Effects of vitamin D supplementation on depression in patients with colorectal cancer

Background: The relation and possible mechnism of vitamin D supplementation on depression in colorectal cancer (CRC) patients was not clearly ; Objective: This study investigates the effect of vitamin D supplementation on depression in colorectal cancer (CRC) patients. Methods : We recruited 168 CRC patients and 168 healthy control subjects into this study. 17-item Hamilton Depression Rating Scale (HDRS-17) was used to assess depression. Results: We found that 25-hydroxyvitamin D (25(OH)D) concentrations were independently associated with depression among CRC patients. For the 45 depressed patients receiving vitamin D3 supplementation, depression scores decreased markedly with 25(OH)D concentrations increasing to normal. Conclusion: Therefore, we advise monitoring this indicator in CRC patients and supplementing with vitamin D 3 when their 25(OH)D concentrations are low.


Background
Depression is an extremely frequent complication among survivors of colorectal cancer (CRC), with prevalence ranging from 24-57%. [1,2] Depressive complication has been related to reduced quality of life [3] and increased mortality. [4] The profuseness of vitamin D receptors and vitamin D activating enzyme 1α-hydroxylase in the center nervous system suggests involvement of vitamin D in certain psychological processes. [ have demonstrated positive effects of vitamin D supplementation on depression. [8,9] Vitamin D de ciency is extremely frequent complication among CRC patients. [10 ]Low concentrations of vitamin D have been related to increased mortality among survivors of CRC. [11]Moreover, recent studies have demonstrated a positive effect of vitamin D supplementation on prognosis of CRC survivors. [12].
Base on both the involvement of vitamin D in depression in non-CRC individuals and high prevalence of vitamin D de ciency in CRC patients, whether vitamin D supplementation exerts positive effects on depression in CRC patients was examined.

Study population and design
We prospectively recruited 168 outpatients with CRC in the clinics of two facilities in Zhejiang QuHua Hospital and First A liated Hospital of Jiaxing University to participate in this study during the period from May 1, 2016, and October 10, 2018. Eligibility criteria were: (1) Chinese ethnicity; (2) aged 18 years or older; (3) having a diagnosis of CRC in their medical record; (4) having willingness to give written informed consent. Exclusion criteria were: (1) patients with cognitive dysfunction; (2) patients with hypercalcaemia, alone or together with hyperparathyroidism; (3) patients with a history of mental or psychological disease. Meantime, 168 age-and sex-matched healthy volunteers, without pre-existing vitamin D3 supplementation, were consecutively recruited from a health survey. Quali ed patients were included into the cross-sectional study to evaluate the correlation between vitamin D concentrations and depression. Patients without su cient 25-hydroxyvitamin D (25(OH)D) (≤ 75 nmol/L) received vitamin D3 supplementation (cholecalciferol) 2000 IU/d for six months. According to whether there existed depression, we strati ed patients into subgroups further. Regular follow-up visits were carried out after 3 months (T1) and 6 months (T2). Written informed consents were obtained from all participating subjects. The study was approved by the Ethics Committee of Zhejiang QuHua Hospital and all methods were conducted in compliance with our local guidelines and clinical regulations.

Clinical assessment
Depressive symptoms were screened using the 17-item Hamilton Depression Rating Scale (HDRS-17). [13] Patients with a HDRS-17 score of ≥ 7 were given the Chinese version of Structured Clinical Interview for Depression (SCID) and Statistical Manual of Mental Disorders, 4th edition, to make a proper diagnosis.
Pain intensity was assessed using a numerical rating scale from 10 to 0, with 10 for "extremely painful" and 0 indicating "no pain". Social support was examined by two items as follows: (1) When suffering from worries, would you like to pour them to somebody (using a numerical rating scale from 1 to 4: 1 never; 2 only pouring my worries to my spouse or parents; 3 when my friends and relatives asking me, I will pour my worries to them; 4 pouring my worries to others on my own initiative)? (2) When suffering from di culties, would you like to ask help from others (using a numerical rating scale from 1 to 4: 1 never; 2 occasionally; 3 sometimes; 4 always)? Social support of patients was evaluated by the total scores from 2 to 8, with high score indicating good social status. Serum 25(OH)D, an optimal indicator of vitamin D metabolic condition, was measured using the competitive protein-binding assay with the intraassay coe cients of variation of 7-10%.

Outcome measure
The primary outcome evaluated absolute changes in HDRS-17 scores after 3 and 6 months of vitamin D treatment. For the HDRS-17, the widely-accepted de nitions of response (at least a 50% reduction from baseline in the total score) were adopted in this study. [14] Statistical analysis Categorical variables were compared using Pearson χ 2 test. Fisher's exact test was performed instead if any of expected counts were < 5. Student's t test was performed for normally distributed variables, while Mann-Whitney U test used was for parametric variables. Serum concentrations of 25(OH)D were divided into four quartiles (≤ 30.0, 30.1-43.0, 43.1-55.0 and ≥ 55.1 nmol/L), because the raw vitamin D data were skewed. Conditional logistic regression including those factors with p < 0.10 in the univariate analysis was used to examine which variables were independently associated with depressive disorders.
Linear mixed models were used to analyze the repeated measurements with missing values. The results were expressed as adjusted odds ratios (OR) with the corresponding 95% con dence intervals (CI). All statistical calculations were performed using SPSS for Windows, version 19.0 (SPSS Inc., Chicago, IL, USA). Concentration of statistical signi cance was de ned as p < 0.05.

Results
A total of 168 patients were enrolled in the present study. A total of 53 patients (31.5%, 36 men, 17 women) were diagnosed with depression. CRC patients showed markedly lower serum concentrations of 25-hydroxyvitamin D (25(OH)D) as compared to normal controls (45.12 ± 15.45 vs. 63.14 ± 16.46 nmol/L, p < 0.001). No correlation was found between 25(OH)D and age and gender in patients with CRC. Patients with depression had poorer nancial situation, less social support and more pain. Signi cant differences were found between patients with depression and those without depression in 25(OH)D concentration quartiles of CRC patients (p < 0.001). The proportion of patients in the lowest quartile (≤ 30.0 nmol/L) was signi cantly higher in the depression group (p < 0.001), while the proportion of patients in higher quartiles (43.1-55.0 and ≥ 55.1 nmol/L) was markedly lower in the depression group (p < 0.001 and p = 0.011, respectively) ( Table 1). We excluded 38 patients for not meeting the predetermined supplementation criteria (n = 19) or because they declined our invitation (n = 19). Consequently, 130 (45 with and 85 without depression), began to take 2000 IU vitamin D3 per day for six months. Of these patients, the baseline characteristics were similar to those of the entire cohort. We observed reductions in HDRS-17 scores in depressed patients after 3 (9 vs.12, p < 0.001) and 6 months (8 vs. 12, p < 0.001). There was no change being observed in non-depressed patients (Fig. 1). The treatment response was consistent with the restoration of vitamin D concentrations, which increased to normal after 3 and 6 months in patients with (75.13 and 75.47 nmol/L, respectively) and without depression (76.71 and 77.07 nmol/L, respectively) (all p < 0.001). Speci cally, we observed signi cant improvements (at least a 50% reduction from baseline in the total HDRS scores) in the majority of depressed patients after both 3 and 6 months.

Discussion
To our knowledge, this is the rst report investigating the possible effects of vitamin D supplementation on depression in CRC patients. Our results suggest that serum concentrations of vitamin D were signi cantly associated with the presence of depression among CRC patients and vitamin D supplementation can improve depression in most CRC patients, which might have signi cant implications in providing novel proposal for the prevention and treatment of depressive complication in CRC patients.
We observed that serum concentrations of vitamin D were independently related to the presence of depression in CRC patients. Moreover, we found that the correction of vitamin D inadequacy exerts positive effects on depression in CRC patients. Caroline [9 ]found vitamin D supplementation signi cantly ameliorated depressive symptoms in women with chronic liver disease. Meanwhile, one randomized controlled trial showed vitamin D therapy was effective in decreasing perinatal depression concentrations. [8] The exact role of vitamin D in the pathophysiology of depression remains unknown. A possible explanation is the neuroprotective role for vitamin D via its effects on in ammatory response. A growing body of evidences has supported an important role of cytokines in the pathophysiology of depression. [15, 16] CRC patients have increased serum concentrations of the cytokines mentioned above. [17] Vitamin D plays a key role in modulating the secretion of cytokines.
[18] Vitamin D may modulate the association of depression and in ammation via its role in the immune system. [19,20] There are several limitations in this study. First, the effect of other potential factors on serum vitamin D concentrations, such as lifestyle changes, dietary intake, and seasonal variation, was not considered in this study. Second, the present study was not an RCT, a design we avoided owing to ethical concerns, as we were unwilling to withhold treatment for vitamin D inadequacy. Finally, the uctuating characteristic of vitamin D makes it preferable to complete all measurements on the same day.

Conclusion
The results demonstrate depression was independently correlated with vitamin D concentrations in CRC patients. A therapeutic vitamin D supplementation may be recommended in CRC patients with low concentrations of vitamin D. Larger RCTs should be encouraged to con rm this study. Figure 1 Changes in depression during the study