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Vitamin D3 as adjunctive therapy in the treatment of depression in tuberculosis patients: a short-term pilot randomized double-blind controlled study

Objective We aimed to evaluate whether high-dose cholecalciferol has beneficial effects on depression in pulmonary tuberculosis (PTB) patients. Methods This pilot, randomized, and double-blind trial enrolled 123 recurrent PTB patients (aged ≥18 years) meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria of major depressive disorder from four hospitals in Southeast China. Patients were randomly assigned to 8-week oral treatment with 100,000 IU/week cholecalciferol (Vit D group) or a matching placebo (control group). The primary outcome was treatment response, defined as a 50% reduction in symptoms and change in scores of the Chinese version of Beck Depression Inventory (BDI) from baseline to 8 weeks. Relative risks of depression were estimated using multivariable logistic regression. Results Finally, 120 patients were enrolled, including 56 test patients and 64 controls. After 8 weeks, the treatment response or BDI scores did not differ significantly between groups. Multivariate logistic regression showed that BDI scores were not significantly improved in the Vit D group after adjustment for age, time to first negative smear, or 25-hydroxyvitamin D level. Conclusion The use of high-dose Vit D3 supplementation may not be warranted for reducing depressive symptoms in the PTB population. Nevertheless, this finding should be validated by further large-scale studies according to different kinds of depression or Vit D receptor polymorphism genotype.


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Zhang et al of 2.5 mg Vit D3 elevated serum 25(OH)D concentrations in PTB patients receiving intensive phase treatment and reduced time to sputum culture conversion in participants with tt genotype of TaqI Vit D receptor polymorphism. 12 However, Daley et al found inconsistent results without testing such polymorphism. 11 Vit D, an essential nutrient for bone health, also performs other physiological functions such as anti-inflammation, antiproliferation, antibacterial action, prodifferentiation, and immunomodulation. 15 Vit D is also a neurosteroid with fast non-genomic effects and genomic effect, which could be beneficial for mood disorders. 16 Animal and experimental studies show that Vit D receptor interacts with glucocorticoid receptors in the hippocampus 17 and 1,25(OH)2D3 promotes synthesis of monoamine neurotransmitters (eg, serotonin), which importantly protect brain function via immunomodulation, anti-inflammation, and neuroplasticity promotion. 18,19 As for the effects of Vit D supplementation on depressive symptoms, recent metaanalyses of observational studies 20 and randomized controlled trials (RCTs) 21 reported that depressive symptoms were not associated with 25(OH)D concentrations or improved by Vit D supplementation. However, the existing studies are limited by the use of unrepresentative samples (Alzheimer's disease, Parkinson's disease or psychiatric disorders), different diagnostic tools for quantification of depressive symptoms, co-interventions (eg, calcium or psychotropic drugs), and insufficient doses (,2,000 IU daily) to adequately raise 25(OH)D concentrations. 22,23 Other limitations include variability in status and definition cutoffs of Vit D deficiency, inadequate observation duration (,8 weeks), and ignorance of important confounders (eg, physical activity, sun exposure, and dietary Vit D intake).
Thus, this pilot, randomized, and double-blind controlled study aimed to evaluate whether high-dose Vit D3 supplementation as adjunctive therapy has beneficial effects on depressive symptoms in recurrent PTB patients.

study design
This 8-week pilot, randomized, and double-blind controlled study was conducted at four centers in Southeast China.
The study coordinator verified all eligibility criteria before randomization, and divided the patients into two groups via block randomization with a block size of six and an allocation ratio of 1:1. The coordinator generated the allocation sequence independently and concealed in opaque envelopes. Neither investigators nor patients were aware of the allocations. Once study eligibility and informed consent for a patient were verified, the coordinator opened the sealed envelope to ascertain the random treatment assigned to that patient. Once a randomization assignment was made, the coordinator enrolled that patient. Meanwhile, those doing end point psychiatric interviews at baseline and 8 weeks and those assessing outcomes were masked to treatment assignment.

inclusion and exclusion criteria
Recurrent PTB (relapse of original episode or an exogenous reinfection caused by a different strain of Mycobacterium tuberculosis) participants (age $18 years), who were HIV-negative and had depression, were eligible for inclusion if they had taken standard TB re-treatment. Exclusion criteria were as follows: age ,18 years; preexisting renal or hepatic failure, pulmonary silicosis, malignancy, metastatic malignant disease, sarcoidosis, hyperparathyroidism, nephrolithiasis, HIV co-infection, active diarrhea, hypercalcemia, pregnancy or lactation, concurrent steroid, cytotoxic drug treatment or other immunosuppressant therapies in the month before enrollment; intolerance of Vit D or first-line anti-TB therapies; cognitive deficits (eg, considerable memory loss, confusion/dementia, and intellectual disability); illiteracy or inability to answer the questionnaire (difficulty in understanding the questions, visual or hearing impairment); and severe depressive symptoms before treatment.

study procedures
Between July 1, 2015, and July 31, 2017, 123 (23.3%) of 527 patients were screened and consented to participate in the study (Figure 1). The participants were randomly assigned to a bolus oral dose of 100,000 IU/week cholecalciferol (Vit D group) or a matching placebo indistinguishable from cholecalciferol in terms of color, form, or taste (control group) for 8 weeks. This study was approved by the institutional ethics review board of Ningbo University College of Medicine (Approval No 20150126) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment.
Advices on lifestyle modification which helped to alleviate depressive symptoms in PTB patients were also given, such as daily intake of Vit D and Ca from food. Dietary intake at both baseline and over the 8 weeks was assessed by a self-administered food-frequency questionnaire specifically for Women's Health Initiative. 24 The participants were asked to abstain from consuming Vit D-/Ca-containing foods during the study period based on a standard questionnaire. 25 Neuropsychiatric Disease and Treatment 2018:14 submit your manuscript | www.dovepress.com

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Vitamin D3 as adjunctive therapy for depression Safety and adherence of the participants were assessed. Adherence was evaluated by the ratio of actual take to study medication (including placebo) using a questionnaire, and a ratio of $80% indicated good adherence. Study medication was withheld upon the occurrence of any severe adverse event for Vit D (eg, swelling, itching, chapped lips, headache, constipation, diarrhea, pharyngitis, esophagitis, stomatitis, nausea, or vomiting), or any condition wherein discontinuation of Vit D3 treatment was deemed medically necessary by the physician in charge.

evaluation of depression and depressive symptoms
Major depressive disorder was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). Change in scores of depressive symptoms was evaluated with the Chinese version of Beck Depression Inventory (BDI) II. Treatment responders for BDI II were those with at least 50% improvement of total score from baseline ([baseline -post]/baseline $50%). 26 BDI II consists of 21 self-reported items, and each item is rated on a scale of 0-3, producing a possible score from 0 to 63. A BDI II score $11 indicates the presence of depressive symptoms, 27 and a larger score indicates higher severity. 28 Diagnosis and severity of depression for each patient were determined independently by two experienced psychiatrists through structured interviews.

Demographic data, laboratory measurements, and other outcomes
Demographic data, including history of smoking and drinking, income, and family history of mood disorders, were collected by questioning the patients. Information concerning age, sex, occupation, and time to first negative smear was gathered from medical records. Basic laboratory parameters including baseline plasma levels of hemoglobin and Ca were measured via standard methods. Other laboratory data including nutrient indexes (plasma albumin, prealbumin) and inflammatory biomarkers (high-sensitivity C-reactive protein [Hs-CRP], interleukin [IL]-6, tumor necrosis factor [TNF]-α, and interferon [INF]-γ) were also detected. Plasma 25(OH)D (Vit D2 + Vit D3) levels were measured using liquid chromatography-tandem mass spectrometry. 29

statistical analysis
The sample size of 123 in this two-group study was calculated to be adequately powerful (α=0.05 in two-sided t-test) for the tests. Results were expressed as mean ± SD with significance level at P,0.05. Differences in mean values were tested using an independent t-test or Mann-Whitney test. Quartiles were compared with the Kruskal-Wallis test or chi-squared test as appropriate.
Through multifactorial logistic regression, the 95% CIs for the relation between Vit D3 supplementation and

characteristics of patients
During the 8-week period, three of the 123 patients were excluded (two in Vit D group, one in control group) because of poor adherence. Basic laboratory data and sociodemographic characteristics of the 123 patients are depicted in Table 1. No significant between-group difference was found at baseline.

compliance assessment and adverse effects
All participants showed good adherence (taking $80% of study medication), except three patients. Adverse events led to discontinuation of medication in the Vit D group, including itching (1) and nausea (1).

Discussion
To our knowledge, this is the first RCT of adjunctive high-dose Vit D3 for depression in recurrent PTB patients. Multivariable logistic regression models suggest that high-dose Vit D3 supplementation may not be warranted for reducing depressive symptoms compared to the placebo in the PTB population despite a greater rise in plasma 25(OH)D level in the Table 3 Association of Vit D3 supplementation with change in mean BDI II score from baseline to 8-week follow-up Vit D group. The association of Vit D supplementation with depression risk or depressive symptom alleviation has been evaluated in several intervention trials. [30][31][32] However, their findings are inconsistent because of between-study differences in races, study populations, geographic locations, Vit D doses, depression assessment, follow-up duration, use of placebo, sample size, and participant characteristics. Two systematic reviews and meta-analyses based on RCTs showed that low Vit D concentration is associated with depression 20 and Vit D supplementation may be effective in reducing symptoms of clinically significant depression. 33 A recent meta-analysis 34 suggested that Vit D supplementation favorably impacted depression ratings in major depression with a moderate effect size, but the authors thought this finding must be considered tentative owing to the limited number of trials available (only four) and inherent methodological bias noted in a few of the trials. Another systematic review showed no significant reduction in depression after Vit D supplementation, which may be because the enrolled studies mostly focused on individuals with low depression and sufficient serum Vit D at baseline. 21 Meanwhile, some researchers think the depressive state may be a cause rather than a consequence of Vit D deficiency, since plasma Vit D level alleviates physical activity (time spent outdoor) after the occurrence of depression.

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Zhang et al The pathways for the TB and depression associations are probably complex and multidirectional. 35 First, under chronic pulmonary conditions, hypoxia can directly make patients anxious and depressed. Likewise, general factors associated with chronic disease such as weight loss, fatigue, and psychological and social losses may trigger depressive reactions. 36 In our study, albumin and prealbumin levels were tested to provide evidence for the mechanism by which high-dose Vit D3 supplementation might improve depression, but these two nutrient indexes were not significantly altered by the supplementation after 8-week follow-up. Nevertheless, experts agree that people with chronic diseases and comorbid depression can benefit from chronic disease treatments. Second, anti-TB medications, especially isoniazid, the first monoamine oxidase inhibitor to be considered for the treatment of mental disorders in the 1950s 37 and now a core drug in anti-TB treatment, may significantly interact with selective serotonin reuptake inhibitors, 37 which are WHO-recommended drugs for depression treatment in the Mental Health Gap Action Programme guideline. In addition, TB patients may develop depression as a result of chronic infection or related psychosocioeconomic stressors. 36 Finally, no evidence suggests that TB and depression may share risk factors. 38,39 Immunological responses have been implicated in the association between chronic disease and depression. Chronic infectious conditions may lead to overproduction of pro-inflammatory cytokines (eg, IL-6), which facilitate cascades of endocrine reactions that may result in depressive symptoms. 38 However, growing evidence shows that depression enhances the production of pro-inflammatory cytokines and directly minimizes the immunological competence of patients by downregulating cellular and humoral responses. 40 Four inflammatory biomarkers (Hs-CRP, IL-6, TNF-α, and INF-γ) were tested in our study to provide evidence for the mechanism by which high-dose Vit D3 supplementation might cause depression. After 8-week follow-up, the 100,000 IU/week Vit D3 supplementation did not significantly alter the BDI II scores as a whole, but significantly changed the mean plasma nutrient indexes. We could not find the reason about these phenomena, owing to our incomplete understanding about the depression and inflammation relation. Thus, these findings need to be assessed in the future.
Some limitations in the present study should be noted. First, although we assessed a broad range of depressive disorders, it was difficult to ascertain the specific causes and phase of depression within the sample. In addition, seasonal affective disorder was not analyzed. Second, like in most previous studies, we did not survey vascular depression, which could benefit from high-dose oral Vit D3 supplementation. 32 Third, we did not test the polymorphism of the Vit D receptor, genetic variance of which influences the susceptibility to age-related changes in cognitive functioning and depressive symptoms. 41 Fourth, the sample size was relatively small, since some statistics (P-value) for the results are critical.

Conclusion
The high-dose Vit D3 supplementation may not be warranted for reducing depressive symptoms in the PTB population. Further large-scale studies are needed to establish whether Vit D supplementation may be beneficial for improving depressive symptoms in PTB groups, according to different types of depression or to Vit D receptor polymorphism genotype.

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