18) 18 (24)**
0 18 (53) 11 (32) 5 (15) 19 (14e41)
77 (100) 0 0 0 6 (0e13)
17.4 (4.3e39.3) 2.4 (2.0e2.7) 3.4 (1.7e4.5)* 39 (18e90) 43.0 (20.0e183.0) 49.0 (11.0e276.0) 80.0 (19.0e914.0) 91 (44e256) 0.8 (0.5e1.9)* 30.0 (16.0e77.0)
16.3 (4.0e49.4) 2.4 (2.0e2.7) 3.1 (1.3e4.1)* 40 (14e89) 35.0 (15.0e263.0) 38.0 (8.0e340.0) 52.5 (12.0e502.0) 82 (36e303) 0.9 (0.5e1.8)* 31.0 (4.6e58.0)
Significant differences between depressed (BDI-II 14) and non-depressed patients (BDI-II <14) are denoted with * (P < 0.05) and ** (P < 0.001). Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BDI-II, Beck Depression Inventory-II; BMI, body mass index; CLD, chronic liver disease; g-GT, gamma glutamyl transpeptidase; NAFLD, non-alcoholic fatty liver disease; PAI, physical activity index; PTH, parathyroid hormone.
concentrations (<30 ng/ml) were identified in 81% of patients (n ¼ 90). Of these, 52% (n ¼ 47) exhibited moderate (20e10 ng/ml) and 24% (n ¼ 22) presented with severe vitamin D deficiency (<10 ng/ml); of these, 38% were sampled in summer/autumn and 62% in winter/spring. A third of patients (n ¼ 34) had mild to moderate depressive symptoms (median score 19, range 14e41); of these, 16 (14%) were on a stable dose of anti-depressants and had a significantly (P ¼ 0.005) higher median BDI-II score than those not on antidepressants, however vitamin D levels did not differ between these groups. Figure 1 shows the number of patients without and with depression in the different vitamin D categories. Overall, 91% versus 77% of depressed and non-depressed patients had inadequate vitamin D levels, however the distribution across vitamin D categories did not differ significantly between the two groups. Significantly more depressed than non-depressed patients a baseline had liver cirrhosis and displayed higher serum phosphate and lower creatinine concentrations as well as a higher BMI (all
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
4
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
Fig. 1. Clinical classification of serum 25-hydroxyvitamin D levels based on patients without and with depression.
P < 0.05). No other differences were detected in an exploratory analysis of the groups. 3.1.2. Vitamin D levels were inversely associated with depressive symptoms Baseline 25-hydroxyvitamin D levels were significantly associated with depression severity in depressed patients (b ¼ 0.483, 95% CI 0.710 to 0.149, P ¼ 0.004; Fig. 2), where lower vitamin D levels correlated with severity of depressive symptoms (i.e. higher BDI-II score). In contrast, no association was observed between these two variables in non-depressed patients (Fig. 2). Uni- and multivariate logistic regression analysis (Table 2A and B) revealed the presence of cirrhosis and female sex as independent predictors of depression, and a post-hoc analysis showed a significant interaction of sex and BMI as independent predictors of depression (Table 2C). 3.2. Interventional results 3.2.1. Allocation to intervention study All patients included in the cross-sectional analysis were screened for the intervention study (Fig. 3). We excluded 34 patients for not meeting the predetermined supplementation criteria or because they declined our invitation. Of these, 20 patients had adequate baseline vitamin D levels (only three with depression), but were still followed up at all time points. Consequently, 77 patients (24 with and 53 without depression) received vitamin D supplementation (Fig. 3). Treatment data were obtained for 92% and 85% of patients, respectively, who were included in the perprotocol analysis. In each group, 79% were available for the final observation analysis at T3. The baseline characteristics of the intervention groups, which are summarised in Table 3, resemble the overall characteristics of the entire cohort (Table 1). Table 3 includes patients who successfully completed treatment until at least three months (T1). In
Fig. 2. Correlation of serum 25-hydroxyvitamin D concentrations with depressive symptoms. Baseline 25-hydroxyvitamin D levels were significantly associated with depressive symptoms in depressed patients (b ¼ 0.483, 95% CI 0.710 to 0.149, P ¼ 0.004, n ¼ 34), in contrast to the non-depressed patients, in whom no association was observed between these two variables (b ¼ 0.008, CI 0.085 to 0.079, P ¼ 0.947, n ¼ 77).
Table 2 Predictors of depression with univariate and multivariate binary logistic regression analysis. Factor
OR
95% CI
P
(A) Univariate analysis with presence of depression as dependent variable Age 1.01 0.98e1.05 0.549 BMI 1.05 0.97e1.13 0.248 Cirrhosis 3.28 1.39e7.71 0.006 Physical activity 1.00 0.98e1.01 0.759 Season 1.74 0.77e3.97 0.185 Sex 2.01 0.89e4.56 0.095 Vitamin D level 0.98 0.94e1.02 0.317 (B) Multivariate analysis with presence of depression as dependent variable Cirrhosis 4.01 1.61e9.97 0.003 Sex 2.62 1.07e6.39 0.035 (C) Multivariate analysis with presence of depression as dependent variable and with sex assessed as interaction with BMI Cirrhosis 3.41 1.32e8.80 0.011 Sex*BMI 1.05 1.01e1.08 0.008 Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio. Bold values represents the significant values.
brief, 70% of patients with depression were women, compared to 40% without depression (P ¼ 0.02). The only baseline differences between the two groups were that significantly more depressed patients had liver cirrhosis (P ¼ 0.02), higher serum ALT (P ¼ 0.02), and lower serum creatinine levels (P ¼ 0.003).
3.2.2. Depressive symptoms improved during the treatment period The significant improvement in depressive symptoms after vitamin D supplementation is illustrated in Fig. 4 (panel A), with reductions in BDI-II scores in depressed patients after three (13 vs. 18; P ¼ 0.003) and six months (14 vs. 18; P ¼ 0.004). Of note, this effect was not due to anti-depressant medication as the majority of benefits were seen in patients not taking anti-depressants (77% vs. 23%). No change was observed in patients without depression. The
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
5
Fig. 3. Flow chart of patient participation in the study. Table 3 Characteristics of patients completing the intervention study. Depression Sociodemographic N (male/female) 23 (7/16)* Age, years, median (range) 55 (30e77) Lifestyle and health indicators (%) PAI (inactive/moderately 17/17/35/31 inactive/moderately active/active) BMI, kg/m2, median (range) 27.0 (17e36) Indicators of CLD Primary liver disease, n (%) Chronic hepatits C virus infection 10 (43) Chronic hepatits B virus infection 3 (13) Autoimmune hepatitis 1 (4) Alcoholic liver disease 1 (4) NAFLD 3 (13) Other 5 (23) Liver cirrhosis, n (%) 10 (43)* Depression based on BDI-II category, n (%) None (0e13 points) 0 Mild (14e19 points) 13 (57) Moderate (20e28 points) 7 (30) Severe (29e63 points) 3 (13) BDI-II score, median (range) 18 (14e39) Biochemical serum markers, median (range) 25-hydroxyvitamin D (ng/ml) 17.0 (4.3e29.3) Calcium (mmol/l) 2.4 (2.0e2.6) Phosphate (mg/dl) 3.3 (1.7e4.5) PTH (pg/ml) 40 (18e90) AST (U/l) 40 (26e183) ALT (U/l) 54 (11e276)* g-GT (U/l) 80 (20e914) AP (U/l) 91 (44e256) Creatinine (mg/dl) 0.7 (0.6e1.0)** Urea (mg/dl) 29.5 (16.0e60.0)
No depression 50 (30/20)* 56 (20e81) 10/32/20/38 25.7 (19.4e54.5)
17 (34) 12 (24) 8 (16) 2 (4) 5 (10) 6 (12) 9 (18)* 50 (100) 0 0 0 6 (0e13) 12.2 (4.0e27.7) 2.4 (2.0e2.6) 3.1 (1.3e4.1) 39.5 (16.0e89.0) 35 (16e263) 35 (8e340)* 49.5 (12.0e502.0) 79.5 (36.0e303.0) 0.9 (0.5e1.8)** 32.0 (4.6e58.0)
Significant differences between depressed (BDI-II 14) and non-depressed patients (BDI-II <14) are denoted with * (P < 0.05) and ** (P < 0.001). Abbreviations: see Table 1.
treatment response coincided with the restoration of serum vitamin D levels, which increased to normal after three and six months in both depressed (38.1 and 38.2 ng/ml, respectively) and nondepressed (36.3 and 35.1 ng/ml, respectively) patients (all P < 0.0001). Improvements in depressive symptoms remained significant when carrying out an ITT analysis (data not shown). Figure 4 further illustrates the delta (absolute change) of BDI-II scores in depressed patients, with marked improvements in the majority after both three (panel B) and six months (panel C). Specifically, half of the patients with depression displayed improvements of five points or more (responders), synonymous with a clinically meaningful reduction in depression [22]. With regard to secondary outcomes, LFTs did not change during the study in either groups. As expected given the safety of vitamin D supplementation at the dose used and the sample size, no major study-related adverse events occurred. One patient complained of general malaise and withdrew from the study; another patient was withdrawn due to acute hearing loss, which was assessed as unrelated to the study.
3.2.3. Subgroup analyses identified women as responders Depression is known to be more prevalent in females [25]. We therefore carried out a subgroup analysis comparing response to vitamin D therapy between sexes. Vitamin D levels significantly (P < 0.001) increased to normal after three and six months in both sexes, but non-significantly higher 25-hydroxyvitamin D concentrations were displayed in women (41.1 and 39.5 ng/ml) as compared to men (35.1 and 36.1 ng/ml). During the intervention period, a distinct response on the BDI-II questionnaire was observed in women with scores returning to normal levels at three and six months (13 and 11 points, both P ¼ 0.002) as compared to a
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
6
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
Fig. 4. Changes in depressive symptoms during the study. Depressive symptoms, as assessed with the BDI-II score, demonstrated significant improvements (panel A) after 3 (T1) and 6 (T2) months of vitamin D supplementation, as compared to baseline (T0); there was a non-significant deterioration 6 months post supplementation, but this value was still significantly lower than baseline. Horizontal dashed line denotes cut-off for normal level. Depressed patients were also categorised based on deltas (absolute changes) of BDI-II scores with vitamin D supplementation for (panel B) 3 months and (panel C) 6 months. A negative change denotes an improvement (i.e. reduction of BDI-II score), and a positive change is a deterioriation (i.e. a higher score).
score of 21 at baseline, whereas no change was observed in men (18 and 19 points), in comparison to a score of 18 at baseline. The BDI-II can be subdivided into cognitive and somatic subscales and both subscales improved equally in women. In depressed patients, a markedly higher BMI was illustrated for the 11 female responders as compared to the five non-responders (30.8 vs. 26.3 kg/m2); we observed no differences between the two male responders and the five non-responders. Moreover, no within subject changes in BMI were detected during the study. All results still remained significant after removing patients over 65 years. 3.3. Observational (post-intervention) results After six months without vitamin D supplementation (T3), both groups showed declines in vitamin D levels, which were significant for both depressed (21.3 ng/ml, P ¼ 0.0004) and non-depressed patients (21.0 ng/ml, P < 0.0001). This coincided with increased BDI-II scores in patients with depression (median score 17; Fig. 4, panel A). For individual patient data, a clinically significant deterioration (þ5 points on the BDI-II) was observed in 21% of patients. 4. Discussion The findings herein support the primary study hypothesis that the correction of vitamin D deficiency ameliorates depressive symptoms in patients with CLD. In our outpatient cohort, we found a reduction in depressive symptoms as assessed with the BDI-II
after only three months of vitamin D supplementation, which coincided with establishing normal serum 25-hydroxyvitamin D concentrations in most patients. Interestingly, a subgroup analysis revealed marked improvements in depression to occur predominantly in women. The cross-sectional analysis identified 31% of patients as having depression. This finding is in line with those of others, with one in every three CLD patients presenting with depressive symptoms [10]. Eighty percent of the cohort also had inadequate vitamin D levels, further reinforcing previous studies reporting vitamin D deficiency in these patients [2]. Furthermore, our results concur with earlier studies and a meta-analysis showing inverse associations of depressive symptoms with vitamin D levels in healthy populations [8,26]. Though such an association does not prove causality, studies investigating the efficacy of vitamin D replacement therapy for depression look e albeit inconsistently e promising [27]. A recent meta-analysis of randomised controlled trials (RCTs) in fact reported the favourable effect of 800 IU/day vitamin D supplementation for the management of depression to be similar to that of anti-depressant medication when accompanied by an increase in serum 25hydroxyvitamin D concentrations [28]. One of the main criticisms regarding contradictory findings in association and intervention studies is, however, that many do not correct existing vitamin D deficiencies but rather administer blanket supplementation across cohorts who are not all vitamin D depleted [29]. It might be more relevant to assess whether
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
correcting vitamin D deficiency provides such improvements, and the meta-analysis [28] controlled for this and found significant benefits. Heaney highlighted [29] that nutrients such as vitamin D act dissimilarly to drugs, and that a null response to supplementation may be seen in those with almost adequate stores of the nutrient in question. We achieved very high success rates in terms of improving vitamin D concentrations by supplementing all patients with a deficiency with 20,000 IU cholecalciferol per week. This dose appears to circumvent vitamin D metabolism-related defects that might be expected in patients with CLD, given the inherent role of the liver in its activation. The strength of this study is its prospective nature. Moreover, vitamin D levels were cross-checked with a gold standard LC-MS/ MS method. A limitation is that the intervention was not an RCT, a design we avoided also based on ethical grounds as we did not want to withhold treatment for vitamin D deficiency. A further limitation is the relatively small sample size in the respective groups. Given that vitamin D therapy significantly improved depressive symptoms to normal levels predominantly in women, the functional mechanisms underlying this preliminary finding warrant further investigation, particularly because of the small sample size in this subgroup. There are numerous plausible mechanisms by which vitamin D supplementation may reduce depressive symptoms. Firstly, it is known that not only 1,25-dihydroxyvitamin D but also 25hydroxyvitamin D crosses the blood brain barrier [30]. Recently, vitamin D was reported to regulate the synthesis of serotonin (5hydroxyltryptamine [5-HT]) in brain known to affect mood [31]. Of major interest are the recently identified vitamin D response elements (VDREs) on two tryptophan hydroxylase (TPH) genes that have been associated with serotonin synthesis [32]. An experimental study in which rats with hepatic steatosis received cholecalciferol reported improved cognitive effects and reduced TNF-a levels in brain [33]. Therefore, the observed benefits may have resulted from the anti-inflammatory properties of vitamin D [34], a finding that supports the inflammatory hypothesis for some types of depression. We have previously demonstrated that vitamin D deficiency increases mortality in those with advanced cirrhosis, and this association was also found in patients with alcoholic-related liver disease [35,36]. Thus, there are many justifications for correcting vitamin D concentrations in CLD and, coupled with the fact that these patients often suffer from co-morbid depression, vitamin D substitution could play a more prominent part in future clinical care of patients presenting with CLD and inadequate vitamin D levels. In conclusion, a large majority of patients with CLD present with inadequate vitamin D levels, which appear to correlate with depressive symptoms. No study has to date evaluated the possibility of vitamin D correction in ameliorating depressive symptoms in CLD. Interestingly, the results herein indicate that vitamin D substitution might significantly improve depressive symptoms in CLD in a manner which is clinically meaningful, and in particular in women with low baseline vitamin D levels. Larger RCTs are needed to substantiate this finding and to further explore the possible gender disparities. Vitamin D nevertheless, holds potential as a cost-effective adjunctive measure with minimal side effects. Ethical standards The authors declare that all procedures related to this study comply with the ethical standards of the respective national and institutional committees on human experimentation and with the Declaration of Helsinki.
7
Funding and competing interests The present study did not receive external funding. All authors declare that no support was received from any organisation for the submitted work. Contributorship statement CS, CB, MR and FL designed the study. CS collected the study data. All authors contributed to the analysis and interpretation of the work. All authors revised the manuscript for important intellectual content and the final version has been approved by all authors for publication. Conflict of interest None declared. Acknowledgements The authors would like to thank the team in the Department of Medicine II for CFF tests. CSS is also very grateful to the European Association for the Study of the Liver (EASL) for a full bursary to present some of the findings of this paper at the 2014 International Liver Congress. This manuscript has been presented, in part, at the Annual Meeting of the European Association for the Study of the Liver (EASL), London, April 2014, and published in abstract form in the Journal of Hepatology 2014; 60(1):S226. References [1] Crawford BA, Labio ED, Strasser SI, McCaughan GW. Vitamin D replacement for cirrhosis-related bone disease. Nat Clin Pract Gastroenterol Hepatol 2006;3:689e99. [2] Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci 2010;55:2624e8. ~ iga S, Firrincieli D, Housset C, Chignard N. Vitamin D and the vitamin D [3] Zún receptor in liver pathophysiology. Clin Res Hepatol Gastroenterol 2011;35: 295e302. [4] Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005;29:21e30. [5] Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp RG, van Heemst D. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging 2009;30:466e73. [6] Groves NJ, Kesby JP, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav Brain Res 2013;241:120e31. [7] Ozkayar N, Altun B, Ulusoy S, Yildirim T, Halil M, Yilmaz R, et al. Relationship between vitamin D levels and depressive symptoms in renal transplant recipients. Int J Psychiatry Med 2014;47:141e51. [8] Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatr J Ment Sci 2013;202:100e7. [9] Stewart CA, Enders FT, Mitchell MM, Felmlee-Devine D, Smith GE. The cognitive profile of depressed patients with cirrhosis. Prim Care Companion CNS Disord 2011:13. [10] Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014;40:880e92. [11] Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:811e9. [12] Hung CI, Liu CY, Hsiao MC, Yu NW, Chu CL. Metabolic syndrome among psychiatric outpatients with mood and anxiety disorders. BMC Psychiatry 2014;14:185. [13] Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 2008;264:599e609. [14] Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357e66.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
8
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
[15] Antoniucci DM, Sellmeyer DE, Bilezikian JP, Palermo L, Ensrud KE, Greenspan SL, et al. Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis. J Clin Endocrinol Metab 2007;92:942e7. [16] K/DOQI clinical practice guidelines for chronic kidney disease. evaluation, classification, and stratification. American journal of kidney diseases. Official J Natl Kidney Found 2002;39:S1e266. [17] Geib T, Meier F, Schorr P, Lammert F, Stokes CS, Volmer DA. A simple microextraction plate assay for automated LC-MS/MS analysis of human serum 25hydroxyvitamin D levels. J Mass Spectrom 2014;50:275e9. [18] Wareham NJ, Jakes RW, Rennie KL, Schuit J, Mitchell J, Hennings S, et al. Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutr 2003;6:407e13. [19] Babor TF, Higgins-Biddle JC, Saunders JB. The alcohol use disorders identification test. Guidelines for use in primary health care. Second ed. Geneva: World Health Organisation; 2001. [20] World Health Organisation. International statistical classification of diseases and related health problems. Geneva: World Health Organisation; 2011. [21] Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561e71. [22] Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain Off J Am Pain Soc 2008;9: 105e21. [23] Hiroe T, Kojima M, Yamamoto I, Nojima S, Kinoshita Y, Hashimoto N, et al. Gradations of clinical severity and sensitivity to change assessed with the Beck Depression Inventory-II in Japanese patients with depression. Psychiatry Res 2005;135:229e35. [24] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrin Metab 2011;96:1911e30.
[25] Karger A. Gender differences in depression. Bundesgesundheitsblatt, Gesundheitsforsch Gesundheitsschutz 2014;57:1092e8. [26] Chung HK, Cho Y, Choi S, Shin MJ. The association between serum 25hydroxyvitamin D concentrations and depressive symptoms in Korean adults: findings from the Fifth Korea National Health and Nutrition Examination Survey 2010. PLoS One 2014;9:e99185. [27] Annweiler C, Rastmanesh R, Richard-Devantoy S, Beauchet O. The role of vitamin D in depression: from a curious idea to a therapeutic option. J Clin Psychiatry 2013;74:1121e2. [28] Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients 2014;6: 1501e18. [29] Heaney RP. Vitamin Debaseline status and effective dose. N. Engl J Med 2012;367:77e8. [30] Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol 2011;347: 121e7. [31] Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 2003;37:357e73. [32] Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004;305:217. [33] Erbas O, Solmaz V, Aksoy D, Yavasoglu A, Sagcan M, Taskiran D. Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome. Life Sci 2014;103:68e72. [34] Vojinovic J. Vitamin D receptor agonists' anti-inflammatory properties. Ann N. Y Acad Sci 2014;1317:47e56. [35] Stokes CS, Krawczyk M, Reichel C, Lammert F, Grünhage F. Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. Eur J Clin Invest 2014;44:176e83. [36] Trepo E, Ouziel R, Pradat P, Momozawa Y, Quertinmont E, Gervy C, et al. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J Hepatol 2013;59:344e50.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease Caroline S. Stokes a, *, Frank Grünhage a, Crystal Baus b, Dietrich A. Volmer c, Stefan Wagenpfeil d, Matthias Riemenschneider b, Frank Lammert a a
Department of Medicine II, Saarland University Medical Center, Homburg, Germany Department of Psychiatry and Psychotherapy, Saarland University Medical Center, Homburg, Germany Institute of Bioanalytical Chemistry, Saarland University, Saarbrücken, Germany d Institute of Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Campus Homburg, Germany b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 9 March 2015 Accepted 8 July 2015
Background and aims: Vitamin D deficiency and depression frequently occur in patients with chronic liver diseases (CLD). Depression has recently been inversely associated with vitamin D in a meta-analysis, and vitamin D receptor is expressed in brain. This pilot study investigates whether vitamin D replacement ameliorates depressive symptoms in CLD patients and consists of a cross-sectional and an interventional analysis. Methods: Overall, 111 patients with CLD were included in the cross-sectional analysis. The Beck Depression Inventory II (BDI-II) was used to assess depression. Chemiluminescence immunoassay and LC-MS/MS quantified serum 25-hydroxyvitamin D levels. For the interventional analysis, 77 patients with inadequate vitamin D concentrations received 20,000 IU vitamin D per week for six months. The final follow-up was carried out six months post supplementation. Results: In the cross-sectional analysis, 81% of patients (median age 55 years, 47% women) had inadequate baseline vitamin D levels (<30 ng/ml), and 31% presented with depressive symptoms (BDI-II score 14). Depression severity correlated inversely with vitamin D level in depressed patients (b ¼ 0.483, P ¼ 0.004). Depression scores improved significantly from baseline in depressed patients after three and six months (P ¼ 0.003 and P ¼ 0.004, respectively) of supplementation, with vitamin D levels increasing to normal (P < 0.0001). Subgroup analyses revealed this anti-depressant effect of vitamin D to occur predominantly in women. The final follow-up showed increases in median BDI-II scores in the setting of decreased vitamin D levels. Conclusions: Vitamin D levels correlated with BDI-II scores, and vitamin D replacement significantly improved depressive symptoms in women with CLD. Adjuvant vitamin D may be considered in these patients. Registration No: DRKS00007782 German Clinical Trials Registry (DRKS) © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Beck Depression Inventory Cirrhosis Mood Supplementation Women 25-Hydroxyvitamin D
1. Introduction Chronic liver diseases (CLD) are often associated with vitamin D deficiency, which contributes to the manifestation of metabolic bone disease and other systemic complications [1,2]. This might be, in part, attributed to the involvement of the liver in the metabolism
* Corresponding author. Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany. Tel.: þ49 6841 16 23222; fax: þ49 6841 16 23267. E-mail address: [email protected] (C.S. Stokes).
of vitamin D. The first vitamin D hydroxylation step occurs in the liver, yielding 25-hydroxyvitamin D (the primary circulating form and accepted marker of vitamin D status). The second oxidation step in kidney produces the most biologically active vitamin D metabolite, 1,25-dihydroxyvitamin D, which subsequently enters all target cells, exerting its functions mainly through the vitamin D nuclear receptor (VDR) [3]. Given the broad expression of VDR in many organs, numerous non-skeletal benefits for vitamin D have been observed. In brain, vitamin D binds to VDR in many areas implicated in depression pathophysiology, such as neurons and glial cells of the limbic
http://dx.doi.org/10.1016/j.clnu.2015.07.004 0261-5614/© 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
2
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
system [4]. Indeed, VDR gene variants are reported to influence susceptibility to depressive symptoms [5]. Neurosteroidal effects of vitamin D have recently been illustrated in an experimental study, in which adult mice displayed behavioural and brain alterations upon the induction of vitamin D deficiency [6]. In humans, crosssectional studies have shown serum 25-hydroxyvitamin D concentrations to be inversely correlated with the severity of depressive symptoms [7]. A recent meta-analysis by Anglin and coworkers underscored this relationship [8]. Co-morbid depression often affects patients with CLD, with a reported prevalence of approximately 30% [9,10]. Standard antidepressant therapy, however, is not always feasible. Certain antidepressant medications are contraindicated in advanced CLD due to their side effects. Selective serotonin reuptake inhibitors, for instance, can induce gastrointestinal bleeding, possibly because of increased gastric acidity or via defective platelet aggregation due to reduced platelet serotonin [11]. Moreover, patients might be dissuaded by treatments for depression because of unwanted sideeffects, namely fatigue and the aggravation of features of the metabolic syndrome, such as weight gain and dyslipidemia [12]. Consequently, non-pharmacological options warrant further investigation, particularly if they are free from major side effects and also deliver additional health benefits. Vitamin D supplementation may fulfil these criteria and has previously been reported to ameliorate depressive symptoms in overweight subjects [13]. Whether vitamin D has direct benefits on depressive symptoms in patients with CLD has to date not been investigated. The primary aim here was to assess for antidepressant effects of vitamin D in CLD patients. We hypothesised that depressive symptoms can be mitigated by correcting inadequate vitamin D concentrations in these patients. 2. Patients and methods 2.1. Study patients We prospectively recruited adult patients attending the Hepatology Outpatient Clinic (Department of Medicine II, Saarland University Medical Center). Patients with CLD (diagnosed six months previously) were invited to participate, unless they had any of the following exclusion criteria: severe hepatic encephalopathy as quantified by Critical Flicker Frequency (CFF; HEPAtonorm analyzer; Accelab, Kusterdingen, Germany) and defined by CFF <35 Hz [14]; current interferon therapy; and specifically for the intervention phase: presence of hypercalciuria (urinary calcium >8.0 mmol/d); hypercalcaemia (any value above the upper normal limit, serum calcium >2.7 mmol/l), alone or in combination with hyperparathyroidism (parathyroid hormone [PTH] >65.0 pg/ml) [15]; history of calcium-containing kidney stones; allergy or hypersensitivity to any of the supplement ingredients (gelatine, peanuts, soy); sarcoidosis; stage IV or V chronic kidney disease (as defined by the National Kidney Foundation [16]), or pregnancy. Patients with adequate serum 25-hydroxyvitamin D levels (30 ng/ ml) did not receive vitamin D but were monitored during the intervention. The local research ethics committee approved the € study protocol (Arztekammer des Saarlandes, Ref. 57/11), which conforms with the declaration of Helsinki. All patients provided written informed consent. 2.2. Study design Eligible patients were included in a cross-sectional analysis assessing the association of vitamin D with depression. Patients with serum 25-hydroxyvitamin D concentrations <30 ng/ml then received six-month replacement therapy. This consisted of an oral
dose of 20,000 IU cholecalciferol/vitamin D3 (Dekristol®, Jenapharm, Jena, Germany) contained in one capsule, daily for the first seven days, then weekly thereon. Patients were further stratified into subgroups based on whether depressive symptoms were present. All patients were followed up after three (T1) and six months (T2), after which vitamin D supplementation was stopped. A final follow-up took place 12 months from baseline (T3) after a six-month pause from vitamin D. Compliance was determined from increases in serum 25-hydroxyvitamin D concentrations, together with the discrete interval pill-count method. Patients abstained from taking other nutritional supplements during the study, unless medically indicated. Patients on anti-depressant therapy were only recruited if their dose had remained stable for the preceding eight weeks, and were instructed to inform the study coordinator immediately upon any dosage or medication changes. 2.3. Study procedures Serum 25-hydroxyvitamin D analyses were conducted by chemiluminescence immunoassay LIAISON® 25-OH Vitamin D TOTAL Assay (DiaSorin, MN, USA). A subset of samples was validated by liquid chromatography-tandem mass spectrometry (LCMS/MS), 96-well micro-extraction (AC Extraction Plate, Tecan, €nnedorf, Switzerland), 25-hydroxyvitamin D isotope calibration Ma and quality control kits (Recipe, Munich, Germany) and 5500 QTRAP electrospray ionisation LC-MS/MS (Sciex, Concord, ON, Canada), as previously reported [17]. Other standard biochemical analyses in our central clinical laboratory included: calcium, phosphate, creatinine, urea, PTH as well as standard liver function tests (LFTs): alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), and gamma glutamyl transpeptidase (g-GT) activities, bilirubin, albumin, international normalised ratio (INR), and urinary calcium and phosphate concentrations. We monitored plasma and 24-h urine calcium levels and renal function at three-month intervals or more frequently, as indicated. Clinical examinations included lifestyle and health indicators. Bioelectrical impedance analysis assessed body composition (Tanita BC-418 MA, Sindelfingen, Germany). Physical activity was documented through self-report questions enabling classification into one of four physical activity index groups (inactive; moderately inactive; moderately active; active) as per the European Prospective Investigation into Cancer and Nutrition (EPIC) study questionnaires [18]. Patients completed the Alcohol Use Disorders Identification Test (AUDIT) to evaluate alcohol intake [19]. Diagnosis of depression and assessment of depressive symptoms was conducted using the International Classification of Diseases (ICD-10) system [20] and the validated German version of the revised Beck Depression Inventory II (BDI-II) [21]. This self-report instrument comprises 21 questions on a four-point likert scale. Final scores range from 0 (no depression) to 63 (severe depression); scores 14 represent the cut-off for depression. In addition, patients were asked whether any traumatic event may have occurred to significantly influence their score. 2.4. Outcome parameters The primary outcome assessed absolute changes in depressive symptoms after three and six months of vitamin D supplementation. In contrast to depression, no formal recommendations for interpreting the BDI-II in CLD patients exist, however a consensus statement from IMMPACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials [22]) suggests a reduction of five points as being clinically meaningful based on their systematic analysis of BDI in chronic pain studies. This recommendation was
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
also endorsed by other researchers [23]. We therefore interpreted a change (reduction) of five points on the BDI-II scale as being clinically meaningful, enabling the classification of a patient as ‘responder’. Secondary outcomes included liver biochemistry changes after vitamin D supplementation. 2.5. Statistical analyses Statistical analyses were performed with SPSS 20.0 (IBM, Ehningen, Germany). Non-parametric statistics were used, since the primary outcome variable was not normally distributed. We evaluated differences between categorical variables with c2 tests and the ManneWhitney U test was employed for continuous unpaired variables. Differences between blood parameters and clinical characteristics were examined using Kruskall-Wallis or ManneWhitney tests, where appropriate. We examined the association of season sampling on both vitamin D levels and depressive symptoms by comparing patients with blood taken during summer and autumn months with winter and spring months. Serum 25hydroxyvitamin D concentrations were further categorised based on thresholds reflecting clinical cut-offs for vitamin D inadequacy (<30 ng/ml), deficiency (<20 ng/ml) and severe deficiency (<10 ng/ ml) [24]. We investigated whether 25-hydroxyvitamin D levels were associated with depression severity using uni- and multivariate analyses after adjusting for possible confounders including age, sex, body mass index (BMI), season of blood sampling, physical activity or presence of cirrhosis. The presence of depressive symptoms was dichotomised and defined as clinically relevant for BDI-II 14 and was included as the dependent variable in all analyses. Significant variables (P value set to 0.1) in univariate analysis were included in the multivariate model with backward logistic regression (cross-checked with forward logistic regression, and only reported the results if they differed). Non-significant covariates with an established influence on depression (BMI, season) were also included in this multivariate model. Related samples (e.g. pre and post-intervention BDI-II scores) were analysed using Wilcoxon signed rank test. Given that both increasing age and women have a higher predisposition to depression, we carried out subgroup analyses excluding patients over 65 years of age, and comparing men with women. For the intervention study data, we used per-protocol analysis in addition to intention-to-treat analysis (ITT), where the last observation carried forward method was implemented to compare absolute changes in depression scores (a zero value was imputed for change score in drop-outs). Patients who returned for the first or second follow-up were retained in the per-protocol analysis. A two-sided P value < 0.05 was set as the threshold for statistical significance, and significant results are indicated with an asterisk. Results are presented as medians and ranges as well as absolute and relative frequencies, unless stated otherwise. 3. Results 3.1. Cross-sectional results 3.1.1. Patient characteristics Table 1 summarises the main characteristics of the outpatient cohort (n ¼ 111), for which the median age was 55 years and 52 were women. CLD resulted from chronic viral hepatitis in over half of the cohort with 40% of patients (n ¼ 41) having a normal BMI (<25 kg/m2). The remainder were either overweight (40%, BMI 25.0e29.9 kg/m2) or obese (20%, BMI 30 kg/m2). All but two patients had a normal AUDIT score assessing alcohol intake. A third of patients had developed liver cirrhosis, classified as Child-Pugh stages A (n ¼ 30) or B (n ¼ 5). Inadequate vitamin D serum
3
Table 1 Baseline characteristics of the cross-sectional study population. Entire cohort Sociodemographic N (male/female) 111 (59/52) Age, years, median (range) 55 (20e81) Lifestyle and health indicators (%) 13/27/26/34 PAI (inactive/moderately inactive/moderately active/active) BMI, kg/m2, median (range) 26.1 (17.0e54.5) Indicators of CLD Primary liver disease, n (%) Chronic hepatitis C 39 (35) virus infection Chronic hepatits B 21 (19) virus infection Autoimmune hepatitis 10 (9) Alcoholic liver disease 8 (7) NAFLD 12 (11) Other 21 (19) Liver cirrhosis, n (%) 35 (32) Depression based on BDI-II category, n (%) None (0e13 points) 77 (69) Mild (14e19 points) 18 (16) Moderate (20e28 points) 11 (10) Severe (29e63 points) 5 (5) BDI-II score, median (range) 10 (0e41) Biochemical serum markers, median (range) 25-hydroxyvitamin D (ng/ml) 16.9 (4.0e49.4) Calcium (mmol/l) 2.4 (2.0e2.7) Phosphate (mg/dl) 3.2 (1.3e4.5) PTH (pg/ml) 40 (14e90) AST (U/l) 37.5 (15.0e263.0) ALT (U/l) 39.5 (8.0e340.0) g-GT (U/l) 63.0 (12.0e914.0) AP (U/l) 84 (36e303) Creatinine (mg/dl) 0.8 (0.5e1.9) Urea (mg/dl) 31.0 (4.6e77.0)
Depression
No depression
34 (14/20) 56 (30e77)
77 (45/32) 54 (20e81)
18/18/37/27
10/31/22/37
27.1 (17.0e36.0)
25.1 (18.5e54.5)*
14 (41)
25 (33)
4 (12)
17 (22)
1 (3) 4 (12) 4 (12) 7 (20) 17 (50)**
9 (12) 4 (5) 8 (10) 14 (18) 18 (24)**
0 18 (53) 11 (32) 5 (15) 19 (14e41)
77 (100) 0 0 0 6 (0e13)
17.4 (4.3e39.3) 2.4 (2.0e2.7) 3.4 (1.7e4.5)* 39 (18e90) 43.0 (20.0e183.0) 49.0 (11.0e276.0) 80.0 (19.0e914.0) 91 (44e256) 0.8 (0.5e1.9)* 30.0 (16.0e77.0)
16.3 (4.0e49.4) 2.4 (2.0e2.7) 3.1 (1.3e4.1)* 40 (14e89) 35.0 (15.0e263.0) 38.0 (8.0e340.0) 52.5 (12.0e502.0) 82 (36e303) 0.9 (0.5e1.8)* 31.0 (4.6e58.0)
Significant differences between depressed (BDI-II 14) and non-depressed patients (BDI-II <14) are denoted with * (P < 0.05) and ** (P < 0.001). Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BDI-II, Beck Depression Inventory-II; BMI, body mass index; CLD, chronic liver disease; g-GT, gamma glutamyl transpeptidase; NAFLD, non-alcoholic fatty liver disease; PAI, physical activity index; PTH, parathyroid hormone.
concentrations (<30 ng/ml) were identified in 81% of patients (n ¼ 90). Of these, 52% (n ¼ 47) exhibited moderate (20e10 ng/ml) and 24% (n ¼ 22) presented with severe vitamin D deficiency (<10 ng/ml); of these, 38% were sampled in summer/autumn and 62% in winter/spring. A third of patients (n ¼ 34) had mild to moderate depressive symptoms (median score 19, range 14e41); of these, 16 (14%) were on a stable dose of anti-depressants and had a significantly (P ¼ 0.005) higher median BDI-II score than those not on antidepressants, however vitamin D levels did not differ between these groups. Figure 1 shows the number of patients without and with depression in the different vitamin D categories. Overall, 91% versus 77% of depressed and non-depressed patients had inadequate vitamin D levels, however the distribution across vitamin D categories did not differ significantly between the two groups. Significantly more depressed than non-depressed patients a baseline had liver cirrhosis and displayed higher serum phosphate and lower creatinine concentrations as well as a higher BMI (all
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
4
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
Fig. 1. Clinical classification of serum 25-hydroxyvitamin D levels based on patients without and with depression.
P < 0.05). No other differences were detected in an exploratory analysis of the groups. 3.1.2. Vitamin D levels were inversely associated with depressive symptoms Baseline 25-hydroxyvitamin D levels were significantly associated with depression severity in depressed patients (b ¼ 0.483, 95% CI 0.710 to 0.149, P ¼ 0.004; Fig. 2), where lower vitamin D levels correlated with severity of depressive symptoms (i.e. higher BDI-II score). In contrast, no association was observed between these two variables in non-depressed patients (Fig. 2). Uni- and multivariate logistic regression analysis (Table 2A and B) revealed the presence of cirrhosis and female sex as independent predictors of depression, and a post-hoc analysis showed a significant interaction of sex and BMI as independent predictors of depression (Table 2C). 3.2. Interventional results 3.2.1. Allocation to intervention study All patients included in the cross-sectional analysis were screened for the intervention study (Fig. 3). We excluded 34 patients for not meeting the predetermined supplementation criteria or because they declined our invitation. Of these, 20 patients had adequate baseline vitamin D levels (only three with depression), but were still followed up at all time points. Consequently, 77 patients (24 with and 53 without depression) received vitamin D supplementation (Fig. 3). Treatment data were obtained for 92% and 85% of patients, respectively, who were included in the perprotocol analysis. In each group, 79% were available for the final observation analysis at T3. The baseline characteristics of the intervention groups, which are summarised in Table 3, resemble the overall characteristics of the entire cohort (Table 1). Table 3 includes patients who successfully completed treatment until at least three months (T1). In
Fig. 2. Correlation of serum 25-hydroxyvitamin D concentrations with depressive symptoms. Baseline 25-hydroxyvitamin D levels were significantly associated with depressive symptoms in depressed patients (b ¼ 0.483, 95% CI 0.710 to 0.149, P ¼ 0.004, n ¼ 34), in contrast to the non-depressed patients, in whom no association was observed between these two variables (b ¼ 0.008, CI 0.085 to 0.079, P ¼ 0.947, n ¼ 77).
Table 2 Predictors of depression with univariate and multivariate binary logistic regression analysis. Factor
OR
95% CI
P
(A) Univariate analysis with presence of depression as dependent variable Age 1.01 0.98e1.05 0.549 BMI 1.05 0.97e1.13 0.248 Cirrhosis 3.28 1.39e7.71 0.006 Physical activity 1.00 0.98e1.01 0.759 Season 1.74 0.77e3.97 0.185 Sex 2.01 0.89e4.56 0.095 Vitamin D level 0.98 0.94e1.02 0.317 (B) Multivariate analysis with presence of depression as dependent variable Cirrhosis 4.01 1.61e9.97 0.003 Sex 2.62 1.07e6.39 0.035 (C) Multivariate analysis with presence of depression as dependent variable and with sex assessed as interaction with BMI Cirrhosis 3.41 1.32e8.80 0.011 Sex*BMI 1.05 1.01e1.08 0.008 Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio. Bold values represents the significant values.
brief, 70% of patients with depression were women, compared to 40% without depression (P ¼ 0.02). The only baseline differences between the two groups were that significantly more depressed patients had liver cirrhosis (P ¼ 0.02), higher serum ALT (P ¼ 0.02), and lower serum creatinine levels (P ¼ 0.003).
3.2.2. Depressive symptoms improved during the treatment period The significant improvement in depressive symptoms after vitamin D supplementation is illustrated in Fig. 4 (panel A), with reductions in BDI-II scores in depressed patients after three (13 vs. 18; P ¼ 0.003) and six months (14 vs. 18; P ¼ 0.004). Of note, this effect was not due to anti-depressant medication as the majority of benefits were seen in patients not taking anti-depressants (77% vs. 23%). No change was observed in patients without depression. The
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
5
Fig. 3. Flow chart of patient participation in the study. Table 3 Characteristics of patients completing the intervention study. Depression Sociodemographic N (male/female) 23 (7/16)* Age, years, median (range) 55 (30e77) Lifestyle and health indicators (%) PAI (inactive/moderately 17/17/35/31 inactive/moderately active/active) BMI, kg/m2, median (range) 27.0 (17e36) Indicators of CLD Primary liver disease, n (%) Chronic hepatits C virus infection 10 (43) Chronic hepatits B virus infection 3 (13) Autoimmune hepatitis 1 (4) Alcoholic liver disease 1 (4) NAFLD 3 (13) Other 5 (23) Liver cirrhosis, n (%) 10 (43)* Depression based on BDI-II category, n (%) None (0e13 points) 0 Mild (14e19 points) 13 (57) Moderate (20e28 points) 7 (30) Severe (29e63 points) 3 (13) BDI-II score, median (range) 18 (14e39) Biochemical serum markers, median (range) 25-hydroxyvitamin D (ng/ml) 17.0 (4.3e29.3) Calcium (mmol/l) 2.4 (2.0e2.6) Phosphate (mg/dl) 3.3 (1.7e4.5) PTH (pg/ml) 40 (18e90) AST (U/l) 40 (26e183) ALT (U/l) 54 (11e276)* g-GT (U/l) 80 (20e914) AP (U/l) 91 (44e256) Creatinine (mg/dl) 0.7 (0.6e1.0)** Urea (mg/dl) 29.5 (16.0e60.0)
No depression 50 (30/20)* 56 (20e81) 10/32/20/38 25.7 (19.4e54.5)
17 (34) 12 (24) 8 (16) 2 (4) 5 (10) 6 (12) 9 (18)* 50 (100) 0 0 0 6 (0e13) 12.2 (4.0e27.7) 2.4 (2.0e2.6) 3.1 (1.3e4.1) 39.5 (16.0e89.0) 35 (16e263) 35 (8e340)* 49.5 (12.0e502.0) 79.5 (36.0e303.0) 0.9 (0.5e1.8)** 32.0 (4.6e58.0)
Significant differences between depressed (BDI-II 14) and non-depressed patients (BDI-II <14) are denoted with * (P < 0.05) and ** (P < 0.001). Abbreviations: see Table 1.
treatment response coincided with the restoration of serum vitamin D levels, which increased to normal after three and six months in both depressed (38.1 and 38.2 ng/ml, respectively) and nondepressed (36.3 and 35.1 ng/ml, respectively) patients (all P < 0.0001). Improvements in depressive symptoms remained significant when carrying out an ITT analysis (data not shown). Figure 4 further illustrates the delta (absolute change) of BDI-II scores in depressed patients, with marked improvements in the majority after both three (panel B) and six months (panel C). Specifically, half of the patients with depression displayed improvements of five points or more (responders), synonymous with a clinically meaningful reduction in depression [22]. With regard to secondary outcomes, LFTs did not change during the study in either groups. As expected given the safety of vitamin D supplementation at the dose used and the sample size, no major study-related adverse events occurred. One patient complained of general malaise and withdrew from the study; another patient was withdrawn due to acute hearing loss, which was assessed as unrelated to the study.
3.2.3. Subgroup analyses identified women as responders Depression is known to be more prevalent in females [25]. We therefore carried out a subgroup analysis comparing response to vitamin D therapy between sexes. Vitamin D levels significantly (P < 0.001) increased to normal after three and six months in both sexes, but non-significantly higher 25-hydroxyvitamin D concentrations were displayed in women (41.1 and 39.5 ng/ml) as compared to men (35.1 and 36.1 ng/ml). During the intervention period, a distinct response on the BDI-II questionnaire was observed in women with scores returning to normal levels at three and six months (13 and 11 points, both P ¼ 0.002) as compared to a
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
6
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
Fig. 4. Changes in depressive symptoms during the study. Depressive symptoms, as assessed with the BDI-II score, demonstrated significant improvements (panel A) after 3 (T1) and 6 (T2) months of vitamin D supplementation, as compared to baseline (T0); there was a non-significant deterioration 6 months post supplementation, but this value was still significantly lower than baseline. Horizontal dashed line denotes cut-off for normal level. Depressed patients were also categorised based on deltas (absolute changes) of BDI-II scores with vitamin D supplementation for (panel B) 3 months and (panel C) 6 months. A negative change denotes an improvement (i.e. reduction of BDI-II score), and a positive change is a deterioriation (i.e. a higher score).
score of 21 at baseline, whereas no change was observed in men (18 and 19 points), in comparison to a score of 18 at baseline. The BDI-II can be subdivided into cognitive and somatic subscales and both subscales improved equally in women. In depressed patients, a markedly higher BMI was illustrated for the 11 female responders as compared to the five non-responders (30.8 vs. 26.3 kg/m2); we observed no differences between the two male responders and the five non-responders. Moreover, no within subject changes in BMI were detected during the study. All results still remained significant after removing patients over 65 years. 3.3. Observational (post-intervention) results After six months without vitamin D supplementation (T3), both groups showed declines in vitamin D levels, which were significant for both depressed (21.3 ng/ml, P ¼ 0.0004) and non-depressed patients (21.0 ng/ml, P < 0.0001). This coincided with increased BDI-II scores in patients with depression (median score 17; Fig. 4, panel A). For individual patient data, a clinically significant deterioration (þ5 points on the BDI-II) was observed in 21% of patients. 4. Discussion The findings herein support the primary study hypothesis that the correction of vitamin D deficiency ameliorates depressive symptoms in patients with CLD. In our outpatient cohort, we found a reduction in depressive symptoms as assessed with the BDI-II
after only three months of vitamin D supplementation, which coincided with establishing normal serum 25-hydroxyvitamin D concentrations in most patients. Interestingly, a subgroup analysis revealed marked improvements in depression to occur predominantly in women. The cross-sectional analysis identified 31% of patients as having depression. This finding is in line with those of others, with one in every three CLD patients presenting with depressive symptoms [10]. Eighty percent of the cohort also had inadequate vitamin D levels, further reinforcing previous studies reporting vitamin D deficiency in these patients [2]. Furthermore, our results concur with earlier studies and a meta-analysis showing inverse associations of depressive symptoms with vitamin D levels in healthy populations [8,26]. Though such an association does not prove causality, studies investigating the efficacy of vitamin D replacement therapy for depression look e albeit inconsistently e promising [27]. A recent meta-analysis of randomised controlled trials (RCTs) in fact reported the favourable effect of 800 IU/day vitamin D supplementation for the management of depression to be similar to that of anti-depressant medication when accompanied by an increase in serum 25hydroxyvitamin D concentrations [28]. One of the main criticisms regarding contradictory findings in association and intervention studies is, however, that many do not correct existing vitamin D deficiencies but rather administer blanket supplementation across cohorts who are not all vitamin D depleted [29]. It might be more relevant to assess whether
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
correcting vitamin D deficiency provides such improvements, and the meta-analysis [28] controlled for this and found significant benefits. Heaney highlighted [29] that nutrients such as vitamin D act dissimilarly to drugs, and that a null response to supplementation may be seen in those with almost adequate stores of the nutrient in question. We achieved very high success rates in terms of improving vitamin D concentrations by supplementing all patients with a deficiency with 20,000 IU cholecalciferol per week. This dose appears to circumvent vitamin D metabolism-related defects that might be expected in patients with CLD, given the inherent role of the liver in its activation. The strength of this study is its prospective nature. Moreover, vitamin D levels were cross-checked with a gold standard LC-MS/ MS method. A limitation is that the intervention was not an RCT, a design we avoided also based on ethical grounds as we did not want to withhold treatment for vitamin D deficiency. A further limitation is the relatively small sample size in the respective groups. Given that vitamin D therapy significantly improved depressive symptoms to normal levels predominantly in women, the functional mechanisms underlying this preliminary finding warrant further investigation, particularly because of the small sample size in this subgroup. There are numerous plausible mechanisms by which vitamin D supplementation may reduce depressive symptoms. Firstly, it is known that not only 1,25-dihydroxyvitamin D but also 25hydroxyvitamin D crosses the blood brain barrier [30]. Recently, vitamin D was reported to regulate the synthesis of serotonin (5hydroxyltryptamine [5-HT]) in brain known to affect mood [31]. Of major interest are the recently identified vitamin D response elements (VDREs) on two tryptophan hydroxylase (TPH) genes that have been associated with serotonin synthesis [32]. An experimental study in which rats with hepatic steatosis received cholecalciferol reported improved cognitive effects and reduced TNF-a levels in brain [33]. Therefore, the observed benefits may have resulted from the anti-inflammatory properties of vitamin D [34], a finding that supports the inflammatory hypothesis for some types of depression. We have previously demonstrated that vitamin D deficiency increases mortality in those with advanced cirrhosis, and this association was also found in patients with alcoholic-related liver disease [35,36]. Thus, there are many justifications for correcting vitamin D concentrations in CLD and, coupled with the fact that these patients often suffer from co-morbid depression, vitamin D substitution could play a more prominent part in future clinical care of patients presenting with CLD and inadequate vitamin D levels. In conclusion, a large majority of patients with CLD present with inadequate vitamin D levels, which appear to correlate with depressive symptoms. No study has to date evaluated the possibility of vitamin D correction in ameliorating depressive symptoms in CLD. Interestingly, the results herein indicate that vitamin D substitution might significantly improve depressive symptoms in CLD in a manner which is clinically meaningful, and in particular in women with low baseline vitamin D levels. Larger RCTs are needed to substantiate this finding and to further explore the possible gender disparities. Vitamin D nevertheless, holds potential as a cost-effective adjunctive measure with minimal side effects. Ethical standards The authors declare that all procedures related to this study comply with the ethical standards of the respective national and institutional committees on human experimentation and with the Declaration of Helsinki.
7
Funding and competing interests The present study did not receive external funding. All authors declare that no support was received from any organisation for the submitted work. Contributorship statement CS, CB, MR and FL designed the study. CS collected the study data. All authors contributed to the analysis and interpretation of the work. All authors revised the manuscript for important intellectual content and the final version has been approved by all authors for publication. Conflict of interest None declared. Acknowledgements The authors would like to thank the team in the Department of Medicine II for CFF tests. CSS is also very grateful to the European Association for the Study of the Liver (EASL) for a full bursary to present some of the findings of this paper at the 2014 International Liver Congress. This manuscript has been presented, in part, at the Annual Meeting of the European Association for the Study of the Liver (EASL), London, April 2014, and published in abstract form in the Journal of Hepatology 2014; 60(1):S226. References [1] Crawford BA, Labio ED, Strasser SI, McCaughan GW. Vitamin D replacement for cirrhosis-related bone disease. Nat Clin Pract Gastroenterol Hepatol 2006;3:689e99. [2] Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci 2010;55:2624e8. ~ iga S, Firrincieli D, Housset C, Chignard N. Vitamin D and the vitamin D [3] Zún receptor in liver pathophysiology. Clin Res Hepatol Gastroenterol 2011;35: 295e302. [4] Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005;29:21e30. [5] Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp RG, van Heemst D. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging 2009;30:466e73. [6] Groves NJ, Kesby JP, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav Brain Res 2013;241:120e31. [7] Ozkayar N, Altun B, Ulusoy S, Yildirim T, Halil M, Yilmaz R, et al. Relationship between vitamin D levels and depressive symptoms in renal transplant recipients. Int J Psychiatry Med 2014;47:141e51. [8] Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatr J Ment Sci 2013;202:100e7. [9] Stewart CA, Enders FT, Mitchell MM, Felmlee-Devine D, Smith GE. The cognitive profile of depressed patients with cirrhosis. Prim Care Companion CNS Disord 2011:13. [10] Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther 2014;40:880e92. [11] Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:811e9. [12] Hung CI, Liu CY, Hsiao MC, Yu NW, Chu CL. Metabolic syndrome among psychiatric outpatients with mood and anxiety disorders. BMC Psychiatry 2014;14:185. [13] Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 2008;264:599e609. [14] Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357e66.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004
8
C.S. Stokes et al. / Clinical Nutrition xxx (2015) 1e8
[15] Antoniucci DM, Sellmeyer DE, Bilezikian JP, Palermo L, Ensrud KE, Greenspan SL, et al. Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis. J Clin Endocrinol Metab 2007;92:942e7. [16] K/DOQI clinical practice guidelines for chronic kidney disease. evaluation, classification, and stratification. American journal of kidney diseases. Official J Natl Kidney Found 2002;39:S1e266. [17] Geib T, Meier F, Schorr P, Lammert F, Stokes CS, Volmer DA. A simple microextraction plate assay for automated LC-MS/MS analysis of human serum 25hydroxyvitamin D levels. J Mass Spectrom 2014;50:275e9. [18] Wareham NJ, Jakes RW, Rennie KL, Schuit J, Mitchell J, Hennings S, et al. Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutr 2003;6:407e13. [19] Babor TF, Higgins-Biddle JC, Saunders JB. The alcohol use disorders identification test. Guidelines for use in primary health care. Second ed. Geneva: World Health Organisation; 2001. [20] World Health Organisation. International statistical classification of diseases and related health problems. Geneva: World Health Organisation; 2011. [21] Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561e71. [22] Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain Off J Am Pain Soc 2008;9: 105e21. [23] Hiroe T, Kojima M, Yamamoto I, Nojima S, Kinoshita Y, Hashimoto N, et al. Gradations of clinical severity and sensitivity to change assessed with the Beck Depression Inventory-II in Japanese patients with depression. Psychiatry Res 2005;135:229e35. [24] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrin Metab 2011;96:1911e30.
[25] Karger A. Gender differences in depression. Bundesgesundheitsblatt, Gesundheitsforsch Gesundheitsschutz 2014;57:1092e8. [26] Chung HK, Cho Y, Choi S, Shin MJ. The association between serum 25hydroxyvitamin D concentrations and depressive symptoms in Korean adults: findings from the Fifth Korea National Health and Nutrition Examination Survey 2010. PLoS One 2014;9:e99185. [27] Annweiler C, Rastmanesh R, Richard-Devantoy S, Beauchet O. The role of vitamin D in depression: from a curious idea to a therapeutic option. J Clin Psychiatry 2013;74:1121e2. [28] Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients 2014;6: 1501e18. [29] Heaney RP. Vitamin Debaseline status and effective dose. N. Engl J Med 2012;367:77e8. [30] Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol 2011;347: 121e7. [31] Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 2003;37:357e73. [32] Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004;305:217. [33] Erbas O, Solmaz V, Aksoy D, Yavasoglu A, Sagcan M, Taskiran D. Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome. Life Sci 2014;103:68e72. [34] Vojinovic J. Vitamin D receptor agonists' anti-inflammatory properties. Ann N. Y Acad Sci 2014;1317:47e56. [35] Stokes CS, Krawczyk M, Reichel C, Lammert F, Grünhage F. Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. Eur J Clin Invest 2014;44:176e83. [36] Trepo E, Ouziel R, Pradat P, Momozawa Y, Quertinmont E, Gervy C, et al. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J Hepatol 2013;59:344e50.
Please cite this article in press as: Stokes CS, et al., Vitamin D supplementation reduces depressive symptoms in patients with chronic liver disease, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.07.004